Pharmac. Ther. Vol. 46, pp. 119-136, 1990 Printed in Great Britain.All rights reserved
0163-7258/90$0.00+ 0.50 © 1990PergamonPress plc
Specialist Subject Editor: S. E. FILl;
MULTIPLE NEUROCHEMICAL A N D BEHAVIORAL CONSEQUENCES OF STRESSORS: IMPLICATIONS FOR DEPRESSION HYMIE ANISMAN a n d ROBERT M. ZACHARKO Psychology Department, Carleton University, Ottawa, Ontario, Canada Abstract--Animal models of clinical depression have frequently focused on the contribution of stressors to the induction of behavioral impairments and pharmacological intervention in the amelioration of these disturbances. Stressors provoke various behavioral disturbances and influence the activity of central neurotransmitters implicated in depression. It is our contention that those variables which favor the provocation of amine depletions or prevent the development of a neurochemical adaptation will increase vulnerability to behavioral disturbances. It is essential to consider, however, that marked interindividual and interstrain differences exist in the behavioral and neurochemical response to stressors, and in the effectiveness of antidepressant treatments. CONTENTS 1. Introduction 2. Central Neurotransmitter Changes associated with Stressors 3. Behavioral Changes associated with Stressors 4. Genetic and Individual Differences in response to Stressors 5. Summary Acknowledgements References
instances treatments that are ineffective in alleviating the symptoms of depression in humans are effective in eliminating the behavioral effects associated with stressors in rats and mice (see Zacharko and Anisman, 1989). Even if one were to accept that a particular behavior was suitable as a model of human depression, it is still necessary to consider that considerable variability exists in response to stressors, symptoms of depression, neurochemical concomitants of the illness and the effectiveness of treatments. Fortunately, the interindividual variability that is evident in the human condition is also present in animal research, and could potentially be used as a tool to identify some of the organismic, experiential and environmental factors that subserve depressivelike behaviors.
1. I N T R O D U C T I O N The notion that aversive events may provoke or exacerbate clinical depression in humans is an intuitively appealing one. Indeed, both human and animal experimentation has provided evidence commensurate with this position, although it may be premature to dismiss the proposition that the reaction to a stressor is symptomatic of an already existent depression. Despite the appreciable data assessing the stressor~lepression topography, several issues have received only scant attention. Among other things, it ought to be considered that (1) those events that are perceived as being stressful to one individual may not be stressful to another, (2) the behavioral, emotional and even the neurochemical impact provoked by stressors may be different across individuals, (3) even if a depressive syndrome is evident, the symptoms associated with the depression may vary widely across individuals, (4) heterogeneity may exist with respect to the neurochemical substrates of depression, and perhaps as a result (5) variability exists with respect to the treatments effective in alleviating depression. Few would disagree that the development of an adequate animal model of human depression is exceedingly difficult. Often the stressor induced behaviors examined in animals have borne little resemblance to the symptoms typically associated with human depression (see Willner, 1985), and in some j~r~/1-1
119 119 124 130 132 132 132
2. CENTRAL N E U R O T R A N S M I T T E R CHANGES ASSOCIATED WITH STRESSORS We have described on several occasions the neurochemical concomitants associated with stressors (Anisman, 1984; Anisman and Zacharko, 1982a; Zacharko and Anisman, 1989). Accordingly, a detailed account of this literature will not be provided at this point, but rather only some of the more pertinent data will be discussed. Moreover, although stressors have been shown to induce variations of a number of neurotransmitters and hormones, the 119
120
H. ANISMAN and R. M. ZACHARKO Resting State
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Severe or Uncontrollable Stress
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Re-exposure to
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Uncontrollable Stress
Uncontrollable Stress
FIG. 1. Schematic representation of norepinephrine (NE) variations which occur under various stressor conditions. When the stressor is mild or controllable NE utilization is increased, and this is accompanied by increased synthesis. Accordingly, the concentration of the amine is unaltered. However, if the stressor is uncontrollable, further increases of utilization may occur, ultimately exceeding synthesis, and resulting in a net decline of amine concentrations. Following a chronic stressor regimen a compensatory increase of synthesis may be engendered, and amine concentrations may equal or exceed control values. Additionally, under such conditions subsensitivity of fl-NE receptors may occur, and NE-stimulated adenylate cyclase (cAMP) activity may be reduced. The lower portion of the figure depicts the effects of stressor reexposure as a function of the organism's prior stressor history. In mildly stressed animals reexposure to the stressor provokes a modest increase of amine or amine turnover; however, in animals previously exposed to a traumatic stressor, subsequent reexposure to the environmental insult may provoke a marked NE release, which may exceed synthesis, thereby resulting in induced NE levels. Indeed, reexposure to cues previously associated with a stressor may augment NE turnover. In animals that had been exposed to a chronic stressor that resulted in neurochemical adaptation, reexposure to the stressor may provoke elevated NE concentrations, presumably owing to a rapid and marked increase of NE synthesis (from Anisman and Zacharko, 1986). Reprinted with the permission of the copyright holder, the New York Academy of Sciences, New York.
