Modulatory role of serotonin in neural information processing: implications for human psychopathology.

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Psychological Bulletin 1992, Vol. 112, No. 2, 330-350

Copyright 1992 by the American Psychological Association, Inc. OQ33-2909/92/$3.00

Modulatory Role of Serotonin in Neural Information Processing: Implications for Human Psychopathology Michele R. Spoont

Department of Psychiatry St. Paul Ramsey Medical Center Investigation of the role of 5-hydroxytryptophan (5-HT), which functions as a modulator in the central nervous system, across behavioral contexts suggests that a general principle of transmitter function may be derived that is independent of specific behaviors and specific neural loci. A functional principle of 5-HT action in neural information processing in the central nervous system is proposed. Extremes deviations in 5-HT activity result in biases in information processing that may have direct effects on behavior. Such biases may predispose to pathological conditions such as violent suicide and aggression.

Investigations of the role played by centrally active neurotransmitters in behavior have traditionally focused on two areas of interest: (a) the ability of a neurotransmitter to evoke either inhibitory or excitatory pre- or postsynaptic potentials on target cell populations and (b) the excitatory or inhibitory effect of the neurotransmitter on a specific behavior (e.g., sleep), often within a localized brain region. As proposed in an article on catecholamines (Oades, 1985), a general principle of neurotransmitter function in information processing may be derived that is independent of specific neural loci and specific behavioral responses. For instance, in spite of its generally inhibitory effects on target cells, dopamine (DA) appears to facilitate the functional processes in various structures located throughout the brain. This facilitatory effect is thought to occur as a result of DAs ability to switch on functional circuits (Oades, 1985). A primary example of this switch mechanism concerns DAs initiation of locomotor activity (see below). The nucleus accumbens (NAS) receives a very large array of limbic system efferent inputs. This input creates a motivational signal to the motor system, where the NAS serves as an integration center that passes along the limbic input to the ventral palladium (VP). The VP, in turn, projects to the significant initiation center for locomotor activity (LA): the supplemental motor area. Of relevance to this discussion, passage of the limbic input to the VP is directly dependent on the activity of DA within the NAS. DA switches on the output of the NAS to the VP under appropriate motivational circumstances. The notion that DA acts as a facilitator of information flow is consistent with recent neural models of complex behavioral functions: Complex functions are thought to be subserved by a network of neural centers, where each center, or node, in the network is devoted to an elementary function that constitutes one aspect of the complex function. Such a neural model is completely

dependent on a facilitation mechanism not only to facilitate processes within nodes of the network but also to facilitate the flow of information around networks. In a similar vein, it is proposed that a general role of 5-hydroxytryptamine (5-HT, or serotonin) in information processing is one of modulatory constraint, whereby 5-HT has a net effect on information flow that is inhibitory in nature. Although a proposed role of inhibitory modulation for central 5-HT activity is not new (Jacobs, Heym, & Steinfels, 1984; Ogren, 1985b; Soubrie, 1986; Valzelli, 1981), data related to information processing and to the consequent behavioral significance of this role, beyond that of motoric inhibition (e.g., Soubrie, 1986), has not been previously integrated or emphasized. Because the modulatory role of constraint for 5-HT refers primarily to the control of information flow, the primary focus of this article is on the ascending projections of the 5-HT system. The most striking correspondence between central nervous system (CNS) 5-HT activity and human behavior is found in the area of aggression, in which low 5-HT activity appears to be related to aggressive and suicidal behavior (Brown, Goodwin, & Bunney, 1982). Thus, when reviewing the role of 5-HT in behavior, special emphasis is placed on aggression and how the role of 5-HT in information processing may account for the relationship between low 5-HT states and aggression. To establish more thoroughly a general principle of 5-HT functioning in behavior, I review the effects of 5-HT manipulations on a diverse set of behavioral systems. In a subsequent section, the functional role of 5-HT at the level of information processing is explored. The final section of this article explores the constraint principle to the role of 5-HT in human aggression.

Anatomy of the 5-HT System The majority of 5-HT cells in the CNS arise from the midbrain raphe nuclei. Of the nine or so cell groups that have been described, the activity of two nuclei, the dorsal and median raphe, constitute approximately 80% of forebrain 5-HT (Azmitia, 1978). Perhaps the most salient anatomical feature of the median and dorsal raphe nuclei (MR and DR) is the widespread nature of their projections. Of the six major ascending

I would like to thank Jeffrey A. Gray and anonymous reviewers for their helpful comments on an earlier version of this article. Correspondence concerning this article should be addressed to Michele R. Spoont, Department of Psychiatry, St. Paul Ramsey Medical Center, 640 Jackson Street, St. Paul, Minnesota 55101-2595.

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projections arising from the two nuclei, the DR accounts for four of these and shares a fifth with the MR (Azmitia, 1978). Two tracts follow the medial forebrain bundle (MFB), one from the DR and one from the MR (Azmitia, 1978). The DR-MFB tract innervates the lateral forebrain structures, such as the basal ganglia, amygdala, and nucleus accumbens, whereas the MR-MFB tract innervates the medial forebrain structures, including the cingulate cortex, septum, and hippocampus (Azmitia, 1978; Azmitia & Gannon, 1986). Included in the four nonMFB tracts is the innervation of the periventricular system, which arises from the rostral pole of the DR and projects to the periaqueductal gray, the inferior and superior colliculi, and surrounds the periventricular portions of the thalamus and hypothalamus (Azmita, 1978; Mize & Homer, 1989; Parent, Descarries, & Beaudet, 1981). The other two ascending non-MFB DR tracts comprise the cortical tract, which projects to the caudate-putamen and to the cerebral cortices (particularly the tempoparietal cortex), and the arcuate tract, which runs through the midbrain tegmentum and innervates such structures as the substantia nigra and the suprachiasmatic nucleus (Azmitia, 1978; Azmitia & Gannon, 1986). The cortical tract shows some phylogenetic specificity, because it appears to be relatively more important in primates than in rodents (Azmitia & Gannon, 1986). The final non-MFB ascending tract originates in both the MR and DR and innervates such structures as the interpeduncular nucleus and the mammilary body (Azmitia, 1978). Interestingly, of the raphe projections to the cerebral cortices, the DR 5-HT cells show greater specificity than the MR, projecting primarily to the frontal cortex, whereas the MR 5-HT projections are more uniform and extend to more caudal portions of the cortex (Azmitia, 1978; O'Hearn & Molliver, 1984). Because of the widespread nature of the 5-HT projection pattern, 5-HT activity can influence virtually all types of cortical functions at many levels of information processing. The diffuse and widespread nature of the 5-HT innervation pattern, however, suggests that 5-HT is more likely to perform a threshold function in information processing as opposed to serving mediating roles in specific behaviors. A threshold function for 5-HT is also indicated by the morphology of 5-HT cells, which have a tendency to form relatively few classical synaptic connections, allowing for control over the excitability of much more than discrete target cells (Azmitia, 1978; Jacobs, Heym, & Steinfels, 1984). Of interest, more synaptic connections are formed by 5-HT cells in primates than in rodents, suggesting greater specificity of 5-HT action with increased cortical sophistication. In general, however, except for greater myelination of 5-HT fibers in humans and other primates in relation to structurally more primitive animals, the topographical and morphological properties of the 5-HT system appear essentially similar across species (Azmitia & Gannon, 1986; Schofield & Everitt, 1981). Thus, the behavioral effects of manipulations of 5-HT systems in animals are easily paralleled with conceptually similar behavior in humans.

Role of Serotonin in Behavioral Functions Locomotor Activity Spontaneous LA is one indicator of motivated, goal-directed activity (Brudzynski & Mogenson, 1985; Mogenson, Jones, &

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Yim, 1980). LA is nonspecific as an indicator of goal-directed behavior and, therefore, is more ambiguous (and perhaps more contaminated) than distinct forms of motivated behavior (e.g., active avoidance). However, as LA is an important component of virtually all motivated behaviors, the role of 5-HT in LA is of interest. The component of LA most closely tied to an underlying motivational state is the initiation phase (vs. motor programming phase or execution phase). A considerable body of evidence indicates that the initiation of spontaneous LA is achieved specifically by DA activation in the A-10 mesolimbic pathway from the ventral tegmental area (VTA) to the NAS (Brudzynski & Mogenson, 1985; Costall, Domeney, & Naylor, 1984; Grabowska, 1974; Jones, Mogenson, & Wu, 1981; Kalivas & Miller, 1985; Kelly, 1977; Mogenson et al, 1980), although DA inhibition of the prefrontal cortex's tonic inhibition over the NAS is a necessary correlate under natural physiologic conditions. The nigrostriatal DA pathway is also involved in motor behavior, but this pathway appears to be more associated with sensorimotor integration, posture, and rseponse selection and coordination than with the actual initiation of LA (Freed & Yamamoto, 1985). Because DA underlies the initiation and facilitation of LA, the modulatory action of 5-HT in LA can best be understood in reference to its interaction with DA. The role of 5-HT in LA is controversial because manipulations of 5-HT, when considered alone, have yielded inconsistent results. For example, although facilitation of 5-HT functional activity is primarily inhibitory in spontaneous LA (Applegate, 1980; Gerson & Baldessarini, 1980; Jones et al, 1981), very high levels of activity are associated with a state of hyperactivity called the serotonin syndrome (Curzon, 1981; Gerson & Baldessarini, 1980; Green, 1981; Jacobs, 1986; Ogren, 1985b; Siever, Guttmacher, & Murphy, 1984). These disparate results seen with 5-HT activation may be due, in part, to the effects of 5-HT on different neurobiologic systems. The serotonin syndrome is thought to result primarily from excitation of the descending 5-HT raphe fibers (Gerson & Baldessarini, 1980; Ogren, 1985b). Moreover, the forward locomotion (and partially the backward locomotion) component of this syndrome is due to the action of central dopaminergic neurons (Curzon, 1981; Dickinson, Andrews, & Curzon, 1984; Ogren, 1985b). On the other hand, inhibition of spontaneous LA is achieved by activation of ascending 5-HT pathways, most probably those arising from the dorsal raphe nucleus (DR; Applegate, 1980; Gerson & Baldessarini, 1980; Jones etal, 1981). Although decreases in 5-HT functional activity have been associated with an increase in LA (Gately, Poon, Segal, & Geyer, 1985; Waldbillig, Bartness, & Stanley, 1981 a), a number of studies report either a lack of change or a decrease in LA (Black & Robinson, 1985; Curzon, 1981; Heffner & Seiden, 1982; Heym &Gladfelter, 1982; Kostowski, Plaznik, Pucilowski, Bidzinski, & Hauptmann, 1981). Many of these inconsistencies seen in studies in which 5-HT function is decreased are likely due to methodological differences between studies. Major methodological issues include (a) test procedure used, in which increases in LA are found in the tilt cage test, but decreases are seen in the open field test (Gerson & Baldessarini, 1980), (b) time of testing postsurgery or postneurochemical administration because compensatory postsynaptic receptor supersensitiv-


