Effects of oral yohimbine on the performance of a perceptual-motor task in nonhuman primates

Pergamon

Journal of Anxiety Disorders, Vol. 8, No. 4, pp. 301-310.1994 Copyright 0 1994 Else&r Science Ltd Printed in the USA. All rights reserved 0887-6185194 $6.00 + .OO

0887-6185(94)00019-O

Effects of Oral Yohimbine on the Performance of a Perceptual-Motor Task in Nonhuman Primates STEVENFRIEDMAN,PH.D. Department of Psychiatry, SUNY/Health Science Center at Brooklyn

MICHAEL

W. ANDREWS,PH.D.ANDLEONARDA. ROSENBLUM,PH.D.

Department of Psychiatry and Primate Laboratory, SUNY/Health Science Center at Brooklyn

JEREMY COPLAN,M.D.

Department of Psychiatry, Columbia University, College of Physicians and Surgeons Abstract - Ethical and practicalconstraintslimit the range of studiesthat can be performedon patientswithanxiety disorders. A nonhuman primate model allows for a variety of experimental manipulations that cannot be attempted in humans. In this paper, we report on the further development of a nonhuman primate model of pathological anxiety, which we have labeled acute endogenous distress (AED). Bonnet macaques were challenged with the oral administration of the alpha-2 antagonist, yohimbine. Whereas our previous work has documented the behavioral response to yohimbine provocation, in this paper we report the drug’s effects on the monkey’s performance on a novel video computer device that presents well defined perceptualmotor tasks of varying difficulty. Under yohimbine challenge, animals virtually stopped initiating a complex task requiring sustained attention and perceptual-motor control; however, they showed no decrease in initiating and performing an easy task under the same pharmacological challenge, thus demonstrating that the effect was cognitive rather than motor in nature.

This work was supported in part by NIMH Grants #42545, #lR24RR05321, and #MHl5965, and funds from the Department of Psychiatry’s Practice Plan. Correspondence should be addressed to Steven Friedman, Ph.D., Department of Psychiatry/Box 1203, State University of New York/Health Science Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, New York 11203. 301

302

S. FRIEDMAN ET AL.

Panic disorder remains an important health care issue in urgent need of greater understanding (Barlow, 1988). Ethical and practical constraints, however, limit the range of scientific studies that may be performed using human subjects. In our laboratory we have successfully developed a nonhuman primate model directly relevant to panic disorder (Coplan, Rosenblum, Friedman, Bassoff, & Got-man, 1992; Sunderland, Friedman, & Rosenblum, 1989; Friedman, Sunderland & Rosenblum, 1988). Using sodium lactate and yohimbine, which have proven effective in eliciting panic attacks in panicprone humans (Charney, Woods, Goodman, & Heninger, 1987; Charney, Heninger, & Breir, 1984; Liebowitz, Fyer, Gorman, Dillon, Appleby, Levy, Anderson, Levitt, Pulig, Davies, & Klein, 1984), we have reliably produced several features of panic attacks in unrestrained monkeys. In our earliest studies (Friedman et al., 1988) lactate was found to produce temporally circumscribed episodes of agitation, wariness, and motor responses normally elicited under stressful and threatening conditions for these monkeys. Since panic disorder in humans almost always includes cognitive symptoms such as the fear of dying, losing control, or going crazy, and such symptoms are not ascertainable in animals, we have labeled the symptoms induced by pharmacological challenge in our subjects as Acute Endogenous Distress (AED). We have also shown that pretreatment with imipramine, a tricyclic antidepressant, and alprazolam, a triazolobenzodiazepine, blocks the AED symptoms produced by administration of sodium lactate (Sunderland et al., 1989). In part because the mechanism of action of sodium lactate is poorly understood, we have focused one aspect of our work on AED susceptibility to a relatively specific noradrenergic probe, the alpha-2 antagonist yohimbine (Coplan et al., 1992). We have studied both maternally reared animals and animals reared under conditions of maternal deprivation. Yohimbine at dosages ranging from 0.2 to 2.0 mg/kg significantly increased tension (such as vocalization, clinging, and toe curling) and behavioral inhibition, and decreased species-typical “normal” behaviors in maternally reared subjects. Deprivationreared subjects showed blunted response to yohimbine. Thus far, our studies have focused on spontaneously occurring behaviors in our subject monkeys. Based on our knowledge of the behavioral repertoire of these animals (Kaufman & Rosenblum, 1966), the pattern of spontaneous behaviors provides a considerable amount of insight into their emotional state. Such analyses, however, provide little opportunity for detailed analysis of cognitive functioning. In contrast, in human patients some of the most critical elements for the diagnosis of panic are cognitive symptoms such as the report by the patient of a fear of dying, losing control, or going crazy. In addition, fear of having another panic attack or what has been called “fear of fear” (Chambless & Goldstein, 1986) is a fundamental component of the disorder. Patients who report that they are experiencing panic/anxiety are also more likely to report catastrophic cognitions and a general urge to flee the situation (Kenardy, Evans, & Oei, 1989). In addition, patients often complain of their “mind going blank” or the inability to think clearly when they experience high levels of anxiety and/or panic (Dalgleish & Watts, 1990). Along these lines, human studies have measured subjects’ reports of cognitive symptoms and catastrophic cognitions during pharmacological challenges, and have found

