247

Brain Research, 551 (1991) 247-255 © 1991 Elsevier Science Publishers B.V. 0006-8993/91/$03.50 A DONIS 000689939116672M

BRES 16672

Controllable and uncontrollable footshock and monoaminergic activity in the frontal cortex of male and female rats Rob P.W. Heinsbroek, Frans van Haaren, Matthijs G.P. Feenstra, Pien Boon and Nanne E. van de Poll Netherlands Institute for Brain Research, Amsterdam (The Netherlands)

(Accepted 8 January 1991) Key words: Shock controllability; Noradrenaline; Dopamine; Serotonin; Frontal cortex; Corticosterone, Male and female rats

Effects of controllable and uncontrollable footshock on monoaminergic activity in the frontal cortex and plasma corticosterone levels were studied in male and female rats. Subjects were exposed to a shuttle-box procedure for a period of either 30 min (60 shocks) or 90 min (180 shocks). A shuttle response ended shock presentation for escape subjects, whereas their yoked, same-sex, counterparts were unable to escape from shock presentation. A third group was exposed to the experimental environment, but did not receive any shocks. Concentrations of noradrenaline, serotonin and dopamine and their major metabolites were measured in the frontal cortex by high performance liquid chromatography with electrochemical detection. Plasma corticosterone was measured by radioimmunoassay. Results of this experiment show that: (1) exposure to the experimental environment without shock already increased the activity of all 3 transmitter systems. In particular, serotonin was very responsive to mere confinement to the shuttle-box. Changes induced by exposure to the experimental environment were similar for males and females. (2) Presentation of footshocks further increased transmitter activity. The activation of noradrenaline and dopamine was larger after uncontrollable shock than after controllable shock. Moreover, uncontrollable shock resulted in higher serotonin levels than controllable shock. (3) Sex-dependent effects of controllability were found for noradrenaline and dopamine, but not for serotonin. Differences in catecholaminergic activity between controllable and uncontrollable shock were larger in females than in males. (4) In both males and females, corticosterone levels in plasma were increased by exposure to the experimental environment. A further elevation was found in response to footshock presentation, which was independent of the controllability of shock. INTRODUCTION In rats, differences between the sexes in response to aversive stimulation have been osbserved both at the physiological and behavioral level. For instance, higher plasma levels of corticosterone ( C O R T ) and adrenocorticotrophin h o r m o n e ( A C T H ) have been measured in females than in males after various types of aversive stimulation 8,15,16'18'19. Similarly, exposure to aversive stimulation p r o d u c e d larger increments in plasma levels of catecholamines, prolactin, vasopressin and oxytocin in females than in males 6'19"43. Recently, sex differences in physiological responses to aversive stimulation were also observed in central parameters. Exposure to inescapable footshock (IS) activated central noradrenergic ( N A ) , d o p a m i n e r g i c ( D A ) and serotonergic (5-HT) systems to a larger extent in females than in males. M o r e o v e r , the increased activity of central N A neurons was accompanied by a decrease in tissue levels of N A , and the N A depletion was m o r e p r o m i n e n t in males than in females 14. Behavioral consequences of IS have also been found to be sex-dependent. Males and females were tested in a

shuttle-box escape task at various intervals after exposure to IS. W h e r e a s the shuttle-box escape behavior of males was seriously disrupted after prior exposure to IS, a similar but less p r o m i n e n t effect was found in females 13. During exposure to IS, suppression of l o c o m o t o r activity in the presence of shock was m o r e p r o n o u n c e d in male rats than in female rats and this behavioral suppression was found to correlate positively with the behavioral deficit subsequently o b s e r v e d in the shuttle-box escape task 26. Behavioral differences b e t w e e n the sexes have also been observed in different avoidance p r o c e d u r e s and it has been suggested that b e h a v i o r a l inhibition induced by aversive stimulation in males m a y explain the sex differences in passive and active avoidance p r o c e d u r e s 12" 32-36

In males, it is well-established that the physiological and behavioral effects of aversive stimulation are a function of the presence or absence of behavioral control over the presentation of stimulation. U n c o n t r o l l a b l e shock interferes with subsequent avoidance-escape performance and it has been d e m o n s t r a t e d that this deficit is minimized when shocks are controllable 21. A l t e r e d

Correspondence: R.P.W. Heinsbroek, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands.