present discussion will be limited to those which are thought to be most closely aligned with depression. It has been our position that acute exposure to environmental insults will lead to neurochemical changes which may be of adaptive value. As the stressor continues, further variations may occur, presumably to meet environmental demands. Such alterations may occur within a transmitter system (e.g. a compensatory increase in the synthesis of a transmitter to assure adequate amine supplies or receptor regulation thereby increasing or decreasing efficiency) or between systems (i.e. variations within a particular transmitter system may lead to compensatory changes of a second transmitter). However, under certain conditions the system may become overly taxed, or alternatively the within- or between-system adaptations do not occur, and hence vulnerability to pathology will be increased (Anisman and Zacharko, 1982a; Zacharko and Anisman, 1989). The effects of stressors on norepinephrine (NE) activity have received greater attention than any of the other transmitter systems. Figure 1 displays a schematic representation of the N E variations that occur under various stressor conditions. It is well established that under stressful conditions N E utilization and synthesis are increased. If the stressor is
sufficiently severe or behavioral methods of coping are unavailable, then utilization of the transmitter may come to exceed synthesis and consequently concentrations of the amine decline (Anisman, 1984; Anisman et al., 1980a; Tsuda and Tanaka, 1985; Weiss et al., 1976). Not surprisingly, stressor severity influences the variations of N E turnover and levels, and it appears that the amine variations are provoked more readily in some brain regions than in others (Tanaka et al., 1982). In addition, organismic factors, such as the age of the animal, appear to be fundamental in determining the N E alterations, with older animals exhibiting greater vulnerability and more persistent decreases of N E than younger animals (Ida et al., 1982; Ritter and Pelzer, 1978). While the amine variations are relatively transient, persisting for as little as a few minutes to as long as 72 hr, depending on the stressor severity or the brain region examined (Weiss et al., 1981), aversive events have also been shown to proactively influence the response to subsequently applied stressors. In particular, in animals that had previously been exposed to an acute stressor, subsequent reexposure to cues that had been associated with the stressor come to increase the utilization of N E (Cassens et al., 1980; Irwin et al., 1986a), and reexposure to the stressor
121
Neurochemical and behavioral consequences of stressors will more readily reinduce NE reductions (Anisman and Sklar, 1979; Irwin et al., 1986a). More recently, stressors have also been shown to increase unit activity in the locus coeruleus of cats (Abercrombie et al., 1986; Morilak et al., 1986; Rasmussen and Jacobs, 1986). Moreover, the locus coeruleus unit activity was also enhanced in response to stimuli previously paired with a stressor (Rasmussen et al., 1986). Such effects were not apparent in response to cues which previously signalled reward or to neutral cues. Interestingly, when these cats were confronted with potentially arousing stimuli (e.g. rats) overt signs of behavioral excitation were elicited, but no significant deviations from baseline activity were noted from the locus coeruleus (Abercrombie et at., 1986). Following repeated exposure to a stressor or during the course of protracted exposure to a continuous stressor (e.g. restraint) a further series of adaptive changes occur. The synthesis of NE increases appreciably, and as a result the reduction in transmitter levels is precluded (Irwin et al., 1986a; Kvetnansky et al., 1977; Roth et al., 1982). The enhanced synthesis may persist for some time after stressor termination, and concentrations of the amine may actually come to exceed those of nonstressed animals (Anisman et al., 1986; Irwin et al., 1986b; Roth et al., 1982). Presumably, the enhanced synthesis is essential for the organism to deal effectively with the ongoing stressor. The fact that the increased synthesis persists after stressor termination may be essential in assuring that amine supplies will be sufficient to deal with impending stressors. Just as the acute effects of stressors (e.g. the enhanced utilization) may be influenced by cues that had been associated with the stressor, it seems that the enhanced synthesis associated with a chronic stressor may be subject to conditioning-like effects (see Fig. 2). In particular, having been exposed to a repeated stressor which resulted in the neurochemical adaptation, later exposure to cues associated with the stressor resulted in increased accumulation of the NE metabolite, as well as increased concentrations of NE, suggesting that exposure to the stressor-related cues provoked a marked and rapid increase of NE synthesis (see Irwin et al., 1986a). The conditions which delay or preclude the neurochemical adaptation have not been extensively evaluated. It was demonstrated that when the stressor is applied at unpredictable times, the adaptation progresses more slowly than when the stressor is presented on a predictable basis (Anisman et al., 1986). It might be supposed that still slower adaptation occurs when the stressor regimen involves different types of stressors (as opposed to a single type of stressor applied repeatedly). It is our contention that a stressor regimen, which does not favor the development of adaptation, is more likely to be associated with depressive symptoms than a chronic, predictable, stressor regimen. Likewise, in those organisms in which the neurochemical adaptation does not develop readily (as a result of genetic or experiential variables), stressor-related depressive symptoms will be more likely to develop. The effects of chronic stressors are not limited to alternations in the synthesis and concentrations of NE. In a series of reports, Stone and his associates
• 12,"
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PRETREATMENT FI6. 2. Mean (+SEM) norepinephrine (NE) and MHPG concentrations in hypothalamus of mice that received either no shock, a single session of 360shocks (2sec, 150#A) (acute), or 14 sessions of 360 shocks on consecutive days (chronic). Fourteen days afterward mice were either placed in the apparatus and not shocked (open bars) or were exposed to 60 shocks (2 sec duration) (closed bars). It will be noted that in the acutely stressed mice the shock reexposure treatment provoked a reduction of NE concentrations, while the same treatment applied to mice that had previously been exposed to a chronic stressor regimen resulted in enhanced NE concentrations (from Irwin et al., 1986a). Reprinted with the permission of the copyright holder, Elsevier Science Publishers BV, Amsterdam.
(Stone, 1979, 1983; Stone and Herrera, 1986; Stone and Platt, 1982; Stone et al., 1984, 1986; see review in Stone, 1987) as well as other investigators (e.g. Nomura et al., 1981; U'Pritchard and Kvetnansky, 1980) have demonstrated that following a chronic stressor regimen the sensitivity of fl-NE receptors is reduced, as is the sensitivity of the cAMP response to catecholamines. Inasmuch as chronic antidepressants result in a similar fl-NE down-regulation, Stone offered the view that the reduced sensitivity of the NE receptors and of the cAMP response associated with chronic stressors, like the response to antidepressant drugs, may reflect an adaptive change which limits the development of depressive symptoms (Stone, 1983). In accordance with this view, it was demonstrated that behavioral depression (i.e. immobility in a forced swim test and anorexia) was reduced in parallel with the development of the receptor subsensitivity (Platt and Stone, 1982; Stone and Platt, 1982). It might be noted at this juncture, that the reduction of fl-NE receptor sensitivity and the down-regulation of the cAMP response associated with chronic stressor application may be subserved by independent mechanisms. In particular, although chronic stressors have been shown to reduce the density of fl-NE
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H. ANISMANand R. M. ZACHARKO