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ity may result with increased time periods (Siever, Guttmacher, & Murphy, 1984), (c) lack of specificity of many of the pharmacological agents and assay methods used (Ogren, 1985b; Soubrie, 1986), and (d) the use of electrolytic lesions of raphe nuclei, in which damage to nonserotonergic fibers may account for behavioral effects (Siever et al., 1984). For example, electrolytic lesions of the MR, which destroy both 5-HT and non-5-HT fibers, consistently produce hyperactivity (Gerson & Baldessarini, 1980; Gray, 1982), whereas lesioning of MR 5-HT fibers with selective 5-HT neurotoxins usually fails to produce this effect (Black & Robinson, 1985; Gerson & Baldessarini, 1980; Heym & Gladfelter, 1982). The effects of 5-HT manipulations on LA are consistent if LA is concomitantly stimulated by increased DA neurotransmission. As recently reviewed (Gerson & Baldessarini, 1980), increases in 5-HT consistently inhibit, whereas decreases facilitate, the excitatory effects of amphetamine on LA. DA agonistinduced LA is facilitated by decreased 5-HT functioning regardless of the depletion method used, because synthesis inhibition with /?-chlorophenylalanine (PCPA), postsynaptic receptor antagonism, and selective lesioning of 5-HT fibers with 5,6-dihydroxytryptamine (5,6-DHT) all potentiate DA agonist-induced LA (Grabowska, 1974; Jenner, Sheehy, & Marsden, 1983; Kelly, 1977; Mogilnicka, Scheel-Kruger, Klimek, & GolemkiowskaNikitin, 1977). More specifically, 5, 7-DHT lesions of the substantia nigra, striatum, or NAS enhance either amphetamineor apomorphine-induced increases in LA but block the cataleptic effects of neuroleptics (Carter & Pycock, 1978, 1979; Jenner et al., 1983), whereas bilateral injections of 5-HT directly into the NAS antagonize amphetamine-induced LA (Pycock, Horton, & Carter, 1978). The inhibition of LA by 5-HT is also implicated in experiments involving the destruction of VTA DA neurons with 6-hydroxydopamine (6-OHDA), because of upregulation of DA postsynaptic receptors in the NAS, which produces a hyperlocomotion syndrome in neonatal rats (Heffner & Seiden, 1982). Doses of amphetamine that normally produce increases in LA antagonize the 6-OHDA-induced hyperactivity, an effect that is probably due to amphetamine's action on 5-HT fibers, because this inhibitory effect of amphetamine was blocked by methysergide (a 5-HT antagonist) but not by spiroperidol (a DA antagonist), phentolamine, propanolol, naloxone, or atropine (Heffner & Seiden, 1982). Furthermore, facilitation of 5-HT activity either by the receptor agonist quipazine or by the release of 5-HT from neuronal stores by fenfluramine attenuated the 6-OHDA hyperactivity syndrome (Heffner & Seiden, 1982). In summary, increased 5-HT activity consistently inhibits, and decreased 5-HT facilitates, LA mainly when DA activity is stimulated concomitantly. The specific manner in which 5-HT modulates LA is not known, but several possibilities exist. As suggested by others (Jones et al., 1981), the 5-HT input in NAS circuitry must be "downstream" of DA terminals in the NAS because 5-HT administration in the NAS can totally abolish DA-stimulated activity. More specifically, 5-HT may directly inhibit DA release and synthesis in the NAS at DA terminals through 5-HT heteroreceptors, which are postulated to be 5-HT receptors located on the terminal buttons of DA neurons (Hetey, Kudrin, Shemanow, Rayevsky, & Oelssner, 1985). In this way, 5-HT can inhibit the initiation of LA by DA (i.e., constrain

the DA enabling signal for LA) and thereby modulate the degree of resulting activity. In view of the role of DA in the NAS as a facilitator of motivated behavior, 5-HT quite likely plays a critical role in constraining the expression of effective behavior patterns in general and the expression of LA in particular. Exploratory Behavior Exploration of novel environments indicates incentive-reward motivation, because novelty itself is thought to be inherently rewarding (File, 1985). In addition to its reward value, novelty may also function as a fear-inducing stimulus. In fact, the prepotent response of an animal to a novel stimulus is one of fear (i.e., neophobia). Elicitation of exploratory behavior in novel environments occurs only when the novel stimulus is deemed nonthreatening. When this occurs, the animal's behavior switches from a neophobic to an exploratory pattern. The likelihood of an exploratory versus a neophobic response to a novel stimulus is a function of the state of the animal and of the properties inherent in the stimulus context (File, 1985). Thus, pharmacological manipulations that alter the state of the animal may affect the relative balance of the animal's neophobic and exploratory response tendency. Most studies investigating the role of 5-HT in exploration have used the open-field paradigm, which has produced inconsistent results because the complex environment of the open field incorporates both novelty and fear-inducing components (File, 1985). Consequently, studies using this paradigm are not reviewed here. A considerable body of evidence suggests that the neuroanatomical substrate for the experience of incentive-type reward is the mesolimbic and mesocortical DA pathways (Beninger, Mason, Phillips, & Fibinger, 1980a, 1980b; Goeders, Dworkin, & Smith, 1986; Goeders & Smith, 1983; Hand & Franklin, 1985; Hoffman & Beninger, 1985). Because exploratory behavior may be an indicator of incentive-reward motivation, it would be expected that DA activation is facilitatory in exploration. One line of evidence supporting this is that enhanced DA activity in the NAS increases both the frequency and the duration of spontaneous exploratory behavior in novel environments (as long as the environment does not induce fear; Oades, 1985). In part, DA-mediated facilitation of exploration may be due to the increased propensity to switch to alternate response strategies with enhanced DA activity (Oades, 1985). For instance, blockade of DA autoreceptors results in an increased alteration in response strategies in exploratory contexts, whereas DA depletion results in perseveration of response strategies (Oades, 1983, 1985; Oades, Simon, & Le Moal, 1985). Serotonin appears to have an inhibitory effect on DA-mediated facilitation of exploration. Although depletion of 5-HT with either intraventricular or MR infusion of the 5-HT neurotoxin 5,7-DHT does not affect the quality of exploratory behavior (as typically measured in the holeboard task; Geyer, Petersen, & Rose, 1980), given an extended test period, a potentiation of exploration is seen (Gately et al., 1985). These animals tended to engage in an increase in the number of holepokes interspersed with other activities in the latter half of the test session, suggesting a difficulty in maintaining a continuous behavioral pattern (i.e., an increased propensity to switch to alternate behaviors; Gately et al, 1985). This difficulty in main-



taining a set behavioral response to the test conditions was exacerbated by the addition of amphetamine to the animals with 5, 7-DHT lesions (Gately et al, 1985). Although the lesioned animals still demonstrated the amphetamine-induced enhancement of exploratory behavior, the patterning of the exploratory behavior was disrupted toward the latter half of the test session, deteriorating into a purposeless form of stereotyped hyperlocomotion (Gately et al, 1985). Thus, the 5-HT depletion disinhibited the amphetamine-induced switch on, and a repetitive switching to an "on" position was elicited. Because exploratory behavior requires both incentive-reward and LA, 5-HT depletion may release both components of DA-facilitated exploration. Enhancement of 5-HT attenuates exploratory behavior. For example, at high doses, LSD administration decreases exploration (at low doses, LSD enhances exploration, probably because of its action on presynaptic 5-HT autoreceptors, stimulation of which decreases 5-HT release into the synapse (Adams & Geyer, 1985; Cooper, Bloom, & Roth, 1982). The ability of LSD to inhibit exploration at higher doses may be due to a potentiation of the innate neophobic response (Adams & Geyer, 1985). Neophobia is also potentiated by administration of the 5-HT agonist 5-MeOMDT, an effect that can be antagonized by methysergide (a 5-HT antagonist; Shephard, Buxton, & Broadhurst, 1982). Similarly, intraamygdaloid infusion of 5-HT also results in potentiation of neophobia (Pucilowski, Plaznik, & Kostowski, 1985). In summary, depletions of 5-HT are associated with an increase in exploratory behavior over time; however, there is also an inability to maintain the integrity of that behavior because an increased propensity to switch to alternate behaviors occurs. Increases in 5-HT, on the other hand, may potentiate the primary response of the animal to the novel environment: neophobia. That is, during very high 5-HT states, the animal's ability to switch to an alternate behavioral pattern (i.e., exploration) may be impaired, whereas in low 5-HT conditions, switching is facilitated. Thus, although 5-HT activity is not necessary for the expression of exploratory behavior, it may function so as to maintain a control of that expression by constraining DAs ability to switch on alternate signal sources. Operant Behavior The hypothesis that 5-HT mediates behavioral inhibition arose from a number of studies showing impairments in punishment-induced behavioral suppression with depletions of 5HT. Decreases in 5-HT functioning achieved by postsynaptic antagonism, synthesis inhibition, or neurotoxic lesioning fairly consistently releases punishment-induced behavioral suppression (Graeff & Schoenfeld, 1970; Gray, 1982; Hodges & Green, 1984; Leone, De Aguir, & Graeff, 1983; Soubrie, 1986; Stein, 1981; Stein, Wise, & Belluzzi, 1975; Thiebot, Hamon, & Soubrie, 1983), an effect attenuated by administration of 5-hydroxytryptophan (5-HTP; Hodges & Green, 1984; Stein, 1981). The effect appears to be fairly specific to the 5-HT system because no release from punishment has been found with morphine, DA agonists and antagonists, imipramine, iproniazid, or b- or a-adrenergic antagonists (Geller, Kulak, & Seifter, 1962; Geller & Seifter, 1960; Stein, 1981; Wise, Berger, & Stein, 1973). On the

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other hand, -y-aminobutyric acid (GABA) does appear to be involved in punishment activity because benzodiazepines elicit a strong antipunishment effect (Hodges & Green, 1984; Thiebot et al., 1983; Thiebot, Soubrie, Hamon, & Simon, 1984). Although it has been postulated that the antipunishment effects of the benzodiazepines are achieved through their action on central 5-HT neurons (Stein, 1981), the nature of the interaction between 5-HT and GABA in releasing punishment-induced suppression is complex. For instance, the releasing effect of chlordiazepoxide can be antagonized by prior 5, 7-DHT lesioning of the DR (Thiebot et al, 1983), but release from suppression by 5-HT synthesis inhibition with PCPA can be antagonized by picrotoxin (a GABA' ergic antagonist; Hodges & Green, 1984). Moreover, the combined manipulations of neurotoxic lesioning of the 5-HT innervation of the substantia nigra and of diazepam administration showed greater release than either treatment alone (Thiebot et al, 1984). Similarly, benzodiazepine treatment has been shown to release punished responding to a greater extent than depletion of 5-HT and can intensify the release achieved by the latter manipulation (Hodges & Green, 1984; Thiebot et al, 1984). Thus, while GABA' ergic agonists may achieve a release of punished behavior in part through their action on 5-HT neurons, there appears to be an additional component of their action that augments the decreased 5-HT-mediated effect. Responding to nonreward is also increased with reductions in 5-HT activity, especially during the first number of trials when reward is still anticipated (Beninger & Phillips, 1979; Hodges & Green, 1984; Soubrie, 1986). Because there is reduced 5-HT-mediated inhibitory modulation of DA in low 5HT states, the DA reward system (Beninger, 1983) apparently continues to be activated by contextual cues associated with reward for a longer period of time. Reward responding may also be facilitated by impaired 5-HT neurotransmission, although evidence is equivocal (Deakin, 1983; Hodges & Green, 1984; Leone et al, 1983; Thiebot et al, 1983). As was the case of LA, facilitated reward responding may occur mainly when the DA-based reward system is concomitantly activated. For example, methergoline (a 5-HT antagonist) facilitated reward responding in a manner that was amphetamine dose dependent (Leone et al, 1983). Moreover, the methergoline-facilitated reward responding occurred at doses of amphetamine that had been behaviorally ineffective when amphetamine was administered alone (i.e, it reduced the threshold for amphetamine-enhanced behavior; Leone et al, 1983). The role of 5-HT in modulating DA-dependent reward behavior becomes more clear when the reward is activation of the DA reward pathways themselves. As noted earlier, the neurophysiologic basis of the incentive type of reward is the mesolimbic and neocortical DA projections. Serotonergic activity does not appear to be a necessary component of the reward pathway because whereas the relative potencies of cocaine and other rewarding drugs in its class correlate with their ability to inhibit [3H] mazindol binding to DA transporters in the striatum, there is no relationship between the rewarding properties of these drugs and 5-HT transport inhibition (Ritz, Lamb, Goldberg, & Kuhar, 1987). Rather, 5-HT appears to have an inhibitory action on DA reward pathways. For example, drugs that