248 neurotransmitter-functioning has been implicated to mediate the deleterious behavioral effects of uncontrollable shock. In particular, NA has been associated with shock-induced behavioral disturbance 39'4°. Uncontrollaand is more likely to result in a decrease in the transmitter content than controllable shock 3°'39'4°. Re-

duced by uncontrollable and controllable shock have been found to show a different time-dependent pattern during and after exposure to shock. Elevated C O R T levels were found for a longer period after uncontrollable shock as compared to controllable shock 27. Central N A activity was found to be higher after uncontrollable shock compared to controllable shock only when shock ex-

duced central levels of N A have been associated with a diminished capacity to initiate and maintain motor

posure was prolonged. After a relatively brief exposure to shock, controllability resulted in a larger activation of

activity, leading to disturbed performance in avoidanceescape tasks where high activity is required 39'4°.

central N A in comparison to uncontrollable shock 3°. These time-dependent changes appear to reflect the gradual

Although sex differences have been described with respect to physiological and behavioral responses to uncontrollable aversive stimulation, it is u n k n o w n

acquisition of an effective coping response 3" and sustained activation if control is not present 27. The present experi-

ble shock induces a more rapid utilization of central N A

whether or not male and female rats differentially respond to the presence or absence of control over

ment studied neurochemical and hormonal consequences of 30 min and 90 min uncontrollable and controllable footshock presentation in male and female rats.

aversive stimulation. The present experiment was therefore designed to investigate the effects of controllability on neurotransmitter activity in male and female rats.

MATERIALS AND METHODS

Measurements were not limited to central NA parameters but also involved the D A and 5-HT systems. These latter transmitter systems have not been studied as

Subjects. Fifty-six male and 56 female Wistar rats were obtained from the Animals House TNO (Zeist, The Netherlands). Animals were 9 weeks old upon arrival. They were group-housed in standard cages (single-sex) and maintained under a reversed light-dark cycle (lights on from 7:00 p.m. to 7:00 a.m.). Prior to experimentation subjects were weighed twice a week in the experimental room. In the animal-quarters food and water were always available to the subjects. Apparatus. Experiments took place in 3 locally constructed shuttle-boxes. The floor (45 cm long, 25 cm wide) consisted of 30 grids spaced 1.5 cm apart and was connected to a Grason-Stadler shock source (model 700). The back wall and the two side walls (23 cm high) as well as the cover of the box were made of black Plexiglas. The front wall was made of transparent Plexiglas. A metal plate in the centre divided the box in 2 compartments of equal size. A rectangular opening (6.9 x 7.9 cm) in the centre of the metal plate provided access to both sides of the box in 2 of the 3 shuttle-boxes (escape and control). No opening was present in the metal plate of the 3rd shuttle-box (yoked). White houselights were mounted on the side walls in both compartments of each box, 21 cm above the gridfloor. All 3 shuttle-boxes were placed in soundattenuated enclosures (Grason-Stadler model 1101) with a fan to provide fresh air (70 dB background white noise). Programming of the experimental conditions was accomplished using Grason-Stadler 1200-Series programming equipment, located in the experimental room itself. Procedure. All subjects were run in same-sex triplets (n = 8). One of the subjects was allowed to control the duration of the shock presented in the shuttle-box (escape), one subject received the same duration shock as the escape subject but could not control shock duration (yoked), while the 3rd subject did not receive any shocks (control). Shocks (1 mA) were presented on a variable interval 30 s (VI 30) schedule. The minimum interval was 10 s. The escape subject could control shock duration by moving from one compartment into the other one through the opening in the metal plate (shuttle response). The latency to escape from shock was recorded. Shock duration was 30 s when no response occurred. The yoked animal was exposed to the shock duration determined by the escape subject, but could not escape from shock presentation. Finally, control subjects were placed in the 3rd shuttle-box for the duration of the experiment without receiving shocks. A door opening was present in the 3rd box allowing the subject to freely shuttle from one side of the box to the other. Different groups of same-sex triplets were exposed to the experimental conditions which lasted either 30 min or 90 min.