receptors in rat cortex, this effect was relatively transient, being absent 24hr following stressor termination (U'Pritchard and Kvetnansky, 1980; see also Stone et al., 1984). In contrast, the cAMP response is reduced to a comparable degree immediately and 24 hr after a chronic stressor regimen (Stone et al., 1984). This does not necessarily imply that the mechanisms governing the response to a chronic stressor are different from those mediating the response to antidepressants, since some antidepressant agents have also been shown to reduce the NE-cAMP response without affecting the density of fl-NE receptors (Mishra et al., 1980). In considering the NE subsensitivity and the cAMP down-regulation associated with antidepressant therapy, it should be made clear that such effects are probably not secondary to the blockade of NE reuptake, since these effects are evident using atypical antidepressants (see review in McNeal and Cimbolic, 1986). It does seem, however, that there is a role for serotonin (5-HT) in the provocation of the receptor subsensitivity associated with antidepressant treatment. In particular, intracerebral administration of the 5-HT neurotoxin, 5,7 dihydroxytryptamine, resulted in the elimination of the fl-NE subsensitivity associated with desmethylimipramine treatment, but did not influence the down-regulated cAMP response (see Janowsky and Sulser, 1987). The mechanisms underlying the chronic stressor provoked fl-NE subsensitivity have yet to be elucidated, although it does appear that in rat hypothalamus phospholipid metabolism may be involved (Torda et aL, 1981). It remains to be determined, however, whether 5-HT activity plays a role in the development of the stressor induced NE receptor subsensitivity. The dopamine (DA) variations associated with stressors are less widespread than those of NE. In contrast to early reports that revealed increases or no change of DA concentrations in large tissue samples, later reports revealed marked reductions of DA and increases of utilization in certain brain regions. Reports by Kvetnansky et al. (1976) and Kobayashi et al. (1976) indicated that restraint stress produced marked DA reductions which were restricted to the arcuate nucleus of the hypothalamus. In other hypothalamic nuclei, DA concentrations were either unaffected or were increased by the stressor. It was subsequently determined, as well, that environmental insults profoundly influenced mesolimbic and mesocortical DA activity~ but did not affect nigrostriatal DA activity (Deutch et al., 1985; Herman et al., 1982; Herve et al., 1979; Thierry et al., 1976). For instance, several forms of stressors have been shown to increase DOPAC accumulation in the mesocortex and the nucleus accumbens, without appreciably influencing DOPAC accumulation in the substantia nigra (see Fig. 3). Moreover, it appears as if the mesocortex is particularly sensitive to the effects of the stressor and reductions of the amine are readily apparent (Anisman and Zacharko, 1986; Herman et al., 1982). Indeed, it was demonstrated that in the mesocortex, DA utilization may be enhanced by cues that had been associated with a previously applied stressor (Herman et al., 1982; see also Deutch et al., 1985). Additionally, it has been reported that the enhanced mesocortical DOPAC accumulation associated with
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FIG. 3. Dopamine (DA), DOPAC, and homovanillic acid (HVA) as a percent of control values (±SEM) in hypothalamus (Hypo), frontal cortex (Fc), nucleus accumbens (Nac), caudate, substantia nigra (SN), and ventral tegmentum (VTA) of mice that had received either 30 or 360 footshocks (1501~A, 2 sec duration) (from Anisman and Zacharko, 1986). Reprinted with the permission of the copyright holder, the New York Academy of Sciences, New York. an acute stressor may be prevented by pretreatment with the anxiolytic, diazepam, or by treatment with the fl-NE inhibitor, chlorpropanol, which acts as an anxiolytic, but without primary sedative action (Fadda et al., 1978; Fekete et al., 1981). Thus, it is conceivable that anxiety induced by the stressor is fundamental in provoking the mesolimbic/mesocortical DA changes. Following a chronic stressor regimen the mesocortical DA reductions ordinarily associated with an acute stressor may be absent. Unlike the enhanced synthesis which is responsible for the increased NE associated with repeated stress, there is some evidence suggesting that the DA adaptation is determined, at least in part, by moderation of the excessive DA utilization (Anisman and Zacharko, 1986; Herman et al., 1984). That is, although a chronic stressor enhances DA utilization, the DOPAC accumulation after such treatment is less pronounced than after an acute stressor. In accordance with the data indicating that DA mesocortical neurons are particularly responsive to stressors, Kramarcy et al. (1984) reported that the enhanced DOPAC accumulation associated with acute footshock was also accompanied by enhanced DA synthesis, as determined from the accumulation of [3H]-DA following incubation with [3H]-tyrosine. Curiously, following repeated stressor application, the enhanced DA synthesis associated with acute shock was absent. Unfortunately, the latter effect was exhibited in a separate experiment where the effects of acute shock were not monitored. The absence of the necessary comparison group in this experiment prevents a strong conclusion from being drawn. There are data available suggesting that aversive environmental events will influence DA receptor sensitivity. In particular, it has been demonstrated that like the progressive enhancement of the behavioral effects associated with repeated treatment with amphetamine, exposure to a stressor may augment the
Neurochemical and behavioral consequences of stressors behavioral response ordinarily elicited by amphetamine (Anisman et al., 1985; Robinson et al., 1985), and conversely, amphetamine treatment may augment the behavioral effects of a mild stressor (Antelman et al., 1980). Based on their work assessing electrophysiological recordings from DA neurons, Antelman and Chiodo (1983) suggested that repeated treatment with amphetamine (as well as repeated electroconvulsive shock) resulted in a time-dependent subsensitivity of DA autoreceptors (as gauged by the response to low doses of apomorphine). Presumably, the subsensitivity of autoreceptors would result in increased DA release ordinarily provoked by a stimulant. The data concerning the effects of stressors on serotonergic activity are less extensive than those concerning NE and DA, and there appears to be greater inconsistency, as well. Several investigators reported that stressful events may influence the turnover and/or concentrations of 5-HT (Joseph and Kennett, 1981; Kennett and Joseph, 1981). It has been demonstrated, for instance, that stressors will increase the utilization of 5-HT; however, it appears that the severity of the stressor required to alter 5-HT utilization is greater than that necessary to elicit the alterations of NE activity (Thierry et al., 1968). Other investigators (Hellhammer et al., 1983) have reported that stressors increase 5-HT concentrations in some brain regions (e.g. pons/medulla, septum, striatum), but decrease concentrations of the amine in other areas (midbrain, posterior hypothalamus). In the posterior hypothalamus the reduced 5-HT concentrations were accompanied by reduced levels of 5-HIAA. More recently, Dunn (1988) reported that a 15 min session of footshock resulted in increased accumulation of 5-HIAA and reduced concentrations of 5-HT in the prefrontal cortex and in the hypothalamus in CD-1 mice. With a longer stressor period (30min), amine utilization increased still further, as reflected by greater accumulation of 5-HIAA; however, following such a stressor regimen 5-HT levels were comparable to those of nonstressed animals, while brain tryptophan levels increased appreciably. Possibly, the increased availability of tryptophan resulted in increased synthesis of 5-HT, thus replenishing the amine stores. Paralleling some of these findings, Adell et al. (1988) reported that following chronic restraint, 5-HT levels increased in several brain regions. These increases were accompanied by increased accumulation of 5-HIAA, suggesting that the enhanced 5-HT concentrations likely stemmed from a compensatory increase in synthesis. In our laboratory, we observed (Shanks et al., 1988) profound alterations of 5-HT and 5-HIAA following application of footshock (360 shocks, 2 sec applied over 1.1 hr) in the mesolimbic cortex in 5 of 6 strains of mice tested (A/J, BALB/cByJ, C57B1/6J, DBA/2J, C3H/HeJ, but not in CD-I), while in hypothalamus there were no such reductions. Of course, as suggested by the data reported by Dunn (1988), a lesser amount of shock may have permitted expression of the 5-HT reductions in hypothalamus. In both the mesocortex and hypothalamus 5-HIAA accumulation was increased by the stressor treatment, but again this effect was strain specific. Thus, some of the divergent effects reported in the literature may be a reflection of the