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facilitate 5-HT neurotransmission (e.g., 1-tryptophan, fluoxetine, quipazine) gnerally inhibit amphetamine intracranial selfadministration (ICSA; Leccese & Lyness, 1984). Similarly, 5HT uptake inhibition can antagonize amphetamine-induced conditioned place preference (but not morphine-induced place preference; Kruszewska, Romandini, & Saminin, 1986). Of interest, intracranial self-stimulation (ICSS) of the MFB results in increased turnover of both DA and 5-HT in the NAS (Nakahara, Ozaki, Miura, Miura, & Nagatsu, 1989). However, the time course of the increases in turnover of the two amines are different: DA increases simultaneously with ICSS onset and quickly resolves at the cessation of the stimulation, whereas 5-HT turnover increases much more slowly, maintaining a slower resolution that extends beyond the stimulation period (Nakahara et al., 1989). The time course of the increase in 5-HT activity in response to ICSS suggests that the increased 5-HT activity does not mediate the reward behavior but rather may be a compensatory homeostatic response to an increase in DA activity, an effect that has been noted in other brain regions (Dray, 1981). Thus, although facilitation of 5-HT does not appear to be an integral part of the rewarding properties of cocaine and related drugs (indeed, it appears to antagonize the rewarding effects of DA agonists), it may increase in rewardbased increases in DA activity. The effects of decreases in 5-HT neurotransmission on reward are more complex, the impact of which appears to be dependent on the extent and location of neural inhibition. Bilateral 5,7-DHT lesioning of the NAS has no effect on either IV or ICSA amphetamine administration, whereas, similar lesions of the MFB increase ICSA amphetamine responding (Dworkin & Smith, 1987). Of interest, the 5-HT antagonists methysergide and cyproheptadine decrease ICSA amphetamine in a dose-dependent manner, yet cause animals with 5, 7-DHT lesions of the MFB to self-administer to the point of overdose (Leccese & Lyness, 1984). Possibly, 5, 7-DHT lesions of the MFB ablate ascending (cortical) projections and hence release inhibition of DA in the anteromedial prefrontal cortex, which may be the primary site for ICSA responding (Goeders & Smith, 1983). Decreases in 5-HT, therefore, are associated with a release of normally inhibited (or, at least, nonfacilitated) operant behavior in diverse contexts, including punishment, reward, and nonreward. The effects of decreased 5-HT on punished responding are more apparent than those on reward responding (unless the DA system is concomitantly activated), which suggests that decreasing 5-HT activity does not stimulate responding per se but rather results in a failure to constrain behavior in response to relevant environmental cues. Consistent with this interpretation, decreased 5-HT activity in nonreward responding does not elicit the magnitude of responding in relation to controls seen in punishment situations presumably because the constraint-inducing environmental cues are the strongest behaviorally relevant cues in the latter situation. A second type of failure of constraint with decreased 5-HT activity is seen when there is a concomitant stimulation of the DA-based reward system, which results in an overshoot of DA-reward activity (e.g., overdose). Thus, 5-HT has a constraining effect on punished as well as rewarded operant behavior, suggesting that there may be no one-to-one correspondence between 5-HT activity and a particular affective state.

Stimulus Reactivity and Perception Behavioral reactivity to sensory stimuli is most readily indexed by either an orienting or a startle response. Startle may be defined as a short-latency behavioral response to a sudden, unexpected, and alarming stimulus (Davis, 1984). Although this behavioral pattern has no direct relationship to fight or flight behavior (i.e., it lacks orientation), it may act as a priming mechanism so as to increase neural readiness for subsequently selected response programs (Bennett, 1984). Congruent with the supposition that 5-HT constrains information flow and thereby increases the threshold for sensitivity to exogenous stimuli is the tonic inhibitory effect supraspinal 5-HT exerts on the startle response (spinal 5-HT is excitatory in startle; Davis, 1984). Increases in supraspinal 5-HT neurotransmission consistently attenuate startle amplitude, whereas decreases produce potentiated startle (Davis, 1984; Davis, Astrachan, & Kass, 1980; Geyer et al., 1980). The alteration in startle produced by pchloramphetamine (PCA) is commensurate with its action on 5-HT transmission: An initial depression of startle as 5-HT is released from neuronal stores, followed by startle potentiation as the neurons degenerate (Davis, 1984; Ogren, 1985b). Of interest, compounds that increase DA activity potentiate startle and can be further augmented by 5-HT antagonists (Davis, 1984), which would be predicted because both manipulations enhance sensitivity to external stimuli. Alteration of startle threshold with manipulations of 5-HT could result from changes incurred in either sensory or motor regions. The distribution of 5-HT fibers in the cortex and the neural response to sensory stimuli, however, suggest a role for 5-HT in the modulation of sensory signals. For example, in primates, including humans, 5-HT levels are highest in those cortical regions associated with sensory receiving areas (Azmitia& Gannon, 1986). More specifically, there is a dense 5-HT innervation of Areas 17 and 18 of the primary visual cortex and a lesser innervation of Areas 5 and 7 (Morrison & Foote, 1986; Morrison, Foote, & Bloom, 1984). The visual thalamic nuclei (i.e., lateral geniculate nucleus and pulvinar complex) are also densely innervated by 5-HT fibers (Marks, Speciale, Cobbey, & Roffwarg, 1987; Morrison & Foote, 1986; Morrison et al., 1984). The 5-HT innervation of the lateral geniculate nucleus (LGN) is inhibitory because stimulation of the DR results in a decrease in amplitude of the optic-tract, stimulation-elicited field potentials in this nucleus, which can be reversed with 5-HT neurotoxic lesioning (Marks et al., 1987). DR 5-HT fibers also project to the superior colliculus (SC), particularly to the superficial gray layers (Mize & Horner, 1989). Of interest, the superficial gray layers of the SC receive W-type retinal afferents, fibers that also innervate the LGN layer receiving the greatest 5-HT input (Mize & Horner, 1989). Moreover, 5-HT fibers from the lateral wings of the DR supply collateral innervation of the LGN and the SC, allowing 5-HT to have a coordinating influence on visual information processing (Villar, Vitale, Hftkfelt, & Verhofstad, 1988). Finally, 5-HT innervation of the primary visual cortex is directed at Lamina IVa and IVc, which receive primary sensory information as relayed through the thalamic nuclei (Morrison et al., 1984). Thus, 5-HT modulates interrelated structures of the visual system,


5-HT IN INFORMATION PROCESSING particularly the geniculo-striatevisual system, thereby allowing for a coordinated modulation of visual information processing. The 5-HT innervation of primary visual cortex in primates appears to show some complementarity with NE across areas and across layers within areas (Morrison & Foote, 1986). For example, 5-HT appears to be somewhat more dense in Area 17 than Area 18, whereas the reverse is true for NE (Morrison & Foote, 1986). Similarly, 5-HT preferentially innervates Lamina I Va and I Vc of Area 17, whereas NE projects primarily to Layers III and V (Morrison et al, 1984). The functional nature of the reciprocity between 5-HT and NE might be comparable to that demonstrated in the LGN in which 5-HT DR neurons inhibit LGN relay neurons, whereas norepinephrine (NE) has an excitatory role (Kayama, Shimada, Hishikawa, & Ogawa, 1989). More specifically, in the LGN, a decrease in optic-tract, stimulion-evoked field potentials is incurred with decreased NE, whereas an increase in field potential amplitude is achieved with decreases in 5-HT (Marks et al., 1987). The modulatory role of 5-HT in visual information processing appears to have both tonic and phasic components. Single unit recordings from the DR show that 5-HT neurons respond to sensory stimuli by producing a unit activity of excitation followed by inhibition (Jacobs, Heym, & Steinfels, 1984). The temporal effects of auditory and visual stimuli are virtually identical, and the response latency is fairly long, indicating that the neurons tested are not involved in the actual sensory detection pathways and most likely modulate later levels of sensory processing (Jacobs, Heym, & Trulson, 1981). The DR unit response to sensory input does not habituate with repeated presentations (Jacobs et al., 1981; Rasmussen, Strecker, & Jacobs, 1986), suggesting a modulatory function that may be associated with regional cortical excitability. Thus, the 5-HT system may be more involved in modulating the responsivity of the organism to sensory input. For example, endogenously synthesized [3H] 5-HT is released in the substantia nigra in response to simultaneous auditory and visual stimuli (Reisene, Soubrie, Artaud, & Glowinski, 1982). Another example might be the attenuation of adrenocortical responsivity to photic stimulation when 5-HT is depleted (Feldman, Melamed, Conforti, & Weidenfeld, 1984). A third example is the processing of acoustic stimuli. Decreased 5-HT lowers the stimulus intensity threshold to a tone during acquisition of a classically conditioned nictitating membrane response in the rabbit (Gormezano& Harvey, 1980). In summary then, it is possible that 5-HT stabilizes signal passage by constraining the sensitization to stimuli. For example, 5-HT modulates acoustic startle behavior by facilitating startle in 5-HT-depleted animals on later but not initial trials, whereas habituation appears unaffected (Davis, 1984). Because unit activity occurs on initial presentations when the saliency of the stimulus has yet to be determined, the functional role of the transmitter cannot be just sensory inhibition. Thus, it is most likely that the modulatory action of 5-HT in sensory processing is the constraint of information flow, protecting the animal from interference from nonsalient alternate signal sources and from sensitization to potentially threatening stimuli. This may be achieved by the phasic increase in unit activity in response to sensory stimulation, which may act by decreasing the signal amplitude (as in the LGN).