extensively as N A with respect to controllability, but several findings indicate that D A and 5-HT are also differentially affected by uncontrollable and controllable shock23.27,40. Changes in N A and 5-HT activity induced by aversive stimulation can be observed in most of the areas innervated by these transmitters, but the response of central D A is region-specific. The mesocortical D A innervation of the frontal cortex (FCX) is more sensitive to aversive stimuli than other D A systems 1'4"9'2s. Moreover, previous experiments with respect to sex differences in neurochemical responses to shock showed that the shock-induced changes in N A and 5-HT activity in the FCX were very similar to changes observed in the hypothalamus, the amygdala, the striatum, the mesencephalon and the medulla/pons area of the male and female brain 14. Therefore, studying neurotransmitter activity in the present experiment was limited to the FCX only. To obtain an accurate impression of the neurochemical responses to controllable and uncontrollable shock, both transmitter and metabolite concentrations were measured simultaneously. Experimental data strongly supports the suggestion that changes in metabolite concentration reflect changes in utilization of the transmitter 1'4'~1. Plasma C O R T levels were also determined to provide an index of the shock-induced activation of the pituitary/adrenal axis. Uncontrollable aversive stimulation has been found to induce a higher or longer lasting activation of the pituitary/adrenal axis than controllable aversive stimulation5'7"27. Both the hormonal and neurochemical changes in-

249 Subjects were sacrificed by rapid decapitation immediately after the session. Home-cage control groups (n = 8) were included and consisted of experimentally-naive animals sacrificed immediately after being taken from their home-cage (HC). Trunk blood was collected in heparinized tubes and the brain was rapidly removed from the skull. A frontal cortex sample was taken by cutting the frontal pole in a dorso-caudal to ventro-rostral direction; small remains of the tuberculum olfactorium were removed from the ventral side. Brain samples were frozen on dry ice and stored at -80 °C until assayed. Determination of free NA, DA, 5oHT, MHPG, DOPAC, HVA and 5-HIAA was established by using HPLC procedures with electrochemical detection as previously described by Westerink 41. Blood samples were centrifuged and plasma was stored at -20 °C. CORT was measured by radioimmunoassay.

RESULTS

Behavioral data Fig. 1 shows the mean response latencies for the escape subjects presented per block of 20 trials. Analysis of variance (ANOVA) with the factors sex, session duration and trial block was used to evaluate the existence of possible differences between the treatment groups. Latency scores were log-transformed to improve homogeneity of variance 44. Shock-escape latencies rapidly decreased during the first three block of 20 trials, F2,56 = 88.56, P < 0.001. Escape latencies appeared longer for males than for females during the first 20 trial block, but this difference disappeared with prolonged training (sex x trial block, F2,56 = 5.41, P < 0.01). Fig. 1 shows that shock-escape latencies for the subjects exposed to the 90 min session remained low during trials 60-180. Biochemical data Figs. 2 and 3 show the concentrations of NA, 5-HT and D A and their metabolites in the FCX as well as the plasma C O R T for the different groups of subjects. Treatment effects were analyzed in 2 ways. First of all, effects of exposure to the test box without shock were evaluated by ANOVA with sex and session duration (0, 30 and 90 min) as main factors. For the 0 min exposure home-cage data were used. Secondly, effects of shock and controllability of shock were analyzed by ANOVA with sex, session duration (30 and 90 min) and treatment (escape, yoked and control) as main factors. Home-cage data were not included in this second analysis. For post-hoc tests Newman-Keuls multiple comparisons were used (a = 0.05). NA and MHPG In Fig. 2 data for NA, M H P G as well as the M H P G / N A ratio is presented. A N O V A including homecage controls and groups exposed to the test box for 30 or 90 min without shock, showed that NA tended to decrease as a function of exposure to the test box, F2,42