123
amount of stress applied or the strain of animal examined. Scant information is available concerning the contribution of coping factors to the alterations of 5-HT activity. It has been reported that uncontrollable shock induced 5-HT reductions more readily than did controllable shock, but this effect was evident only within the lateral septum (Sherman and Petty, 1980). In fact, Weiss et al. (1981) reported that in other brain areas, controllable shock was more likely to influence 5-HT concentrations, possibly suggesting that the 5-HT changes reflected the effort associated with the act of emitting an escape response. In addition to the amine variations associated with stressors, it has been reported that aversive events may influence opiate peptide activity. Opiate peptides and receptors have been identified in the central nervous system (Mansour et al., 1988), as well as in neuroendocrine systems, endocrine glands and plasma (Owens and Smith, 1987). fl-Endorphin has been found to be stored with adrenocorticotropic hormone (ACTH) in the pituitary and Met-enkephalin appears to be localized with catecholamines in the adrenal medulla (Owens and Smith, 1987). While the role of opiate peptides in mediating specific behaviors has, of course, not been fully elucidated, it was suggested (Swanson, 1983) that the presence of synaptic 'cocktails' favors multiple receptor activation and the development of complex behavioral states. Acute stressors have been shown reduce pituitary /~-endorphin, while increasing plasma levels of this opiate peptide in rats (Guillemin et al., 1977; Knepel et al., 1983; Madden et al., 1977). The latter effect has also been demonstrated in humans (Owens and Smith, 1987). The altered plasma endorphin levels have been observed following a variety of stressors, including surgery (Owen and Smith, 1987), child birth (Pancheri et al., 1985) and electric footshock (Knepel et al., 1983). In addition to accumulating evidence that stressors activate peripheral opioid mechanisms, there is evidence indicating that aversive events may exert potent central opiate effects (Pert, 1982). It was demonstrated that an acute session of footshock decreased enkephalin availability in the hypothalamus (Fratta et al., 1977; Rossier et al., 1978). Other stressors, such as food deprivation, mild-tail pinch and insulin-induced hypoglycemia decreased dynorphin activity in the cerebral cortex, while restraint or swim stress were ineffective in this respect. Cold exposure, however, produced a significant decrease in hypothalamic dynorphin activity (Morley et al., 1982). It might be noted at this juncture that there is also reason to believe that opiate peptide activity may be subject to conditioning-like effects much like those described for NE and DA. In particular, Chance et al. (1978) observed that cues associated with a stressor resulted in decreased binding of [3H]-N-Leuenkephalin. Although there is considerable evidence to suggest that stressors may produce alterations of opioid activity in cortical and hypothalamic sites, more recent data suggest that opioid variations are associated with the site of origin of the major ascending noradrenergic and dopaminergic pathways. In particular, Jacobs and his associates (Abercrombie and
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H. ANISMANand R. M. ZACHARKO
Jacobs, 1988; Abercrombie et al., 1988; Morilak et al., 1987a,b) observed that the stressor-induced conditioning of locus coeruleus unit activity is profoundly influenced by opioid manipulation. These findings have been substantiated by demonstration of considerable opioid immunoreactivity in and around the area of the locus coeruleus (Finley et al., 1981; Leger et al., 1983), a dense distribution of opioid receptors in the locus coeruleus (Atweh and Kuhar, 1977; Lewis et al., 1985) and inhibition of locus coeruleus unit activity by central opioid administration (Bird and Kuhar, 1977; Guyenet and Aghajanian, 1979). Jacobs has argued that stressors activate the locus coeruleus NE system, which results in fear and/or anxiety, The coactivation of an endogenous opioid system, which functions to inhibit the activity of the locus coeruleus, would favor adaptive behavioral coping. In addition to the potential modulation influence of opioids on central NE activity, it has also been demonstrated that stressor-induced alterations of central DA activity can be influenced by opioid administration. In particular, both Met- and Leuenkephalin, as well as their respective mu and delta receptors, have been identified in the ventral tegmental field (i.e. the VTA, the A I 0 region of the DA containing mesolimbic/mesocortical system). Uncontrollable stressors have been shown to augment endogenous enkephalin activity in the VTA and to induce accelerated DA turnover in mesolimbic/ mesocortical sites. Exogenous administration of enkephalin analogs into the tegmentum, in turn, has been shown to increase stressor-induced DA turnover in both the nucleus accumbens as well as the mesolimbic frontal cortex (Kalivas et al., 1983). Administration of the opioid antagonist, naloxone, prevents the stressor-induced variations of DA activity from the mesocortex (Miller et al., 1984). These results have recently been replicated by Kalivas and Abhold (1987) employing the shorter acting opiate antagonist, naltrexone. It was revealed that direct application of naltrexone into the A10 region attenuated the elevation of DA metabolism normally evident after footshock. It has also been reported that reductions of the neuropeptide, substance P, which appears to be localized in the tegmentum, attenuates mesocortical DA turnover in response to uncontrollable footshock (Bannon et al., 1983). There is also reason to suspect that sensitization/conditioning may be involved in enkephalin/neuropeptide interactions with central DA activity. For example, exposure to inescapable footshock potentiated the augmented DA turnover elicited by intracerebral administration of the enkephalin analog, D-Ala2-MetS-enkephalinamide (DALA) into the VTA, while naltrexone blocked this augmented neurochemical response. Moreover, prior administration of DALA has also been noted to sensitize animals to the subsequent effects of stressor application (Kalivas and Richardson-Carlson, 1986). In accordance with these findings, Cabib et al. (1984) demonstrated that repeated immobilization stress increased sensitivity to DA agonists, an effect which was prevented by prior administration of naloxone. It was concluded that chronic stressors may sensitize central DA systems owing to excessive production of central endogenous opioids. Together these data sug-
gest that although stressors appear to influence DA activity, such alterations may in turn be regulated by endogenous opiate systems and psychological variables associated with the stressor may come to influence the expression of neurochemical processes. In addition to alterations of central opioid concentrations, it appears that stressors may provoke alterations of central opiate receptors. For example, Nabeshima et al. (1985) reported that uncontrollable footshock engendered conformational changes of central opioid receptors as evidenced by increased binding at antagonist receptor sites and decreased binding at agonist receptor sites. Furthermore, Sirakova et al. (1988) reported that immobilization stress (i.e. 24 hr coupled with food and water deprivation) enhanced delta receptor binding, with little if any effect on mu receptor binding in rat whole brain. It is unclear whether these alterations stemmed from the immobilization procedure, the deprivation schedule imposed or a combination of the two. However, it will be noted that fasted rats exhibited decreased levels of fl-endorphin in the hypothalamus (Gambert et al., 1981).