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Other Behaviors Serotonin modulation has been implicated in a number of other behaviors. Activation of central 5-HT neurotransmission through uptake inhibition, forced release from neural stores, receptor agonism, or precursor administration suppresses food intake (Blundell, 1984; Fletcher & Burton, 1986). This effect may be achieved through an increase in the postprandial period and a decrease in bout size, as has been shown with fenfluramine treatment (Fletcher & Burton, 1986). Decreases in 5-HT activity by neurotoxic lesioning dose-dependently increases food consumption and can cause hyperphagia if a highfat diet is introduced (Blundell, 1984; Diaz, Ellison, & Masuoka, 1974; Waldbillig, Bartness, & Stanley, 1981b). PCPA injected intraventricularly also produces an increase in food intake as does cyproheptadine (a 5-HT antagonist), which has been shown to increase appetite and food intake in rats, cats, and humans (Blundell, 1984). The modulation of ingestive behavior by 5-HT is similar to that seen with other behaviors. Increases in 5-HT activity are associated with an altered sensitivity to signals of satiety; decreases in transmitter function are associated with a release of the behavior, especially if the proper stimulus is available (i.e., high-fat foods). Sexual behavior is also influenced by manipulations of the 5-HT system. Decreases in 5-HT activity through neurotoxic lesioning, PCPA administration, or receptor antagonism facilitate sexual behavior in both male and female animals (Daprada, Bonetti, Scherschlicht, & Bondiolotti, 1985; Hansen & Ross, 1983; Messing, 1978; Zemlan, 1978). This facilitation is due to alterations in diencephalic 5-HT (especially the MFB and hypothalamic nuclei; Hansen & Ross, 1983) because intrathecally administered 5,7-DHT has little effect on sexual behavior (Hansen & Ross, 1983). The enhanced sexual behavior induced by decreased 5-HT activity can be reversed with fenfluramine, 5-HTP, 5-HT uptake inhibition, and receptor agonism (Daprada et al., 1985; Messing, 1978; Zemlan, 1978). Increased 5-HT activity alone results in a suppression of sexual behavior (Zemlan, 1978). In part, the altered sexual behavior achieved through manipulations of the 5-HT system are due to interactions with gonadal hormones. For example, the initial facilitation of 5-HT with acute PCA administration inhibits hormoneinduced mating behavior in females, and progesterone applied to the ventral mesencephalic area (i.e., near the B8 and B9 raphe nuclei) facilitates sexual receptivity presumably by inhibiting the ascending 5-HT nuclei (Zemlan, 1978). Similarly, whereas estrodiol facilitates 5-HT in females (guinea pigs), this facilitation can be suppressed by progesterone (O'Connor & Fischette, 1987). Not only do manipulations of 5-HT affect the animal's sexual response to internal signals (i.e., those from gonadal hormones) but they may also alter the animal's response to presentations of sexual stimuli, because treatment with PCPA was shown to facilitate homosexual behavior in male rats (Messing, 1978; Tagliamonte, Tagliamonte, Gessa, & Brodie, 1969). The increase in homosexual behavior appears to be reliant on the interaction of 5-HT with testosterone, because it can be reversed with 5-HTP and abolished by castration (Tagliamonte, Tagliamonte, & Gessa, 1971). The sex differences in the comodulation of 5-HT and gonadal hormones may have implications


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for behavior more generally. For example, androgens suppress 5-HT activity and thereby cause a subsensitivity to serotoninmimetic drugs (Fischette, Biegon, & McEwen, 1984; O'Connor & Fischette, 1987), which suggests that males may have lower basal 5-HT activity. In fact, sex differences in 5-HIAA in various brain regions in humans have been reported, although this may be at least partially accounted for by differences in height and brain weight (Bucht, Adolfsson, Gottfries, Roos, & Winblad, 1981). Social behavior also appears to be sensitive to manipulations of 5-HT. It is difficult to assess the effects of 5-HT manipulations on social behavior because any social interaction is a composite measure of many different behavioral influences (e.g., aggression, anxiety, nonspecific activation; Treit, 1985). Alterations in transmitter function in various loci can result in changes in one or more of these components of social behavior. It is proposed here that the primary effect of 5-HT manipulations on social behavior is related to the processing of cues relevant to social interaction. For example, 5-HT decreases by neurotoxic lesioning of 5-HT neurons with 5,7-DHT in the DR (but not the MR) had no effect on time spent interacting in rats in normal environments but did prevent the suppression of interaction normally elicited by an unfamiliar, brightly lit environment (File, Hyde, & Macleod, 1979; Treit, 1985). When 5, 7-DHT was injected into the amygdala, rats with extreme depletions (at least 80%) showed significantly less interaction than controls (File, James, & Macleod, 1981). This is in contrast to PCPA, which normally elicits a facilitation of social behavior (Vergnes, Depaulis, & Boehrer, 1986). In primates, social behavior is associated with a facilitation of 5-HT (Raleigh, Brammer, & McGuire, 1983). Enhancement of 5-HT with quipazine, fluoxetine, or tryptophan loading were all associated with increases in approach behavior and decreases in avoidance, vigilance, and social solitude (Raleigh et al., 1983). Dominant males showed a greater facilitation of these behaviors than nondominant males and also had higher baseline cerebrospinal fluid 5-HIAA concentrations (Raleigh et al., 1983). Thus, in primates, 5-HT activity is associated with social potency. Despite the facilitation of social behavior with PCPA treatment, it appears that normal social behavior may require an intact 5-HT system and that decreased 5-HT activity results in either a less dominant posture in social interactions or a tendency for increased aggressiveness (which may mimic increased social activity) or both. The effects of 5-HT manipulations on social behavior are not limited to dominant/submissive posturing. For example, alterations in 5-HT activity are associated with changes in the frequency of rat pup vocalizations in response to maternal separation (Gardner, 1985; Winslow & Insel, 1990). Thus, decreases in 5-HT activity may alter the sensitivity of the animal to signals that normally suppress social behavior, so that abnormally low levels of 5-HT activity may result in inappropriate social activity. Aggression Aggression is a heterogeneous construct referring to a number of different, albeit related, behavioral responses to various classes of species-specific eliciting stimuli (Valzelli, 1981,

1982). In humans, two broad higher order categorizations of aggression have been identified: instrumental aggression and hostile aggression (Valzelli, 1981). Instrumental aggression refers to those aggressive responses that are a means to a positive reward and can thus be conceptualized as being a variant or component of achievement motivation. Hostile aggression refers to those aggressive displays that are performed so as to minimize aversive conditions. Although instrumental aggression is an important facet of human behavior, I limit this discussion to acts related to hostile aggression, because it is more clearly associated with the trait construct of aggression in the human personality literature. In animals, hostile aggression refers to both defensive aggression, which is motivated by fear, and to irritable aggression, which is manifest as anger and rage reactions and which may also include a fear component (Valzelli, 1981). In general, the modulation of aggression by 5-HT is inhibitory in nature. Thus, decreases in 5-HT neurotransmission through dihydroxytryptamine compound lesions, synthesis inhibition, postsynaptic receptor antagonism, or dietarily induced substrate depletion result in the facilitation of aggressive displays (File, Hyde, & Macleod, 1979; File, James, & Macleod, 1981; McKenzie, 1981; Valzelli, Bernasconi, & Dalessandro, 1983; Valzelli, 1981,1982; Vergnes & Kempf, 1981), which can be inhibited by increased 5-HT activity (Applegate, 1980; Kempf, Mack, Schleef, & Mandel, 1982; McKenzie, 1981; Valzelli, 1981,1982). The ability of enhanced 5-HT activity to inhibit aggression appears to occur most readily in rat strains that are traitwise nonaggressive, raising the possibility that genetic differences exist in 5-HT modulation of aggression (Valzelli, 1981). Of interest, strain differences in the number and distribution of 5-HT neurons and of [3H] 5-HT uptake sites in the DR have been described, indicating possible genetic control over central 5-HT activity level more generally (Daszuta, Hery, & Faudon, 1984; Daszuta & Portalier, 1985). In addition to a genetic contribution to the phenotypic variance in aggressive behavior, extreme environmental deprivation can be a contributing or causal factor. For example, prolonged isolation produces a consistent aimless aggressive behavior in rodents (Valzelli, 1981). Of interest, induction of irritable aggression by prolonged isolation occurs only in those rodent strains that react to the isolation with decreased 5-HT neurotransmission (Kempf, Puglisi-Allegra, Cabib, Schleef, & Mandel, 1984; Valzelli, 1977, 1978, 1981, 1982; Valzelli & Bernasconi, 1979). This suggests that certain genotypes are vulnerable to responding to aversive environmental conditions with a decrease in 5-HT activity and, consequently, with an enhancement of aggressive behavior. The consistency of enhanced 5-HT activity to inhibit aggression is most probably due to the ubiquity of 5-HT innervation of structures involved in mediating aggressive behavior. That is, 5-HT modulates activity in several structures underlying fight/ flight behavior. The fight/flight system is mediated primarily by amygdaloid and hypothalamic nuclei and extends into the midbrain central gray. A number of hypothalamic nuclei have been implicated as triggers of aggressive behavior, most notably the lateral hypothalamus (LH), electrical stimulation of which potentiates aggressive behavior (Koolhaas, 1978; Valzelli, 1981). Although



the LH is primarily implicated in instrumental forms of aggression, it also appears to play a role in affective forms of aggression. For example, social isolation is associated with decreased 5-HT turnover in the LH, dramatically so in those animals that respond to this treatment with intense irritable aggression (Kempf et al., 1984). The inhibitory role of 5-HT in LH-related irritable aggression is specific, as only infusions of 5-HT produce an inhibition, whereas DA and NE are without effect (Bell & Brown, 1975,1976; Leroux & Myers, 1975). The ventomedial hypothalamus (VMH) is also associated with affective forms of aggression. Stimulation of the VMH elicits aggressive behavior, an effect that can be exacerbated by 5-HT synthesis inhibition with PCPA (Katz & Thomas, 1976). The VMH elicits an aggressive response, in part, through its connections with the periaqueductal gray (PAG), a pathway involving an intermediary synaptic connection in the anteromedial hypothalamus (Fuchs, Edinger, & Siegel, 1985a, 1985b). It is in the PAG, which is also modulated by 5-HT, that aggression or escape behaviors are organized (Bernstson, 1972; Deakin, 1983; Fuchs et al., 1985a; Sander, Schmitt, & Karli, 1985; Valzelli, 1981). Both the VMH and the LH receive afferents from the central, medial, and basal amygdaloid nuclei (Sarter & Markowitsch, 1985). The anterior hypothalamus and the VMH receive fibers from the medial and anterior cortical amygdaloid nuclei (Price, Russchen, & Amaral, 1987). The LH, on the other hand, receives its major amygdaloid projections from the central nucleus, though lesser cortical and medial nuclear projections exist (Price & Amaral, 1981; Price et al., 1987). Stimulation of the centromedial area is facilatatory, and lesions are inhibitory in aggression for both animals and man (King, 1961; Valzelli, 1981). The amygdala modulates hypothalamic elicitation of aggression, although aspects of defense reactions (such as autonomic reactivity) may be organized by direct amygdaloidbrainstem projections from the central nucleus (Applegate, Kapp, Underwood, & McNall, 1982; Price et al., 1987). In the amygdala, 5-HT is inhibitory, and depletion of amygdaloid 5HT facilitates aggressive behavior (File et al., 1981; Sarter & Markowitsch, 1985). On the other hand, increases in 5-HT (at least in the corticomedial area) attenuate both muricidal and irritative aggression (Pucilowski et al., 1985). Apparently, 5-HT modulation of hypothalamic and amygdaloid nuclei is dependent, in part, on the activity of the central nucleus because lesions of this nucleus cause an increase in 5-HT in both cortical structures (Beaulieu, DiPaolo, & Barden, 1985). This is most probably achieved by direct projections to the DR by the central nucleus (Price & Amaral, 1981; Price et al., 1987). The major 5-HT pathway from the raphe nuclei to the amygdala arises primarily from the DR to the central and medial nuclei (Azmitia, 1978; Sarter & Markowitsch, 1985; R. Y Wang & Aghajanian, 1977). Thus, the central nucleus and the DR are reciprocally organized. Congruent with the role of the DR in modulating structures involved in fight/flight behavior, lesions of the DR are associated with facilitation of aggression, but MR lesions are not (Pucilowski et al., 1985; Waldbillig et al., 1981b). Lesions of the central nucleus block the establishment of conditioned fear (operationalized as a potentiated startle response) and release punishment-induced behavioral suppression, suggesting an anatomical association between these behaviors and