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= 3.25, P < 0.05. Changes were small, and post-hoc tests did not reveal differences between particular groups. A N O V A including escape, yoked and control groups did not reveal any significant effect. M H P G levels were also affected by mere exposure to the test box, F2,42 = 4.43, P < 0.05. Post-hoc tests showed that M H P G was elevated after 30 min but no longer after 90 min. Similarly, the M H P G / N A ratio was transiently increased, F2,42 = 3.80, P < 0.05. Footshock presentation resulted in substantially higher M H P G concentrations than mere exposure to the test box, F2,84 -- 70.80, P < 0.001. Post-hoc tests not only showed significant elevations of M H P G in escape and yoked groups, but also higher M H P G concentrations in yoked as compared to escape groups. Furthermore, treatment interacted with sex, F2,84 = 3.01, P < 0.05: significant differences between yoked and escape conditions were only present in females. In addition, M H P G levels were significantly higher in yoked females as compared to yoked males, whereas sex differences were not found in escape groups. The M H P G / N A ratio was also increased in escape and yoked groups, F2,84 = 84.08, P < 0.001, and the ratio was higher in yoked than in escape groups. A marginally significant interaction between treatment and session duration was found for MHPG/NA, F2,84 = 2.75, P = 0.07: differences between escape and yoked groups were significant after 90 min but not after 30 min.

5-HT and 5-HIAA Fig. 2 also presents data for 5-HT, 5-HIAA and the 5-HIAA/5-HT ratio. 5-HT concentrations in the FCX were not significantly altered by placement in the test box for 30 or 90 rain. Exposure to shock did however result in significant alterations in 5-HT concentration, F2,84 = 6.70, P < 0.01 (treatment), and post-hoc tests showed that 5-HT in yoked groups was higher compared to escape and control groups. A significant overall effect of sex was also noted, F1,84 = 8.37, P < 0.01: 5-HT concentrations were higher in females. Significant increments in 5-HIAA and the 5-HIAA/

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Fig. 2. Mean concentrations (+ S.E.M.) of NA, MHPG, 5-HT and 5-HIAA as well as the MHPG/NA and 5-HIAA/5-HT ratios in the frontal cortex (FCX) of male and female rats, measured immediately after a 30 min or 90 min exposure to controllable (escape) or uncontrollable (yoked) shock, or to the test box without shock (control). HC represents data from home-cage control male and female rats.

5-HT ratio were found after 30 and 90 min confinement to the test box without shock, /72,42 = 15.67, P < 0.001 (5-HT) and F2,42 = 21.51, P < 0.001 (5-H1AA/5-HT). Shock presentation further increased these variables, ]72,84 = 31.72, P < 0.001 ( 5 - H I A A ) and/72,84 = 29.55, P < 0.01 (5-HIAA/5-HT). However, differences between shock (escape and yoked) and control conditions were significant after the 90 min session only and not after the 30 min session, resulting in significant interactions between treatment and session duration, F2,84 = 10.52, P < 0.001 ( 5 - H I A A ) and /72,84 = 10.03, P < 0.001 (5H I A A / 5 - H T ) . Effects of treatment were i n d e p e n d e n t of sex, and differences between escape and yoked groups were not found. Finally, 5 - H I A A and 5 - H I A A / 5 - H T

were higher in females than in males, Fl,s4 = 26.57, P < 0.001 ( 5 - H I A A ) and F1,84 = 12.32, P < 0.01 (5HIAA/5-HT).