3. BEHAVIORAL C H A N G E S ASSOCIATED WITH STRESSORS As indicated earlier, considerable attention has been devoted to the analysis of stressors on subsequent behavioral impairments. By far the greatest emphasis has been placed on the analysis of controllable and uncontrollable stressors on shuttle escape performance. Specifically, it was demonstrated that following exposure to escapable shock, shuttle escape performance is typically unaffected; however, in animals that were exposed to an identical amount of shock, applied in a yoked paradigm, severe disturbances of escape performance were apparent. The initial studies, conducted in dogs, demonstrated this effect to be relatively transient, disappearing within about 72 hr of stressor termination. These animals were described as being passive in the face of the stressor, without apparent attempts to escape from the aversive stimuli (Maier and Seligman, 1976). Later studies conducted in rats or mice provided a somewhat different behavioral profile. While inescapable shock reliably disrupted subsequent escape performance, the behavioral deficits were most apparent when the response was either associatively or motorically demanding (Anisman et al., 1978; Maier et aL, 1973). Typically, escape deficits were evident when animals were required to take several seconds of shock before escape was possible (see Fig. 4). Furthermore, unlike the description provided in studies in dogs, in mice and rats, shock onset almost invariably led to heightened motor activity, which decayed rapidly as the shock continued. The initial response excitation seen upon shock onset was evident irrespective of whether animals had initially been exposed to escapable or inescapable shock, whereas the decline in shock-elicited motor activity was particularly marked in mice that initially had been exposed to uncontrollable footshock or tailshock. Thus, it was suggested that the response excitation seen upon shock onset favored proficient responding in tasks
Neurochemical and behavioral consequences of stressors NO PRESHOCK
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0163-7258/90$0.00+ 0.50 © 1990PergamonPress plc
Specialist Subject Editor: S. E. FILl;
MULTIPLE NEUROCHEMICAL A N D BEHAVIORAL CONSEQUENCES OF STRESSORS: IMPLICATIONS FOR DEPRESSION HYMIE ANISMAN a n d ROBERT M. ZACHARKO Psychology Department, Carleton University, Ottawa, Ontario, Canada Abstract--Animal models of clinical depression have frequently focused on the contribution of stressors to the induction of behavioral impairments and pharmacological intervention in the amelioration of these disturbances. Stressors provoke various behavioral disturbances and influence the activity of central neurotransmitters implicated in depression. It is our contention that those variables which favor the provocation of amine depletions or prevent the development of a neurochemical adaptation will increase vulnerability to behavioral disturbances. It is essential to consider, however, that marked interindividual and interstrain differences exist in the behavioral and neurochemical response to stressors, and in the effectiveness of antidepressant treatments. CONTENTS 1. Introduction 2. Central Neurotransmitter Changes associated with Stressors 3. Behavioral Changes associated with Stressors 4. Genetic and Individual Differences in response to Stressors 5. Summary Acknowledgements References
instances treatments that are ineffective in alleviating the symptoms of depression in humans are effective in eliminating the behavioral effects associated with stressors in rats and mice (see Zacharko and Anisman, 1989). Even if one were to accept that a particular behavior was suitable as a model of human depression, it is still necessary to consider that considerable variability exists in response to stressors, symptoms of depression, neurochemical concomitants of the illness and the effectiveness of treatments. Fortunately, the interindividual variability that is evident in the human condition is also present in animal research, and could potentially be used as a tool to identify some of the organismic, experiential and environmental factors that subserve depressivelike behaviors.
1. I N T R O D U C T I O N The notion that aversive events may provoke or exacerbate clinical depression in humans is an intuitively appealing one. Indeed, both human and animal experimentation has provided evidence commensurate with this position, although it may be premature to dismiss the proposition that the reaction to a stressor is symptomatic of an already existent depression. Despite the appreciable data assessing the stressor~lepression topography, several issues have received only scant attention. Among other things, it ought to be considered that (1) those events that are perceived as being stressful to one individual may not be stressful to another, (2) the behavioral, emotional and even the neurochemical impact provoked by stressors may be different across individuals, (3) even if a depressive syndrome is evident, the symptoms associated with the depression may vary widely across individuals, (4) heterogeneity may exist with respect to the neurochemical substrates of depression, and perhaps as a result (5) variability exists with respect to the treatments effective in alleviating depression. Few would disagree that the development of an adequate animal model of human depression is exceedingly difficult. Often the stressor induced behaviors examined in animals have borne little resemblance to the symptoms typically associated with human depression (see Willner, 1985), and in some j~r~/1-1
119 119 124 130 132 132 132
2. CENTRAL N E U R O T R A N S M I T T E R CHANGES ASSOCIATED WITH STRESSORS We have described on several occasions the neurochemical concomitants associated with stressors (Anisman, 1984; Anisman and Zacharko, 1982a; Zacharko and Anisman, 1989). Accordingly, a detailed account of this literature will not be provided at this point, but rather only some of the more pertinent data will be discussed. Moreover, although stressors have been shown to induce variations of a number of neurotransmitters and hormones, the 119
120
H. ANISMAN and R. M. ZACHARKO Resting State
,@o,,,,z.? Level
Mild or Controllable Stress
Severe or Uncontrollable Stress
C
h
Repeated Uncontrollable Stress
-'0-" -'0-, -,®=' I I
I I
-0" - © *
I I
Re-exposure to
Re-exposure to
Re-exposure to
Uncontrollable S t r e s s
Uncontrollable Stress
Uncontrollable Stress
FIG. 1. Schematic representation of norepinephrine (NE) variations which occur under various stressor conditions. When the stressor is mild or controllable NE utilization is increased, and this is accompanied by increased synthesis. Accordingly, the concentration of the amine is unaltered. However, if the stressor is uncontrollable, further increases of utilization may occur, ultimately exceeding synthesis, and resulting in a net decline of amine concentrations. Following a chronic stressor regimen a compensatory increase of synthesis may be engendered, and amine concentrations may equal or exceed control values. Additionally, under such conditions subsensitivity of fl-NE receptors may occur, and NE-stimulated adenylate cyclase (cAMP) activity may be reduced. The lower portion of the figure depicts the effects of stressor reexposure as a function of the organism's prior stressor history. In mildly stressed animals reexposure to the stressor provokes a modest increase of amine or amine turnover; however, in animals previously exposed to a traumatic stressor, subsequent reexposure to the environmental insult may provoke a marked NE release, which may exceed synthesis, thereby resulting in induced NE levels. Indeed, reexposure to cues previously associated with a stressor may augment NE turnover. In animals that had been exposed to a chronic stressor that resulted in neurochemical adaptation, reexposure to the stressor may provoke elevated NE concentrations, presumably owing to a rapid and marked increase of NE synthesis (from Anisman and Zacharko, 1986). Reprinted with the permission of the copyright holder, the New York Academy of Sciences, New York.