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aggression (Hitchcock & Davis, 1986; Shibata, Kataoka, Yamashita, &Ueki, 1986). Fight/flight pathways are modulated by the septum. The septum most probably achieves its inhibitory action over aggression through its reciprocal connections with the LH (Gray, 1982). The septum plays an inhibitory role in both instrumental and affective types of aggression; lesions of this structure are associated with a particularly fierce form of aggression called septal rage (Gray, 1982; Valzelli, 1981). The septum also appears to be involved in isolation-induced aggression, because isolation is associated with a significant decrease in tryptophan hydroxylase activity in this structure (Segal, Knapp, Kuczenski, & Mandell, 1973), suggesting a direct role of 5-HT in septal inhibition. The periaqueductal gray (PAG) may be the final common pathway of the fight/flight system (Sander, Schmitt, & Karli, 1985). Perception of aversive stimuli is mediated, in part, by areas in the PAG, stimulation of which elicits a fear response in both animals and humans (Graeff, 1984). Serotonin decreases the aversiveness of this stimulation, as evidenced by the ability of intraventricular or intrahypothalamic injections of 5-HT or 5-MeOMDT to increase the threshold of aversive PAG stimulation eliciting flight behavior in a dose-dependent fashion (Graeff, 1984; Schutz, De Aguir, & Graeff, 1985). Furthermore, this can be blocked by 5-HT antagonist pretreatment (Graeff, 1984). Conversely, 5-HT antagonists produce a decrease in PAG-stimulation escape latencies, which is not due to general release of response facilitation because this treatment does not release respondingsuppressed by concurrent aversive PAG stimulation (Clark & File, 1982). The modulation by 5-HT of the perception of aversive stimuli may include the nociceptive reflex. The PAG is involved in the nociceptive reflex, a pathway that includes a projection from the nucleus raphe magnus (NRM) to the dorsal horn (Azmitia & Gannon, 1986; Roberts, 1984). Antagonism of 5-HT neurotransmission in the NRM significantly decreases the inhibition of a nociceptive reflex by stimulation of the PAG, presumably by blocking modulatory fibers from the NRM to the PAG, at least some of which may be serotonergic (Lakos & Basbaum, 1988; Mason, Strassman, & Maciewicz, 1988; Roberts, 1984). Also, 5-HT is involved in modulating pain perception in supraspinal structures. Microiontophoretic application of 5-HT to the parafascicularis region (PF) of the thalamus attenuates the PF's response to a painful tail pinch (Andersen & Dafny, 1982). The PF receives a converging input from the DR and signals of noxious stimuli (McClung & Dafny, 1980). It has been suggested that the PAG-NRM-dorsal horn system may be involved in fear-induced preparatory analgesia (Deakin, 1983). However, single-unit recordings from the NRM 5-HT neurons indicate that 5-HT inhibition of nociception is engaged by all forms of arousal, even nonstressful forms, indicating that these 5-HT fibers may have a more general analgesic effect during arousal (Auerbach, Fornal, & Jacobs, 1985). This suggests that 5-HT may modulate the level of excitation of CNS systems during arousal by modulating sensory input. Indeed, 5-HT cells demonstrate a ceiling effect in response to acute stressors, suggesting that 5-HT activity may serve to alter signal-to-noise ratios in target regions (Wilkinson & Jacobs, 1988).


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Although the modulation of aggression by 5-HT is consistent and pervasive, other neurotransmitter systems are involved in modulating aggressive behavior. For example, aggression may be facilitated by enhanced DA transmission, as evidenced by the ability of 1-dihydroxyphenylalanine (L-DOPA), apomorphine (a DA agonist), and amphetamine to increase irritable and defensive aggression (Antelman & Caggiula, 1977; Diringer, Kramarcy, Brown, & Thurmond, 1982; Valzelli, 1981; Winslow & Miczek, 1983). The increased aggressiveness elicited by apomorphine has been shown to be dose dependent and can be inhibited by acute neuroleptic administration (Lai, Gianutsos, & Puri, 1975) and facilitated by postsynaptic supersensitivity induction through chronic haloperidol treatment (Gianutsos, Drawbaugh, Hynes, & Lai, 1974). Additionally, direct infusion of low concentrations of DA into the lateral ventricle also increases shock-induced fighting (i.e., experimentally induced irritative aggression; Geyer & Segal, 1974). Thus, augmentation of DA activity facilitates the expression of aggressive behavior. Not unlike the interaction of DA and 5-HT in modulating other behaviors, enhancement of 5-HT activity suppresses DA-induced aggression (Butterworth, Poignant, & Barbeau, 1975; Hahn, Hynes, & Fuller, 1982; McKenzie, 1981), but antagonism of 5-HT activity usually enhances DA-induced aggression (Hahn et al., 1982; McKenzie, 1981; but see Winslow & Miczek, 1983). In addition to a decrease in 5-HT, isolation treatment also produces a decrease in brain NE (Valzelli, 1981). Furthermore, irritable aggression is enhanced by intraventricular administration of 6-OHDA in doses that preferentially decrease NE and is inhibited by subsequent infusion of NE (Antelman & Caggiula, 1977; Antelman & Chiodo, 1984). The inhibitory modulation of aggression by NE appears to achieve its effect by its action on DA cells. For example, singular administration of clonidine (an «2-adrenergic agonist) has little direct effect on aggression but greatly intensifies apomorphine-induced aggression (Hahn et al, 1982). This suggests that NE is also inhibitory in aggressive behavior; however, the modulatory action of NE on DA-induced aggression may be indirect through its action on 5-HT neurotransmission. The first line of evidence is the ability of M-chlorophenylpiperazine (a 5-HT agonist) to dose-dependently inhibit the aggressive effects of concurrent apomorphine and clonidine treatment, which can be enhanced by 5-HT receptor antagonism with metergoline (Hahn et al, 1982). The modulatory action of clonidine itself may be through its effects on 5-HT because clonidine elevates intracellular 5-HT in the DR, decreases actual 5-HT turnover, and antagonizes the dosedependent increase in 5-HIAA produced by apomorphine (Geyer & Lee, 1984; Hahn et al, 1982). More specifically, this effect may be achieved through the action of a2 receptors on 5-HT neurons, which are known to inhibit 5-HT release or synthesis (Kehr, 1985). This is further supported by the fact that piperoxane (an a-adrenergic antagonist) reverses the clonidine inhibition of DR 5-HT neurotransmission, as well as enhancing striatal DA turnover (which is also decreased by clonidine; Hahn et al, 1982). Another line of evidence suggesting that the NE-based inhibitory modulation of aggression is achieved through its action on 5-HT is that inhibition of NE synthesis with fusaric acid (a fairly specific dopamine-i8-hydroxylase inhibitor) concurrently antagonizes attack behavior and increases

5-HT turnover (Diringer et al, 1982). This compound also decreases DA, however, suggesting that the antiaggressive effect may be achieved by manipulation of both DA and 5-HT transmitter systems. The interaction of NE and 5-HT appears to be one of reciprocal modulation. For example, lesioning the MR 5-HT hippocampal afferents causes an upregulation of «,adrenergic receptors (J. Wang, Console, Vinci, Forloni, & Ladinsky, 1985). Similarly, simultaneous lesions of the MR and DR produce a decrease in [3H]5-HT uptake in the hippocampus and frontal cortex while causing a concomitant upregulation of /?-adrenergic receptor binding in these regions (Stockmeier, Martino, & Kellar, 1985). The inhibitory modulation of aggression by 5-HT presented above suggests that 5-HT may act in an inhibitory fashion at many neural loci involved in the processing of information relevant to aggressive behavior. For instance, a recent review concluded that the medial amygdaloid nucleus may mediate the animal's response to changing response contingencies, perhaps especially with respect to social cues (Luiten, Koolhaas, de Boer, & Koopmans, 1985; Sarter & Markowitsch, 1985). Thus, altered 5-HT modulation of this function could contribute to the development of aggressive behavior through creating a misattunement to social cues. Conclusion On a behavioral level, 5-HT constrains DA-based signals. For example, activation of 5-HT inhibits, whereas decreases facilitate, DA-enhanced LA (Grabowska, 1974; Jenner et al, 1983; Kelly, 1977; Mogilnicka et al, 1977; Pycock et al, 1978). Similarly, depletion of 5-HT releases DA augmentation of operant reward responding (Leone et al, 1983), whereas facilitation of 5-HT activity inhibits the intracranial self-administration of DA agonists (Leccese & Lyness, 1984). Also, 5-HT constrains information signals other than those that rely on DA activity. For instance, behavioral responsivity to gonadal hormones (e.g, sexual behavior) is modulated by alterations in 5-HT activity, with enhancement of response occurring with 5-HT depletion and attenuation with increases in 5-HT (O'Connor & Fischette, 1987; Waldbillig et al, 198 la; Zemlan, 1978). Similarly, 5-HT provides inhibitory modulation of NE-facilitated signals in the dorsal LGN (Marks et al, 1987). The 5-HT constraint of signal flow need not occur solely to signals whose origin is endogenous to the organism. Cortical 5-HT tonically inhibits the startle response (i.e, the organism's response to an unexpected and alarming stimulus), but facilitation of 5-HT activity attenuates startle amplitude, and 5-HT depletions enhance startle (Davis, 1984; Davis et al, 1980; Geyer et al, 1980). Similarly, 5-HT activation decreases the aversiveness of PAG-based aversive stimulation, an effect that can be blocked by suppression of 5-HT activity with 5-HT antagonist pretreatment (Graeff, 1984,1987). Activation of 5-HT also has been shown to attenuate signals associated with pain perception (Roberts, 1984). Constraint of signal amplitude also affects the ability of the organism to learn. For example, decreased 5-HT activity increases the animal's sensitivity to a conditioned stimulus (Gormezano & Harvey, 1980). It has been postulated that alterations in 5-HT-mediated inhibition of aggression may result from the instigation of incor-


5-HT IN INFORMATION PROCESSING rectly tuned sensory control, allowing either inappropriate stimuli or distorted perceptual inputs to produce abnormal aggressive responses (Valzelli, 1982). The data presented above indicate that alterations in 5-HT activity influence the animal's behavioral response to both internal and external signals, perhaps by altering the signal-to-noise ratio. Thus, if the function of 5-HT is to constrain the propagation of neural signals, low 5-HT states would likely influence behavior by eliciting an exaggeration of signal saliency.