DA, D O P A C and HVA Fig. 3 depicts data for D A , D O P A C and HVA. D A concentration in the F C X was altered by exposure to the test box without shock, F2A2 = 5.68, P < 0.01, elevated D A levels were found after 30 min but not after 90 min exposure. Effects of shock were indicated by a significant interaction between treatment and session duration, F2,s3 = 7.53, P < 0.001: after the 90 min session D A concentration was significantly higher in yoked groups compared to control groups.

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Fig. 3. Mean concentrations (+S.E.M.) of DA, DOPAC and HVA, as well as the DOPAC/DA and H V A / D A ratios in the frontal cortex ( F C X ) of male and female rats, measured immediately after a 3 0 min or 90 min exposure to controllable (escape) or uncontrollable (yoked) shock, or to the test box without shock (control). HC represents data from home-cage control male and female rats.

Exposure to the test box without shock also affected D O P A C levels,/72,42 = 3.23, P < 0.05: the DOPAC level after 30 min exposure was slightly elevated and significantly higher than the D O P A C level after 90 min. Exposure to the test box without shock did not affect HVA nor the ratio scores of both D A metabolites. Shock presentation significantly elevated D O P A C and DOPAC/DA values, F2,84 = 124.80, P < 0.001 and F2,83 = 184.40, P < 0.001 respectively. In addition, the shockinduced increment in D O P A C and D O P A C / D A was significantly higher in yoked groups compared to escape groups. Session duration was also significant for DOP A C , FI,84 = 5.77, P < 0.05 and for D O P A C / D A , F1,83 = 20.74, P < 0.001. In addition, the effect of session

duration for the D O P A C / D A ratio depended on treatment, F2,83 = 4.00, P < 0.05. A reduction in D O P A C and D O P A C / D A could be observed in groups exposed to shock when comparing the 30 and 90 min sessions. With respect to the D O P A C / D A ratio this reduction was more obvious in escape groups than in yoked groups. No main effect of sex or interactions with sex were noted for DOPAC and D O P A C / D A . HVA and the H V A / D A ratio were strongly increased by shock, F2,84 = 78.09, P < 0.001 and F2,83 = 112.54, P < 0.001 respectively. Contrary to DOPAC, HVA was further increased by prolonged exposure to shock, F1,84 = 6.27, P < 0.05 (session duration) and a similar effect was found for H V A / D A , F1,83 = 4.05, P < 0.05. For

252 HVA, session duration interacted with treatment, F2,84 ~-5.45, P < 0.01: in yoked but not in escape groups HVA was further increased after 90 min, resulting in a significant difference between escape and yoked groups after 90 and not after 30 min. For both HVA and HVA/DA treatment effects were found to be sexdependent, F2.84 = 3.98, P < 0.05 and F2.83 = 3.25, P < 0.05 respectively (treatment × sex). In yoked groups significantly higher values for HVA and HVA/DA were found in females compared to males, whereas sex differences were not present in escape groups. In females, HVA levels in the yoked condition were significantly higher than HVA levels in the escape condition, whereas, in males, a similar difference between conditions was not found.

Corticosterone Both the mean plasma levels of CORT and the variability in CORT data were considerably higher in females than in males (Fig. 3). Therefore, CORT data were analyzed for males and females separately. In both males and females, confinement to the test box without shock affected CORT concentrations in plasma, F2,21 = 10.40, P < 0.001 (males) and F2,2~ = 3.65, P < 0.05 (females). After 30 min exposure, a significant increment (approximately 200% of the home-cage level) was found in males and females. After 90 min, CORT in males was reduced to 26%, which was significantly lower than the level measured after 30 min. In females, the CORT level found after 90 min (132%) was not different from the level measured after 30 min, or from the home-cage control level. Shock presentation strongly increased plasma levels of CORT in both males, F2,42 = 155.91, P < 0.001 and females, F2,42 = 31.38, P < 0.001. Session duration was significant for males, F1,42 = 13.26, P < 0.001 and females, F1,42 = 7.36, P < 0.01, whereas only in males session duration interacted with treatment, F2,42 = 10.94, P < 0.001. Post-hoc analysis of the data of male groups revealed the already noted time-dependent decrease in CORT in control groups. In females, a decrease in CORT from 30 min to 90 min apparently involved all 3 conditions. In neither males nor females were differences noted between the escape and yoked condition. DISCUSSION The present experiment studied the effects of controllable and incontrollable footshock on neurochemical and hormonal variables in male and female rats. The results show that exposure to the experimental environment without the presentation of shock may significantly affect the activity of NA and D A terminals in the FCX. NA and