present discussion will be limited to those which are thought to be most closely aligned with depression. It has been our position that acute exposure to environmental insults will lead to neurochemical changes which may be of adaptive value. As the stressor continues, further variations may occur, presumably to meet environmental demands. Such alterations may occur within a transmitter system (e.g. a compensatory increase in the synthesis of a transmitter to assure adequate amine supplies or receptor regulation thereby increasing or decreasing efficiency) or between systems (i.e. variations within a particular transmitter system may lead to compensatory changes of a second transmitter). However, under certain conditions the system may become overly taxed, or alternatively the within- or between-system adaptations do not occur, and hence vulnerability to pathology will be increased (Anisman and Zacharko, 1982a; Zacharko and Anisman, 1989). The effects of stressors on norepinephrine (NE) activity have received greater attention than any of the other transmitter systems. Figure 1 displays a schematic representation of the N E variations that occur under various stressor conditions. It is well established that under stressful conditions N E utilization and synthesis are increased. If the stressor is
sufficiently severe or behavioral methods of coping are unavailable, then utilization of the transmitter may come to exceed synthesis and consequently concentrations of the amine decline (Anisman, 1984; Anisman et al., 1980a; Tsuda and Tanaka, 1985; Weiss et al., 1976). Not surprisingly, stressor severity influences the variations of N E turnover and levels, and it appears that the amine variations are provoked more readily in some brain regions than in others (Tanaka et al., 1982). In addition, organismic factors, such as the age of the animal, appear to be fundamental in determining the N E alterations, with older animals exhibiting greater vulnerability and more persistent decreases of N E than younger animals (Ida et al., 1982; Ritter and Pelzer, 1978). While the amine variations are relatively transient, persisting for as little as a few minutes to as long as 72 hr, depending on the stressor severity or the brain region examined (Weiss et al., 1981), aversive events have also been shown to proactively influence the response to subsequently applied stressors. In particular, in animals that had previously been exposed to an acute stressor, subsequent reexposure to cues that had been associated with the stressor come to increase the utilization of N E (Cassens et al., 1980; Irwin et al., 1986a), and reexposure to the stressor
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Neurochemical and behavioral consequences of stressors will more readily reinduce NE reductions (Anisman and Sklar, 1979; Irwin et al., 1986a). More recently, stressors have also been shown to increase unit activity in the locus coeruleus of cats (Abercrombie et al., 1986; Morilak et al., 1986; Rasmussen and Jacobs, 1986). Moreover, the locus coeruleus unit activity was also enhanced in response to stimuli previously paired with a stressor (Rasmussen et al., 1986). Such effects were not apparent in response to cues which previously signalled reward or to neutral cues. Interestingly, when these cats were confronted with potentially arousing stimuli (e.g. rats) overt signs of behavioral excitation were elicited, but no significant deviations from baseline activity were noted from the locus coeruleus (Abercrombie et at., 1986). Following repeated exposure to a stressor or during the course of protracted exposure to a continuous stressor (e.g. restraint) a further series of adaptive changes occur. The synthesis of NE increases appreciably, and as a result the reduction in transmitter levels is precluded (Irwin et al., 1986a; Kvetnansky et al., 1977; Roth et al., 1982). The enhanced synthesis may persist for some time after stressor termination, and concentrations of the amine may actually come to exceed those of nonstressed animals (Anisman et al., 1986; Irwin et al., 1986b; Roth et al., 1982). Presumably, the enhanced synthesis is essential for the organism to deal effectively with the ongoing stressor. The fact that the increased synthesis persists after stressor termination may be essential in assuring that amine supplies will be sufficient to deal with impending stressors. Just as the acute effects of stressors (e.g. the enhanced utilization) may be influenced by cues that had been associated with the stressor, it seems that the enhanced synthesis associated with a chronic stressor may be subject to conditioning-like effects (see Fig. 2). In particular, having been exposed to a repeated stressor which resulted in the neurochemical adaptation, later exposure to cues associated with the stressor resulted in increased accumulation of the NE metabolite, as well as increased concentrations of NE, suggesting that exposure to the stressor-related cues provoked a marked and rapid increase of NE synthesis (see Irwin et al., 1986a). The conditions which delay or preclude the neurochemical adaptation have not been extensively evaluated. It was demonstrated that when the stressor is applied at unpredictable times, the adaptation progresses more slowly than when the stressor is presented on a predictable basis (Anisman et al., 1986). It might be supposed that still slower adaptation occurs when the stressor regimen involves different types of stressors (as opposed to a single type of stressor applied repeatedly). It is our contention that a stressor regimen, which does not favor the development of adaptation, is more likely to be associated with depressive symptoms than a chronic, predictable, stressor regimen. Likewise, in those organisms in which the neurochemical adaptation does not develop readily (as a result of genetic or experiential variables), stressor-related depressive symptoms will be more likely to develop. The effects of chronic stressors are not limited to alternations in the synthesis and concentrations of NE. In a series of reports, Stone and his associates
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(Stone, 1979, 1983; Stone and Herrera, 1986; Stone and Platt, 1982; Stone et al., 1984, 1986; see review in Stone, 1987) as well as other investigators (e.g. Nomura et al., 1981; U'Pritchard and Kvetnansky, 1980) have demonstrated that following a chronic stressor regimen the sensitivity of fl-NE receptors is reduced, as is the sensitivity of the cAMP response to catecholamines. Inasmuch as chronic antidepressants result in a similar fl-NE down-regulation, Stone offered the view that the reduced sensitivity of the NE receptors and of the cAMP response associated with chronic stressors, like the response to antidepressant drugs, may reflect an adaptive change which limits the development of depressive symptoms (Stone, 1983). In accordance with this view, it was demonstrated that behavioral depression (i.e. immobility in a forced swim test and anorexia) was reduced in parallel with the development of the receptor subsensitivity (Platt and Stone, 1982; Stone and Platt, 1982). It might be noted at this juncture, that the reduction of fl-NE receptor sensitivity and the down-regulation of the cAMP response associated with chronic stressor application may be subserved by independent mechanisms. In particular, although chronic stressors have been shown to reduce the density of fl-NE
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receptors in rat cortex, this effect was relatively transient, being absent 24hr following stressor termination (U'Pritchard and Kvetnansky, 1980; see also Stone et al., 1984). In contrast, the cAMP response is reduced to a comparable degree immediately and 24 hr after a chronic stressor regimen (Stone et al., 1984). This does not necessarily imply that the mechanisms governing the response to a chronic stressor are different from those mediating the response to antidepressants, since some antidepressant agents have also been shown to reduce the NE-cAMP response without affecting the density of fl-NE receptors (Mishra et al., 1980). In considering the NE subsensitivity and the cAMP down-regulation associated with antidepressant therapy, it should be made clear that such effects are probably not secondary to the blockade of NE reuptake, since these effects are evident using atypical antidepressants (see review in McNeal and Cimbolic, 1986). It does seem, however, that there is a role for serotonin (5-HT) in the provocation of the receptor subsensitivity associated with antidepressant treatment. In particular, intracerebral administration of the 5-HT neurotoxin, 5,7 dihydroxytryptamine, resulted in the elimination of the fl-NE subsensitivity associated with desmethylimipramine treatment, but did not influence the