Role of Serotonin: An InformationProcessing Perspective The modulation of behavior by 5-HT is believed to be phylogenetically old, because it appears in invertebrates as well as vertebrates. For example, 5-HT influences the behavioral system associated with aggression in lobsters by altering the output of command circuits and the priming exoskeletal muscle responses (Kravitz, 1988). In this way, the animal's responsivity is biased toward specific response patterns when presented with relevant stimuli. Similarly, 5-HT biases the responsivity of the gill- and siphon-withdrawal reflexes in Aplysia by affecting the processes of sensitization and dishabituation (Glanzman et al., 1989). Several lines of evidence support the contention that 5-HT functions in a nonspecific modulatory capacity in mammals: (a) the widespread and diffuse nature of the distribution of 5-HT projections and their tendency to form relatively few classical synaptic connections (Azmitia, 1978; Jacobs et al., 1984), which permits the transmitter to influence the excitability of broad cortical areas, (b) the slow, regular firing of the neurons (Jacobs, 1985, 1986; Jacobs, Heym, & Steinfels, 1984; Jacobs, Heym, & Trulson, 1981), indicating that the action of 5-HT is more tonic in nature than it is discretely phasic, (c) the long latency with which the neurons exert their synaptic effect and the slow termination of this effect (Jacobs et al., 1984), indicating on a neuronal level, control of neural excitability, (d) the nonspecific state-dependent change in unit activity to afferent input (Jacobs, Heym, & Steinfels, 1984; Jacobs, Heym, & Trulson, 1981), demonstrating a lack of differentiation of information carried in the 5-HT signal, and (e) the diversity of behaviors affected by changes in 5-HT neurotransmission (Jacobs et al., 1984; Siever et al., 1984; Soubrie, 1986; Valzelli, 1981), indicating a lack of a specific mediating role with respect to behavior. The ascending 5-HT projections in mammals appear to be evolutionarily stable (Azmitia & Gannon, 1986). The main nuclear organization is essentially the same in primates as in subprimates. However, 5-HT fibers in primates display greater specificity of cortical innervation (vs. uniformity of innervation in subprimates), greater frequency of myelination, and a greater importance of the dorsal raphe cortical tract (DRCT) forebrain projections versus the MFB (Azmitia & Gannon, 1986). The implication is that 5-HT cell groups function in a more discrete capacity in primates than in subprimates, which may relate to the greater cognitive functioning in primates (Azmitia & Gannon, 1986). Thus, in the modulatory function of 5-HT in primates (including humans; Azmitia & Gannon, 1986), the biasing function of 5-HT extends beyond behavioral output circuits and includes higher cortical networks (e.g., medial prefrontal

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cortex; Ashby, Jiang, Kasser, & Wang, 1990). Although 5-HT may not mediate cognitive processes in primates, its modulatory biasing capacity may operate by influencing the signal detection of the networks in which it is involved, as has been hypothesized for catecholamines (Oades, 1985; ServanSchreiber, Printz, & Cohen, 1990). Thus, although the biasing capacity of 5-HT is conceptually similar in primates as in subprimates (and even invertebrates), the nature of the 5-HT projections in primates suggests the possibility of greater specificity of function. The notion of modulation in neurobiologic systems may refer to different functions operating on many levels of neurophysiologic activity. At a more general level, modulation may be conceptualized as a component of a homeostatic system, whereby activity of the modulator helps regulate the activity of the system. This modulatory function can be demonstrated on the level of neurobiologic substrates by considering the interaction of 5-HT and dopamine in the control of extrapyramidal motor behavior. For example, raphe lesions that deplete 5-HT content in the substantia nigra increase nigral DA turnover (Dray, 1981). Conversely, low doses of peripherally administered apomorphine, which preferentially stimulate DA autoreceptors in the DR, increase both intra- and extracellular 5-HT fluorescence in the DR and increase 5-HT turnover in the dorsal striaturn (Lee & Geyer, 1984). Another example of the interactive modulation of 5-HT and DA can also be illustrated on a cellular level with the use of single-unit recordings. Nigral DA neurons located in the anteromedial portion of the zona compacta display elevated discharge rates with 5-HT depletion and quiescence with stimulation of the DR (Antelman & Chiodo, 1984), which provides the primary 5-HT innervation of the substantia nigra (Azmitia, 1978). Thus, in central extrapyramidal motor structures, DA and 5-HT appear to possess reciprocal modulatory capacities, functioning in a homeostatic manner as a system to determine behavioral output. The modulatory action of 5-HT in information-processing systems may be viewed more as one of constraint than one of inhibition because the function of the transmitter is not to suppress information flow (as is suggested by the term inhibitor), but rather to regulate the flow of information through a neural system. The purpose of a constrainer of information flow in a homeostatic system may be conceptualized as (a) preventing an overshoot of other dynamic elements within the system and (b) controlling the sensitivity of the system to perturbation by new elements entering the system. The prevention of overshoot by 5-HT may primarily occur through attenuation of signal amplitude (in which resultant signal amplitude may be a function of firing frequency (Butcher & Woolf, 1982). This is exemplified in transmission of DA unit responses in the zona compacta, in which DA neurons display elevated discharge rates with 5-HT depletion and quiescence with stimulation of the DR (Antelman & Chiodo, 1984). The increased propensity for overshoot in neural systems by decreased 5-HT activity so evident at the behavioral level may be manifested in three ways. First, the magnitude of response in 5-HT deficient conditions would be increased. For instance, decreased 5-HT activity leads to behavioral increases such as sexual behavior (Daprada et al., 1985; Hansen & Ross, 1983; Messing, 1978; Zemlan, 1978), food intake (Blundell, 1984),


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aggression (Diringer et al., 1982; File et al., 1979; File et al., 1981; Kempfetal., 1984; McKenzie, 1981; Valzelli, 1981), and startle responsivity (Davis, 1984; Davis et al, 1980; Geyer et al., 1980), as well as facilitation of signals related to perceptual processes such as enhancement of aversive stimulation of the PAG (Graeff, 1984, 1987) and nociception (Auerbach et al., 1985; Ogren, 1985a). Behaviors modulated by 5-HT appear to be especially facilitated by decreased 5-HT activity when facilitatory signals of either internal or external origin drive the behavior. For example, depletions of 5-HT facilitate LA and operant reward responding mainly when DA activity is enhanced (Gerson & Baldessarini, 1980; Jenner et al., 1983; Kelly, 1977; Leone et al, 1983; Pycock et al, 1978). Similarly, active avoidance is facilitated with the presence of a warning cue, and food intake is increased to the point of hyperphagia if a high-fat diet is available (Lorens, 1978; Waldbillig et al, 1981b). Thus, an overshoot in the system occurs as a result of impaired negative feedback modulation by 5-HT (i.e, the facilitation of signal flow is unconstrained). The second manifestation of systemic overshoot is a decreased sensitivity to cues of suppression, an effect that has been previously associated with 5-HT activity (Deakin, 1983; Depue & Spoont, 1986; Soubrie, 1986). Decreased sensitivity to cues of suppression may be conceptualized as a specific instance of impaired negative feedback modulation because these cues trigger the inhibitory modulatory process (hence 5-HT activity). The most notable example of altered sensitivity to cues of suppression with decreased 5-HT activity is the impairment of punishment-induced suppression of barpress behavior in an operant paradigm (Graeff & Schoenfeld, 1970; Gray, 1982; Hodges & Green, 1984; Leone et al, 1983; Soubrie, 1986; Stein, 1981; Stein, Wise, & Belluzzi, 1975; Stein, Wise, & Berger, 1973; Thiebot et al, 1983; Wise et al, 1973). These 5HT-depleted animals not only continue to barpress for food when there is a warning of a shock, but they continue to show impaired suppression after the punishment has been administered. Other examples of decreased sensitivity to signals of suppression with decreased 5-HT activity are the lack of inhibition of social interaction in novel, brightly lit environments (File et al, 1979; Treit, 1985), a relative insensitivity to the suppressive effects of light on LA in nocturnal animals (Waldbillig et al, 198la), and an insensitivity to signals of satiety in feeding (Blundell, 1984) and to signals of satiety in ICSA for DA agonists (Dworkin & Smith, 1987). The third manifestation of an overshoot in the system reflecting a homeostatic imbalance is a slower recovery time of a behavior that has been initiated in the absence of 5-HT's constraining action. For example, decreased 5-HT activity is associated with a potentiation of exploration over time (Gately et al, 1985), suggesting that the effects of the novelty of the stimulus continue for an extended period of time. Similarly, 5-HT-depleted animals are slow to inhibit responding in a nonreward paradigm (Beninger & Phillips, 1979; Hodges & Green, 1984; Soubrie, 1986). The other homeostatic role of 5-HT, that of modulation of the threshold for system perturbation, has not been directly addressed. This homeostatic function can be illustrated by the role of 5-HT in seizures, a phenomenon that may be conceptualized as both the result and cause (through kindling) of pertur-

bations in cortical homeostasis. Although 5-HT does not appear to be necessary for either the genesis or the amelioration of seizures (Pranzatelli, 1988), its activity does appear to serve a protective function. For example, decreased 5-HT activity has been shown to be related to the development of posthypoxic action myoclonus (Jacobs, 1986). Similarly, decreased 5-HT activity has been found to occur in many brain structures of the genetically epilepsy-prone rat (Jobe, Laird, HoKo, Ray, & Dailey, 1982). Exogenously stimulated seizures are also modifiable by 5-HT activity, such as peterazole-induced seizures, which are exacerbated by PCPA and protected against by pretreatment with 5-HTP and a peripheral decarboxylase inhibitor (DeLaTorre, Kawanga, & Mullan, 1970). The modulatory action of 5-HT on seizure activity may be most important at the initiation phase. Alpha-guanidinoglutaric acid-induced seizures are temporally related to a decrease in cortical 5-HT at the time of seizure initiation but not throughout seizure duration (Shiraga, Hiramatsu, & Mori, 1986). Thus, decreased 5-HT activity, although not necessarily facilitating seizure formation, creates an environment permissive to it. In other words, reduced 5-HT may increase the sensitivity of a neural system to perturbation. Decreased 5-HT activity apparently renders a neural system more susceptible to exogenous influences so that its ability to maintain its self-organization is compromised. One example is the modulation by 5-HT of the threshold for septal stimulationinduced driving of the hippocampal theta rhythm. Decreases in 5-HT by neurotoxic lesioning, synthesis inhibition, or receptor blockade decrease the threshold for driving the theta rhythm and flatten the threshold frequency function (i.e, increase the driving propensity across frequencies; McNaughton, Azmitia, Williams, Buchnan, & Gray, 1980; McNaughton, James, et al, 1977). That is, the ability of alternate signals having input into the system is enhanced. In extreme conditions, the net effect of 5-HT reduction would apparently be to compromise both the specificity of the system and its ability to maintain the integrity of signal flow. An example of affected signal flow is the increase in Markovian dependency between hippocampal cell spike density in PCPA-treated rats that can be reversed with 5-MeODMT treatment (Mushiake, Kodama, Shima, Yamamoto, & Nakahama, 1988). Thus, depletion of 5-HT fosters an abnormal serial dependency in cell firing, which not only reflects altered signal flow, but reflects, on a neural basis, the tendency of the system to overshoot. Any switch to an alternate signal source may be conceptualized as a perturbation to a neural system's current phase. DA has been proposed as having a switching function in neurophysiologic information systems (Oades, 1985). Increases in DA activity are associated with the initiation of new responses, such as LA and exploratory behavior (Brudzynski & Mogenson, 1985), as well as switching between alternate responses (Evenden & Robbins, 1983). Serotonin appears to impede this switching-initiation function of DA. For example, increases in 5-HT were shown to slow the switch from a neophobic to an exploratory behavior pattern (Adams & Geyer, 1985) and to potentiate latency to act in passive avoidance tasks (Altman, Nordy, & Ogren, 1984). Except at abnormally high levels of activity, 5-HT does not completely inhibit the switching-initiation function of DA; rather, it attenuates this activity so that controlled behavioral output (as opposed to unmitigated switching) results.