DA activity were increased after 30 rain exposure to the experimental environment, but no longer after 90 min. 5-HT activity was increased to a greater extent and was not reduced after 90 min. The neurochemical changes induced by exposure to the experimental environment were not sex-dependent. CORT also increased for males and females by mere exposure to the experimental environment for 30 min. CORT was decreased after 90 min, but more so in males than in females. The presentation of controllable and uncontrollable shock induced neurochemical and hormonal changes which were larger than those observed after mere exposure to the experimental environment. Changes in neurochemical parameters, but not in CORT, were different for groups exposed to controllable and uncontrollable shock. Effects of controllability were found to be sex-dependent for NA and DA, however, not for 5-HT. The presentation of uncontrollable shock produced an increase in the NA- and DA-metabolites MHPG, D O P A C and HVA which was larger than that observed after presentation of controllable shock, in addition, continued exposure to uncontrollable but not to controllable shock increased DA concentrations. These findings indicate that controllability of shock reduces the extent to which catecholaminergic systems in the FCX are activated. Similar effects of controllability have repeatedly been reported for central NA 2"27'3°4°. The effects of controllability have usually been established by measuring NA concentrations. Depletion of NA has been reported after uncontrollable shock but was largely prevented by controllability of s h o c k 2'27'30"40. In the present experiment, a small reduction in NA concentration was induced by placement in the test box, but shock presentation did not result in an additional decrease in NA. The shock presentation may have been too mild to induce alterations in NA content, as shock duration was efficiently limited by the escape subject in the present experiment. Maynert and Levi ze have shown that the extent of depletion of central NA is directly dependent on shock duration: shocks of longer duration have a greater effect on NA concentration than shocks of shorter duration. Changes in MHPG concentration however, provide an accurate measure of NA activity 11. The MHPG results of the present experiment therefore confirm the notion that uncontrollable aversive events will result in a stronger activation of NA neurons than controllable aversive events. Data concerning the effects of shock controllability on the response of central D A systems only exist for D A and not for DA-metabolites. Shock-induced alterations in DA levels are less consistent compared to NA levels. Increments 24, decrements 3'~7'28 or no changes 1°'25'29 in DA concentrations have been reported after uncontrol-

253 lable shock. Consequently, differential effects of uncontrollable and controllable shock on central D A were either not found or were difficult to interpret 2'27'4°. The present observations on both transmitter concentrations and metabolite concentrations clearly indicate that, similar to NA, the activity of D A in the PFC is increased more potently by uncontrollable than by controllable shock. Shock-induced increased values of D O P A C and D O P A C / D A , found after 30 min, dropped when shock exposure was extended to 90 min. This decline was more prominent if shock was controllable than when shock presentation could not be controlled. The finding that HVA and HVA/DA were increased after prolonged exposure to shock presentation indicates that the Omethylation of D O P A C to HVA is delayed during shock-induced activation of DA. Alteration of this metabolic step has previously been suggested to occur if the D A activity is changed 4'42. Previous experiments have shown that female rats generally respond with higher elevations of brain D A and NA metabolite concentrations than males when exposed to uncontrollable footshock TM. The present data confirm these findings and, most importantly, indicate that sex differences may depend on the controllability of shock presentation. Higher levels of M H P G and HVA were observed in females compared to males when shock presentation could not be controlled, but not when the presentation of shock could be controlled. These findings suggest that female rats are more responsive to the absence of control. Alternatively, the sex-dependent effects of controllability may have resulted from the fact that females more rapidly than males acquired the shock-escape response. The escape latency data show that males were initially somewhat slower in terminating shock than females. Experiments of Tsuda and Tanaka 3° have shown that control over shock presentation will only reduce NA activity in the brain once the escape response is firmly established. During acquisition of the escape response, NA was activated to an even higher extent compared to uncontrollable shock presentation. Similarly, effects of shock controllability on central NA activity were not observed if the escape response was too complex 31. These observations show that the beneficial effects of control over shock depend on response requirements and response acquisition. In the present experiment sex differences in escape latency were small and temporary, males and females responded with equal accuracy during the major part of both the 30 and 90 min sessions. Nevertheless, these observations cannot exclude the possibility that the response requirements of the shuttle-box escape procedure differ for males and females. In other words, the presently observed sexdependent effects of controllability may depend on the