down-regulated cAMP response (see Janowsky and Sulser, 1987). The mechanisms underlying the chronic stressor provoked fl-NE subsensitivity have yet to be elucidated, although it does appear that in rat hypothalamus phospholipid metabolism may be involved (Torda et aL, 1981). It remains to be determined, however, whether 5-HT activity plays a role in the development of the stressor induced NE receptor subsensitivity. The dopamine (DA) variations associated with stressors are less widespread than those of NE. In contrast to early reports that revealed increases or no change of DA concentrations in large tissue samples, later reports revealed marked reductions of DA and increases of utilization in certain brain regions. Reports by Kvetnansky et al. (1976) and Kobayashi et al. (1976) indicated that restraint stress produced marked DA reductions which were restricted to the arcuate nucleus of the hypothalamus. In other hypothalamic nuclei, DA concentrations were either unaffected or were increased by the stressor. It was subsequently determined, as well, that environmental insults profoundly influenced mesolimbic and mesocortical DA activity~ but did not affect nigrostriatal DA activity (Deutch et al., 1985; Herman et al., 1982; Herve et al., 1979; Thierry et al., 1976). For instance, several forms of stressors have been shown to increase DOPAC accumulation in the mesocortex and the nucleus accumbens, without appreciably influencing DOPAC accumulation in the substantia nigra (see Fig. 3). Moreover, it appears as if the mesocortex is particularly sensitive to the effects of the stressor and reductions of the amine are readily apparent (Anisman and Zacharko, 1986; Herman et al., 1982). Indeed, it was demonstrated that in the mesocortex, DA utilization may be enhanced by cues that had been associated with a previously applied stressor (Herman et al., 1982; see also Deutch et al., 1985). Additionally, it has been reported that the enhanced mesocortical DOPAC accumulation associated with
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FIG. 3. Dopamine (DA), DOPAC, and homovanillic acid (HVA) as a percent of control values (±SEM) in hypothalamus (Hypo), frontal cortex (Fc), nucleus accumbens (Nac), caudate, substantia nigra (SN), and ventral tegmentum (VTA) of mice that had received either 30 or 360 footshocks (1501~A, 2 sec duration) (from Anisman and Zacharko, 1986). Reprinted with the permission of the copyright holder, the New York Academy of Sciences, New York. an acute stressor may be prevented by pretreatment with the anxiolytic, diazepam, or by treatment with the fl-NE inhibitor, chlorpropanol, which acts as an anxiolytic, but without primary sedative action (Fadda et al., 1978; Fekete et al., 1981). Thus, it is conceivable that anxiety induced by the stressor is fundamental in provoking the mesolimbic/mesocortical DA changes. Following a chronic stressor regimen the mesocortical DA reductions ordinarily associated with an acute stressor may be absent. Unlike the enhanced synthesis which is responsible for the increased NE associated with repeated stress, there is some evidence suggesting that the DA adaptation is determined, at least in part, by moderation of the excessive DA utilization (Anisman and Zacharko, 1986; Herman et al., 1984). That is, although a chronic stressor enhances DA utilization, the DOPAC accumulation after such treatment is less pronounced than after an acute stressor. In accordance with the data indicating that DA mesocortical neurons are particularly responsive to stressors, Kramarcy et al. (1984) reported that the enhanced DOPAC accumulation associated with acute footshock was also accompanied by enhanced DA synthesis, as determined from the accumulation of [3H]-DA following incubation with [3H]-tyrosine. Curiously, following repeated stressor application, the enhanced DA synthesis associated with acute shock was absent. Unfortunately, the latter effect was exhibited in a separate experiment where the effects of acute shock were not monitored. The absence of the necessary comparison group in this experiment prevents a strong conclusion from being drawn. There are data available suggesting that aversive environmental events will influence DA receptor sensitivity. In particular, it has been demonstrated that like the progressive enhancement of the behavioral effects associated with repeated treatment with amphetamine, exposure to a stressor may augment the
Neurochemical and behavioral consequences of stressors behavioral response ordinarily elicited by amphetamine (Anisman et al., 1985; Robinson et al., 1985), and conversely, amphetamine treatment may augment the behavioral effects of a mild stressor (Antelman et al., 1980). Based on their work assessing electrophysiological recordings from DA neurons, Antelman and Chiodo (1983) suggested that repeated treatment with amphetamine (as well as repeated electroconvulsive shock) resulted in a time-dependent subsensitivity of DA autoreceptors (as gauged by the response to low doses of apomorphine). Presumably, the subsensitivity of autoreceptors would result in increased DA release ordinarily provoked by a stimulant. The data concerning the effects of stressors on serotonergic activity are less extensive than those concerning NE and DA, and there appears to be greater inconsistency, as well. Several investigators reported that stressful events may influence the turnover and/or concentrations of 5-HT (Joseph and Kennett, 1981; Kennett and Joseph, 1981). It has been demonstrated, for instance, that stressors will increase the utilization of 5-HT; however, it appears that the severity of the stressor required to alter 5-HT utilization is greater than that necessary to elicit the alterations of NE activity (Thierry et al., 1968). Other investigators (Hellhammer et al., 1983) have reported that stressors increase 5-HT concentrations in some brain regions (e.g. pons/medulla, septum, striatum), but decrease concentrations of the amine in other areas (midbrain, posterior hypothalamus). In the posterior hypothalamus the reduced 5-HT concentrations were accompanied by reduced levels of 5-HIAA. More recently, Dunn (1988) reported that a 15 min session of footshock resulted in increased accumulation of 5-HIAA and reduced concentrations of 5-HT in the prefrontal cortex and in the hypothalamus in CD-1 mice. With a longer stressor period (30min), amine utilization increased still further, as reflected by greater accumulation of 5-HIAA; however, following such a stressor regimen 5-HT levels were comparable to those of nonstressed animals, while brain tryptophan levels increased appreciably. Possibly, the increased availability of tryptophan resulted in increased synthesis of 5-HT, thus replenishing the amine stores. Paralleling some of these findings, Adell et al. (1988) reported that following chronic restraint, 5-HT levels increased in several brain regions. These increases were accompanied by increased accumulation of 5-HIAA, suggesting that the enhanced 5-HT concentrations likely stemmed from a compensatory increase in synthesis. In our laboratory, we observed (Shanks et al., 1988) profound alterations of 5-HT and 5-HIAA following application of footshock (360 shocks, 2 sec applied over 1.1 hr) in the mesolimbic cortex in 5 of 6 strains of mice tested (A/J, BALB/cByJ, C57B1/6J, DBA/2J, C3H/HeJ, but not in CD-I), while in hypothalamus there were no such reductions. Of course, as suggested by the data reported by Dunn (1988), a lesser amount of shock may have permitted expression of the 5-HT reductions in hypothalamus. In both the mesocortex and hypothalamus 5-HIAA accumulation was increased by the stressor treatment, but again this effect was strain specific. Thus, some of the divergent effects reported in the literature may be a reflection of the