5-HT IN INFORMATION PROCESSING Thus, 5-HT alters the threshold for changes in a system's current phase that could normally result from DA-based switches to new signal sources or from perturbations in the homeostatic balance of a system (e.g., spread of seizure activity). Decreased 5-HT activity facilitates switching to alternate signal sources, which apparently allows for the initiation of new response programs (e.g., spontaneous locomotion; Gerson & Baldessarini, 1980; Grabowska, 1974; Kelly, 1977; Pycock et al, 1978). This may be why two-way active avoidance behavior, which requires continuous switching, is accompanied by decreased 5-HT activity (Driscoll, Dedek, Martin, & Zivkovic, 1983). Similarly, 5-HT agonism impairs two-way active avoidance (for a review see Altman & Normile, 1988). Furthermore, decreased 5-HT activity may result in an increased sensitivity to signals entering a system. Thus, presentation of a cue to 5-HTdepleted animals during active avoidance learning facilitates the initiation of avoidance behavior (Lorens, 1978). Retrieval (which may be conceptualized as a shift to a new signal that is internal in origin) is often facilitated by decreased 5-HT (Altman et al., 1984; Altman & Normile, 1986,1988). This may be due to an increased sensitivity to the conditioned cue (i.e, a greater likelihood of the cue influencing the phase of the system). Finally, an increased likelihood of switching can have a disruptive effect on ongoing sequential behavior. For example, the integrity of an exploratory behavior pattern is disrupted by depletion of 5-HT, the depleted animals' exploratory behavior becoming interspersed with other behaviors (Gately et al., 1985). Similarly, raphe lesions are associated with impaired choice accuracy in a T maze only if the intertrial delays are increased (Wenk et al, 1987). Perhaps this is why the learning of a spatial delayed response task, in which the instrumental response is contingent on the ability to maintain the spatial position of reward in working memory (Goldman-Rakic, 1987), is associated with an increase in 5-HT turnover in the amygdala, as well as various mesencephalic and medullary regions (Vachon & Roberge, 1981). To maintain the integrity of working memory circuitry, competing inputs must be eliminated. The discussion above suggests that 5-HT is involved in the maintenance of phase coherence in neurophysiologic systems and its relative absence with an increased propensity for phase instability. Facilitation of phase coherence by 5-HT activation may be achieved by an increase in the resolution of neurophysiologic signals that stabilizes signal flow. For example, in humans, acute administration of zimeldine (a 5-HT uptake inhibitor) was found to stabilize the electroencephalogram (EEG) by accentuating and synchronizing the monorhythmic alpha peak (Schenk, Filler, Ranft, & Zerbin, 1981). Similarly, applications of 5-HT or stimulation of the MR inhibit spontaneous hippocampal discharge activity and facilitate the formation of longlatency excitatory potential (M. Segal, 1980). These findings indicate that phase-coherent systems manifest higher thresholds to outside influences, as has been demonstrated by Mandell (Mandell, Knapp, Ehlers, & Russo, 1984). Constraint of information flow may, therefore, be thought of as the extent and probability that a given signal will influence the phase of a neural system. From this standpoint, although the action of 5-HT is inhibitory in nature, its function in an information-processing system is one of signal stabilization.

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Signal stabilization can have both positive and negative neural effects. At high levels of activity, central 5-HT facilitates the formation of neural synchrony. For example, EEG synchronization may be elicited by low-frequency stimulation of the DR (Gardner, 1985; Kayama et al., 1989), ventricular application of 5-HT (Jouvet, 1977; Koella & Czicman, 1966), or low doses of 5-HTP (Delorme, Froment, & Jouvet, 1966; Kayama, et al., 1989), whereas 5-HT depletion is associated with EEG desynchronization (Mushiake et al., 1988). Serotonin appears to be necessary for the formation of deep slow-wave sleep and may actually impede the formation of paradoxical sleep (Sallanon, Janin, Buda, & Jouvet, 1983). The relationship between 5-HT and sleep processes, however, may be dependent on which 5-HT receptor types are stimulated (Dugovic, Wauquier, Leysen, Marrannes, & Janssen, 1989). At very high levels of activity, however, 5-HT may lock in the system's phase, raising the threshold for perturbation by exogenous influences so that no new input into the system is possible. For example, stereotypy produced by large doses of DA agonists can be enhanced by 5-HT release and attenuated by either PCPA pretreatment or administration of 5-HT antagonists (Pycock et al., 1978; M. Segal & Weinstock, 1983; but see Baldessarini, Amatruda, Griffith, & Gerson, 1975). On the other hand, the attenuation of stereoty py by antagonism of 5-HT activity results in a facilitation of forward locomotion (Rebec, Alloway, & Curtis, 1981; M. Segal & Weinstock, 1983), as opposed to a cessation of movement per se, suggesting that the decreased 5-HT activity allows for a switch to a different locomotor pattern. This effect is thought to be due to decreases in 5-HT cellular activity that unlock neostriatal output and hence increase the animal's response selection repetoire (Rebec et al, 1981). Overall, then, the functional principle of constraint for 5-HT activity in information processing as outlined here implies that 5-HT stabilizes signal propagation insofar as it inhibits impingement on the system by exogenous signal sources. Its activity ensures that signals that do interrupt current information flow must be of a sufficient intensity or, from a psychological perspective, must be of sufficient relevance to the organism. Once a signal gains access to the system, 5-HT activity constrains the intensity of that signal as a means of preventing an overshoot in the system.

Psychopathologic Syndromes of Constraint Much of the discussion above is based on behavioral changes in animals incurred through manipulations in the 5-HT system. As mentioned above, the topographical and morphological properties of the 5-HT system appear similar across species (Azmitia & Gannon, 1986; Schofield & Everitt, 1981), thus permitting greater conceptual generalizations from animal studies to human behavior. In view of the functional principle of 5-HT modulatory activity as promoting phase coherence, predictions can be made about behavioral syndromes that may be associated with functional deviations in 5-HT activity. One of the basic effects of reduced phase coherence is a generalized release of behavioral facilitation. This may be conceptualized as a form of behavioral instability that is characterized in four ways: (a) an increase in the likelihood that a given response will occur, (b) an increase in the magnitude of the behavioral


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response, (c) a slowing of the recovery of the response, and (d) an insensitivity to cues that would attenuate or inhibit the behavioral responsivity. The behavioral effect of released behavioral facilitation in low 5-HT states was suggested by Soubrie (1986) in his article investigating the relationship between 5-HT activity and benzodiazepine functioning. The release of behavioral facilitation proposed here, however, is conceptually different in that behavioral facilitation is viewed as one consequence of reduced phase coherency, which extends to cortical systems beyond those involved in behavioral output. Many of these systems may be modulated by 5-HT in tandem. For example, the same bundle of DR fibers that projects to the corticomedial complex of the amygdala also labels the NAS and the lateral septum (Azmitia, 1978). This suggests that modulation of affective labeling of stimuli in the amygdala can be coordinated with input from the septo-hippocampal system and with behavioral output as initiated by the NAS. Thus, depletions of 5-HT are associated not only with a reduced coherency within target systems, but in the coordination of diverse systems as well. Behaviorally, this would lead to what personality theorists conceptualize as a dissociation between the activity of a behavioral inhibition system and affective states that would normally elicit behavioral inhibition (Fowles, 1987; Gray, 1982, 1987). In higher cortical systems, low 5-HT may exacerbate signal instability resulting from decreased cholinergic activity. This is supported by animal studies (Vanderwolf, Baker, & Dickson, 1990) and may relate to significance of the deficit in 5-HT noted in different forms of human dementia (Cross, 1990; Yates, Simpson, & Gordon, 1990). In terms of human personality, the effect of low 5-HT activity on afFective-limbic systems not only may result in a dissociation between behavioral inhibition and affective states but also may result in an increased propensity for affective instability (i.e., greater stress reactivity). For example, metergoline (a 5-HT antagonist) exerts anxiogenic properties in healthy humans (Graeff, 1984). In animals, not only does 5-HT activity increase after prolonged stress, but chronic stress increases the animal's 5-HT response to further stressors (i.e., it is sensitized; Adell, Garcia-Marquez, Armario, & Gelpi, 1988; Boadle-Biber, Corley, Graves, Phan, & Rosencrans, 1989). Given this sensitization of 5-HT reactivity during chronic stress, any propensity for exaggerated reactivity is likely to be more apparent during stressful periods. Of interest, glucocorticoids and 5-HT may affect information processing in a synergistic fashion. For example, either too much or too little corticosterone disrupts the normal activity of the hippocampal theta-driving rhythm by altering the minimum driving frequency in a manner similar to hippocampal 5, 7-DHT lesions, an effect that can be reversed by corticosterone treatment (Azmitia, McNaughton, Tsaltas, Fillenz, & Gray, 1984). Moreover, whereas either 5,7-DHT lesions or adrenalectomy result in an altered theta-driving minimum, combined lesions result in a normal minimum driving frequency (Azmitia et al, 1984). This is important because one of the actions of stress-induced glucocorticoid release is induction of a greater refractoriness in neural tissue to subsequent stimuli (Azmitia, 1978). Thus, not only is behavior less inhibited, but low 5-HT activity may result in an increased vulnerability to stressful stimuli.