nature of the escape response. Further experimentation, systematically varying the response requirements, are required to establish possible sex differences in the impact of controllability per se. Differential effects of shock-controllability were also observed with respect to 5-HT in the FCX: 5-HT concentration increased after uncontrollable shock but not after controllable shock. Previous reports have presented evidence of a decrease in 5-HT levels if shock was uncontrollable and no effects or an increase if shock was controllable 23'4°. As discussed for NA and DA, differences in the effects of controllable and uncontrollable shock on 5-HT may depend on various experimental conditions like the duration of the session and the nature of the coping response 27'3°'31. In addition, it remains to be established which particular aspect of the 5-HT neuronal activity is responsive to controllability. The present 5-HIAA data suggest that utilization of 5-HT was increased equally after controllable and uncontrollable shock, making it more likely that other mechanisms like synthesis or uptake of 5-HT are involved in the differential response of 5-HT to controllable versus uncontrollable shock. The present experimental design may not have been very suitable for establishing effects of shock-controllability on 5-HT activity in the PFC. Apparently, exposure to the experimental environment was sufficient to induce a large increment in the 5-HIAA concentrations in this brain area, although footshocks were never presented. The 5 - H I A A response to the experimental environment was substantial (additional increments induced by shock were only found after the 90 min session) and may very well have interfered with effects of shock-controllability on 5-HIAA levels. At present it is unclear what particular aspect of the experimental environment induced a 5 - H I A A response. The finding that controllability did not affect the C O R T response to shock could be explained by assuming that a single shock-session is insufficient to induce differences between uncontrollable and controllable shock. This interpretation is supported by previous failures to find differential effects of controllability on plasma C O R T after one session 2°'3°'37,38. Lower C O R T levels after controllable shock than after uncontrollable shock are typically found after multiple sessions 5'7,3°. On the other hand, effects of controllability on C O R T have been found by studying the rate of decline after a single shock-session 27, uncontrollable shock resulting in elevated C O R T levels for a much longer period than controllable shock. In summary, the results of the present experiment provide additional information with respect to differential neurochemical responses to uncontrollable and controllable aversive stimulation. Females were more re-

254 s p o n s i v e to u n c o n t r o l l a b l e shock than males, but sex

lable versus c o n t r o l l a b l e shock was less o b v i o u s but m a y

d i f f e r e n c e s in c a t e c h o l a m i n e r g i c activity w e r e a b o l i s h e d if

d e v e l o p m o r e gradually.

shock was c o n t r o l l a b l e . T h e s e findings m a y indicate that

m e n t s are n e e d e d to f u r t h e r e x a m i n e sex d i f f e r e n c e s in

f e m a l e s are m o r e r e a c t i v e to shock than m a l e s if control

the n e u r o c h e m i c a i , phsyiological and b e h a v i o r a l conse-

o v e r shock is not available. D i f f e r e n t i a l activation of

q u e n c e s of controllability.

O b v i o u s l y , additional experi-

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