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amount of stress applied or the strain of animal examined. Scant information is available concerning the contribution of coping factors to the alterations of 5-HT activity. It has been reported that uncontrollable shock induced 5-HT reductions more readily than did controllable shock, but this effect was evident only within the lateral septum (Sherman and Petty, 1980). In fact, Weiss et al. (1981) reported that in other brain areas, controllable shock was more likely to influence 5-HT concentrations, possibly suggesting that the 5-HT changes reflected the effort associated with the act of emitting an escape response. In addition to the amine variations associated with stressors, it has been reported that aversive events may influence opiate peptide activity. Opiate peptides and receptors have been identified in the central nervous system (Mansour et al., 1988), as well as in neuroendocrine systems, endocrine glands and plasma (Owens and Smith, 1987). fl-Endorphin has been found to be stored with adrenocorticotropic hormone (ACTH) in the pituitary and Met-enkephalin appears to be localized with catecholamines in the adrenal medulla (Owens and Smith, 1987). While the role of opiate peptides in mediating specific behaviors has, of course, not been fully elucidated, it was suggested (Swanson, 1983) that the presence of synaptic 'cocktails' favors multiple receptor activation and the development of complex behavioral states. Acute stressors have been shown reduce pituitary /~-endorphin, while increasing plasma levels of this opiate peptide in rats (Guillemin et al., 1977; Knepel et al., 1983; Madden et al., 1977). The latter effect has also been demonstrated in humans (Owens and Smith, 1987). The altered plasma endorphin levels have been observed following a variety of stressors, including surgery (Owen and Smith, 1987), child birth (Pancheri et al., 1985) and electric footshock (Knepel et al., 1983). In addition to accumulating evidence that stressors activate peripheral opioid mechanisms, there is evidence indicating that aversive events may exert potent central opiate effects (Pert, 1982). It was demonstrated that an acute session of footshock decreased enkephalin availability in the hypothalamus (Fratta et al., 1977; Rossier et al., 1978). Other stressors, such as food deprivation, mild-tail pinch and insulin-induced hypoglycemia decreased dynorphin activity in the cerebral cortex, while restraint or swim stress were ineffective in this respect. Cold exposure, however, produced a significant decrease in hypothalamic dynorphin activity (Morley et al., 1982). It might be noted at this juncture that there is also reason to believe that opiate peptide activity may be subject to conditioning-like effects much like those described for NE and DA. In particular, Chance et al. (1978) observed that cues associated with a stressor resulted in decreased binding of [3H]-N-Leuenkephalin. Although there is considerable evidence to suggest that stressors may produce alterations of opioid activity in cortical and hypothalamic sites, more recent data suggest that opioid variations are associated with the site of origin of the major ascending noradrenergic and dopaminergic pathways. In particular, Jacobs and his associates (Abercrombie and
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Jacobs, 1988; Abercrombie et al., 1988; Morilak et al., 1987a,b) observed that the stressor-induced conditioning of locus coeruleus unit activity is profoundly influenced by opioid manipulation. These findings have been substantiated by demonstration of considerable opioid immunoreactivity in and around the area of the locus coeruleus (Finley et al., 1981; Leger et al., 1983), a dense distribution of opioid receptors in the locus coeruleus (Atweh and Kuhar, 1977; Lewis et al., 1985) and inhibition of locus coeruleus unit activity by central opioid administration (Bird and Kuhar, 1977; Guyenet and Aghajanian, 1979). Jacobs has argued that stressors activate the locus coeruleus NE system, which results in fear and/or anxiety, The coactivation of an endogenous opioid system, which functions to inhibit the activity of the locus coeruleus, would favor adaptive behavioral coping. In addition to the potential modulation influence of opioids on central NE activity, it has also been demonstrated that stressor-induced alterations of central DA activity can be influenced by opioid administration. In particular, both Met- and Leuenkephalin, as well as their respective mu and delta receptors, have been identified in the ventral tegmental field (i.e. the VTA, the A I 0 region of the DA containing mesolimbic/mesocortical system). Uncontrollable stressors have been shown to augment endogenous enkephalin activity in the VTA and to induce accelerated DA turnover in mesolimbic/ mesocortical sites. Exogenous administration of enkephalin analogs into the tegmentum, in turn, has been shown to increase stressor-induced DA turnover in both the nucleus accumbens as well as the mesolimbic frontal cortex (Kalivas et al., 1983). Administration of the opioid antagonist, naloxone, prevents the stressor-induced variations of DA activity from the mesocortex (Miller et al., 1984). These results have recently been replicated by Kalivas and Abhold (1987) employing the shorter acting opiate antagonist, naltrexone. It was revealed that direct application of naltrexone into the A10 region attenuated the elevation of DA metabolism normally evident after footshock. It has also been reported that reductions of the neuropeptide, substance P, which appears to be localized in the tegmentum, attenuates mesocortical DA turnover in response to uncontrollable footshock (Bannon et al., 1983). There is also reason to suspect that sensitization/conditioning may be involved in enkephalin/neuropeptide interactions with central DA activity. For example, exposure to inescapable footshock potentiated the augmented DA turnover elicited by intracerebral administration of the enkephalin analog, D-Ala2-MetS-enkephalinamide (DALA) into the VTA, while naltrexone blocked this augmented neurochemical response. Moreover, prior administration of DALA has also been noted to sensitize animals to the subsequent effects of stressor application (Kalivas and Richardson-Carlson, 1986). In accordance with these findings, Cabib et al. (1984) demonstrated that repeated immobilization stress increased sensitivity to DA agonists, an effect which was prevented by prior administration of naloxone. It was concluded that chronic stressors may sensitize central DA systems owing to excessive production of central endogenous opioids. Together these data sug-
gest that although stressors appear to influence DA activity, such alterations may in turn be regulated by endogenous opiate systems and psychological variables associated with the stressor may come to influence the expression of neurochemical processes. In addition to alterations of central opioid concentrations, it appears that stressors may provoke alterations of central opiate receptors. For example, Nabeshima et al. (1985) reported that uncontrollable footshock engendered conformational changes of central opioid receptors as evidenced by increased binding at antagonist receptor sites and decreased binding at agonist receptor sites. Furthermore, Sirakova et al. (1988) reported that immobilization stress (i.e. 24 hr coupled with food and water deprivation) enhanced delta receptor binding, with little if any effect on mu receptor binding in rat whole brain. It is unclear whether these alterations stemmed from the immobilization procedure, the deprivation schedule imposed or a combination of the two. However, it will be noted that fasted rats exhibited decreased levels of fl-endorphin in the hypothalamus (Gambert et al., 1981).
3. BEHAVIORAL C H A N G E S ASSOCIATED WITH STRESSORS As indicated earlier, considerable attention has been devoted to the analysis of stressors on subsequent behavioral impairments. By far the greatest emphasis has been placed on the analysis of controllable and uncontrollable stressors on shuttle escape performance. Specifically, it was demonstrated that following exposure to escapable shock, shuttle escape performance is typically unaffected; however, in animals that were exposed to an identical amount of shock, applied in a yoked paradigm, severe disturbances of escape performance were apparent. The initial studies, conducted in dogs, demonstrated this effect to be relatively transient, disappearing within about 72 hr of stressor termination. These animals were described as being passive in the face of the stressor, without apparent attempts to escape from the aversive stimuli (Maier and Seligman, 1976). Later studies conducted in rats or mice provided a somewhat different behavioral profile. While inescapable shock reliably disrupted subsequent escape performance, the behavioral deficits were most apparent when the response was either associatively or motorically demanding (Anisman et al., 1978; Maier et aL, 1973). Typically, escape deficits were evident when animals were required to take several seconds of shock before escape was possible (see Fig. 4). Furthermore, unlike the description provided in studies in dogs, in mice and rats, shock onset almost invariably led to heightened motor activity, which decayed rapidly as the shock continued. The initial response excitation seen upon shock onset was evident irrespective of whether animals had initially been exposed to escapable or inescapable shock, whereas the decline in shock-elicited motor activity was particularly marked in mice that initially had been exposed to uncontrollable footshock or tailshock. Thus, it was suggested that the response excitation seen upon shock onset favored proficient responding in tasks
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