There is ample evidence for increased aggressive behavior in humans who appear to have low 5-HT activity. Decreased 5-HT activity (inferred from postprobenicid accumulations of CSF 5-HIA A) has been associated with increased aggressive and suicidal behavior, generally, and violent suicidal behavior, particularly (Brown, Ebert, et al., 1982; Brown, Goodwin, Ballenger, Goyer, & Major, 1979; Brown, Goodwin, & Bunney, 1982; Edman, Asberg, Levandser, & Schalling, 1986; Lidberg, Tuck, Asberg, Scalia-Tomba, & Bertilsson, 1985; Van Praag, 1984). Catecholamine alterations (as indexed by metabolite concentrations) have been less consistently related to aggressive or suicidal behavior, although there is a tendency for CSF H VA to be decreased in (at least depressed) suicidals, whereas changes in CSF MHPG are less consistent (Brown & Goodwin, 1986). Although lower CSF HVA levels are fairly consistently associated with depression, they do not appear to be related to suicidal behavior per se (Asberg & Traskman, 1983; Banki & Arato, 1983; Oreland et al., 1981). Postmortem analyses of CNS regional concentration differences in 5-HT and 5-HIAA in completed suicides indicate decreases in both compounds in the brain stem, normal levels in the frontal cortex, decreased 5-HT in the hypothalamus, and decreased 5-HIAA in the NAS (Stanley, Mann, & Cohen, 1986), indicating low 5-HT turnover rates in some cortical regions. Catecholamine and related metabolite concentration distributions have not been widely studied in completed suicides; however, one study reported that HVA in the frontal cortex is greatly increased (100%) and limbic NE is somewhat decreased in completed suicides (Mann, McBride, & Stanley, 1986). These alterations in catecholamine levels could be reflective of altered 5-HT activity because 5-HT modulates both NE and DA activity (Antelman & Chiodo, 1984). Tritiated imipramine binding has been found to be decreased in both the frontal cortex and the hypothalamus (Stanley et al., 1986) of completed suicides (the imipramine-binding site is associated with the 5-HT presynaptic uptake site; Paul, Rehavi, Skolnick, & Goodwin, 1980). This is suggestive of decreased 5-HT neurotransmission because decreased imipramine binding may be indicative of decreased 5-HT release (Stanley et al., 1986). That suicide is associated with decreased 5-HT activity is further supported by reports of increased cortical 5-HT2 receptor densities in the brainstems and frontal cortices of suicide completers (Arora & Meltzer, 1989; Mann, Arango, & Underwood, 1990; Mann, McBride, & Stanley, 1986; Mann, Stanley, McBride, & McEwen, 1986; Owen et al., 1983; Stanley et al., 1986), possibly reflecting a compensatory upregulation of postsynaptic receptors secondary to decreased synaptic transmission. Of interest, two studies have also reported increased cortical /3-adrenergic binding (Mann, McBride, & Stanley, 1986; Zanko & Biegon, 1983). The upregulation of the /3-adrenergic receptors might also be secondary to decreased 5-HT neurotransmission because 5-HT modulates these receptors (Stockmeier et al., 1985). Although the relationship between decreased CSF 5-HIAA and suicidal behavior is fairly consistent across studies, the relationship between the metabolite levels and a diagnosis of depression is not. There does not appear to be any specificity of diagnosis for people who fall on the lower end of the CSF 5HIAA concentration distribution. For example, low CSF 5HIAA levels were found in schizophrenics who made suicide


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attempts (Banki & Arato, 1983; Van Praag, 1983), personalitydisordered people who made suicide attempts (Asberg & Traskman, 1983; Brown, Ebert, et al., 1982; Brown, Goodwin, & Bunney, 1982; Linnoila et al., 1983; Oreland et al., 1981; Traskman-Bendz, Asberg, & Schalling, 1986), arsonists (Virkkunen, Nuutila, Goodwin, & Linnoila, 1987), impulsive violent offenders (Linnoila et al., 1983; Virkkunen et al., 1987), and murderers who had killed a sexual partner (Lidberg et al., 1985). Moreover, the preponderance of violently suicidal people with low CSF 5-HIA A levels receive a diagnosis of borderline personality disorder and not depression (Traskman-Bendz et al., 1986). Because low CSF 5-HI A A concentrations are associated with violent behavior in addition to suicide (e.g., arson and murder), it has been suggested that decreased 5-HT activity may predispose toward violent behavior per se (Brown & Goodwin, 1986; Brown, Goodwin, & Bunney, 1982). In addition to clinical evidence, support for this assertion comes from the strong (negative) relationship that has been found between a history of aggressive behavior and the Minnesota Multiphasic Personality Inventory (MMPI) Psychopathic Deviate (Pd) scale with CSF 5-HI A A levels (Brown, Goodwin, & Bunney, 1982). The MMPI Pd scale may be a marker for hostility, because only the Hostility subscale of the Buss-Durkee Hostility-Guilt Inventory correlated with the Pd scale (r = .64; Brown, Goodwin, & Bunney, 1982). Thus, deviant CSF 5-HI A A levels appear to have a greater specificity for aggression and violence than for depression. As stated above, depression appears to be more consistently associated with decreased CSF HVA concentrations. Although there is support for the association between aggression and low 5-HT levels in humans, the lack of association between planned aggressive acts and 5-HT levels (Linnoila et al., 1983; Virkkunen et al., 1987) raises the question as to whether aggression per se is the behavioral concomitant of reduced 5-HT activity in humans or whether it is the impulsive nature of the aggressive acts that is more important. Indeed, the fact that violent suicidal behavior is associated with low 5-HT states, as opposed to suicidal behavior in general, may lend support to this interpretation, because violent suicidal behavior is usually impulsive (Asberg, Bertilsson, & Martensson, 1984). Impulsiveness appears to be an integral part of the personality structure of people who have low concentrations of CSF 5-HIAA. In both nondepressed suicide attempters and healthy controls, there is a negative correlation between CSF 5-HIAA levels and the personality dimension of Psychoticism as measured by the Eysenck Personality Questionnaire (TraskmanBendz et al., 1986). The trait of Psychoticism is not specific to a particular clinical entity; rather, it appears to reflect a vulnerability to many forms of psychopathology characterized by impulsive nonconformity (Chapman et al., 1984). The Psychoticism scale is correlated most significantly with measures of aggression, impulsivity, interpersonal alienation, and sensation seeking (as opposed to measures of psychotic behavior) and tends to fall on the same higher order factors as other measures of these traits (Tellegen, 1982; Zuckerman, Kuhlman, & Camac, 1988). This suggests that the impulsivity associated with Psychoticism is also associated with traits involving affective states, particularly negative affective states (e.g., aggression). People who made violent suicide attempts also scored higher

on measures of Neuroticism, as compared with people who made suicide attempts by nonviolent means or healthy controls (Banki & Arato, 1983; Traskman-Bendz et al., 1986). Neuroticism is a complex construct that correlates positively with measures of stress reactivity (i.e., dysphoria), interpersonal alienation, and aggression; correlates negatively with measures of well-being, and loads on the same higher order factor as measures of anxiety (Tellegen, 1982; Zuckerman et al., 1988). Thus, in addition to being more impulsively nonconforming, suicide attempters with low 5-HIAA appear to be more stress reactive as well. Greater stress reactivity and impulsivity, then, may be viewed as resulting from the influence of low 5-HT states on personality. Of interest, these traits (except dysphoria) also appear to be associated with low CSF 5-HIAA concentrations in nonpsychiatric controls. This suggests that the greater negative affect in patients with low 5-HIAA may be the result of stressors on a weakly regulated system. The clinical association of negative affect and impulsivity is important because in the general population there is an assumed independence of impulsivity and negative affect that may not hold in this population (e.g., Gray, 1982; Tellegen, 1982).

Concluding Remarks Through its role in supporting phase coherence, 5-HT activity stabilizes information flow resulting in controlled behavioral, affective, and cognitive output. Deviations in 5-HT activity result in altered neural information-processing tendencies. Very high levels of 5-HT activity may contribute to the formation of regionally restricted limit cycles in information flow that manifest as redundant signal propagation or maintenance of prepotent response patterns. Very low levels of 5-HT activity may impair the ability of the neural network to maintain the integrity of the signal flow pattern, resulting in an increased tendency toward switching and unstable, amplified signal passage. These altered information-processing tendencies derived from extremes of 5-HT activity appear to contribute to extremes on a stability-instability dimension. This suggests that human personality dimensions may be thought of as directional tendencies in neural information processing. High levels of 5-HT activity may be associated with a tendency toward hyperrigidity. Low levels of 5-HT activity are likely associated with a trend towards impulsivity and exaggerated stimulus reactivity, tendencies that are characteristic of the unstable behavior. An increased propensity for aggression in people who are characterized by low 5-HT activity may be viewed as a behavioral manifestation of exaggerated reactivity to signals eliciting aggression, coupled with a relative insensitivity to cues that would otherwise suppress the behavior (e.g., vulnerability in a victim). In terms of human personality dimensions, 5-HT activity appears to contribute to a dimension of behavioral constraint or stability, with the low end of the distribution resulting in a tendency toward exaggerated reactivity and, hence, unconstrained, unstable behavior (e.g., impulsivity). The instability does not appear to be simply behavioral, however, because affective stability is also compromised (i.e., there is an increase in negative affect). Moreover, there appears to be a dissociation between affective and behavioral systems that are normally


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Received September 6,1990 Revision received September 3,1991 Accepted September 4,1991 •

Carr Appointed Editor of the Journal of Experimental Psychology: Human Perception and Performance, 1994-1999 The Publications and Communications Board of the American Psychological Association announces the appointment of Thomas H. Carr, PhD, Michigan State University, as editor of the Journal of Experimental Psychology: Human Perception and Performance for a 6year term beginning in 1994. As of January 1,1993, manuscripts should be directed to Thomas H. Carr, PhD Department of Psychology Michigan State University East Lansing, Michigan 48824 Manuscript submission patterns foiJEP: Human Perception and Performance make the precise date of completion of the 1993 volume uncertain. The current editor, James E. Cutting, PhD, will receive and consider manuscripts until December 31,1992. Should the 1993 volume be completed before that date, manuscripts will be redirected to Dr. Carr for consideration in the 1994 volume.

Temporal information processing and psychopathology.

Neural information processing with dynamical synapses.

The serotonin-BDNF duo: developmental implications for the vulnerability to psychopathology.

Models of Innate Neural Attractors and Their Applications for Neural Information Processing.

Executive and modulatory neural circuits of defensive reactions: implications for panic disorder.

Unsupervised Neural Network Quantifies the Cost of Visual Information Processing.

SERT and uncertainty: serotonin transporter expression influences information processing biases for ambiguous aversive cues in mice.

associative learning account of behavioral disinhibition in externalizing psychopathology.

Evoked potential correlates of human information processing.

The role of imagery in hypnosis: an information processing approach.

Human information processing during physical exercise.

Risk for mood pathology: neural and psychological markers of abnormal negative information processing.

Serotonin modulates auditory information processing in the cochlear nucleus of the rat.

The pons and human affective processing--Implications for Parkinson's disease.

Role of methionine in bacterial chemotaxis: requirement for tumbling and involvement in information processing.

Orientation in time: implications for psychopathology and psychotherapy.

Vocal acoustic analysis as a biometric indicator of information processing: implications for neurological and psychiatric disorders.

An information theoretic model of information processing in the Drosophila olfactory system: the role of inhibitory neurons for system efficiency.

Medical information seeking: impact on risk for anxiety psychopathology.

Terminal chaos for information processing in neurodynamics.

Statistics of the vestibular input experienced during natural self-motion: implications for neural processing.

What's an internal clock for? From temporal information processing to temporal processing of information.

Developmental changes in the neural influence of sublexical information on semantic processing.

Neuroimaging evidence for a role of neural social stress processing in ethnic minority-associated environmental risk.