Y0HmEaNFiANDPRIMA,lEs

303

that patients often reported some version of “I must get out of here” (Bonn, Harrison, & Rees, 1971). Because it is not possible to employ verbal reports in our animal subjects, we elected to directly explore cognitive functioning under pharmacological challenge by investigating performance on previously learned, well defined percep tual-motor tasks during experimental induction of the AED state. Using well defined tasks offers two major advantages in pursuing analyses of cognitive functioning. First, because task parameters may be kept constant across sessions for a particular task, a reliable baseline of performance may be established; subsequent deviations from this baseline may be related to the experimental manipulations. Second, because parameters of the tasks are under the control of the experimenter, it is possible to present the monkey with a range of tasks that vary in the demand placed on both motor and cognitive functioning. Recently a double-blind crossover study was performed (Albus, Zahn, & Breier, 1992) in which 20 mg of yohimbine, or placebo, was administered as a challenge to eight panic patients on placebo treatment, seven panic patients on alprazolam treatment, and twelve normal controls. In an attempt to minimize the subject’s concentration on bodily sensations, an important factor in cognitive theories of panic attacks (Barlow, 1988; Clark, 1986; Beck & Emery, 1985), subjects were challenged in situations that required active coping and were designed to distract subjects from the physiological changes induced by yohimbine challenge. The subjects were required to engage actively in two stressors, a remedial arithmetic task and a continuous performance task. Although panic patients, relative to normal subjects, had higher baseline levels of subjective ratings of panic, anxiety, and nervousness, and showed increased heart rate as a result of the yohimbine challenge, they did not show any significant differences on performing the two tasks. The authors concluded that “although anticipation of the task and task performance induced a more pronounced increase in autonomic activity than yohimbine per se, patients did not develop panic attacks” and “tasks that patients can cope with actively seem to prevent patients from developing panic attacks by distracting them from focusing on drug-induced bodily changes” (p. 350). In the present study, our assessments were based upon changes in performance on two tasks resulting from the oral administration of yohimbine. Yohimbine was selected as the panicogenic agent for several reasons. First, it has been shown to be effective in eliciting anxiety-like symptoms in both human and nonhuman primates (Rosenblum, Coplan, Friedman, & Bassoff, 1991; Harris & Newman, 1987; Charney, Heninger, & Breier, 1984); without any evidence of motor impairment (based on observations in our laboratory). Second, the potential mechanism of yohimbine action has been well characterized (Chopin, Pellow, & File, 1986; Redmond & Huang, 1979). Third, in contrast to sodium lactate, yohimbine can be administered to our subject animals orally without stressing the animals with the procedure of capture and intravenous or subcutaneous infusion. We elected to use computer-generated video tasks derived from programs developed by Duane Rumbaugh and his colleagues (Andrews, 1993; Andrews & Rosenblum, in press; Rumbaugh, Richardson, Washburn, SavageRumbaugh, & Hopkins, 1989). Two tasks were used in the present study. The

304

S. FRIEDMAN

ET AL.

“hit” task was relatively easy; using a joystick, the monkey was required to move a cursor to hit a small, stationary target. The “chase” task was more difficult; the monkey had to use the joystick to “capture” a moving target. Completion of a task resulted in a special food-treat reward. To remove food pellets from the small reward cup (4 cm in diameter x 3Scm deep), monkeys had to engage in fine motor movements. The monkeys have demonstrated a high proficiency and consistency of performance in both tasks over more than a year and a half in our laboratory (Andrews & Rosenblum, in press).

METHOD Subjects Five maternally reared, socially experienced, and behaviorally normal bonnet macaque (M. radiant) males were used. Mean age at the start of testing was 13.8 years (range 11.5-16.5 years); mean weight was 12.6 kg (range 10.3-14.3 kg). Subjects lived and were tested in individual cages throughout the study, and were in visual, olfactory, and auditory contact with conspecifics. Drug Administration Yohimbine hydrochloride powder (Palisades Pharmaceutical) was dissolved within a fresh orange slice in order to provide each animal with a dosage of .25 mg/kg of body weight, the dosage shown to be most consistent in eliciting symptoms of AED (Rosenblum et al., 1991). Subjects rapidly consumed the orange presented at the front of their cage. Edeo Cognitive Task (VCT) For each subject, an XT-compatible computer controlled a color video monitor to present problems, activated a pellet dispenser to deliver reinforcement, and recorded performance. As described in detail elsewhere (Andrews, 1993), animals were trained to manipulate a joystick in order to contact a “target” with a computer cursor. When the target was contacted, an auditory signal was produced, followed by the delivery of a 190-mg food pellet into the reward cup. A two-second interval preceded presentation of the next game. Although subjects will play these games at reasonably high rates when food is freely available, to ensure consistent performance in the current study, subjects received all food via the VCT for two weeks prior to the pharmacological intervention. Two levels of game difficulty were used. In the “easy” task the animal was required to move the cursor to hit a stationary green rectangle (2.0 cm x 3.1 cm) that was randomly presented on one of four sides of the screen. The “hard” task required the animal to hit a green target, 2.0 cm x 2.7 cm, which moved in a clockwise path at 4.4 crnlsec, 5 cm from the border of the screen. The games were available throughout the day and night, seven days/week. Subjects had been well trained and had each completed approximately 200,000 games of varying levels of difficulty across an 1%month

YOHIMFtE’JEAND PRIMATES

305

period. Although subjects average 500 games each per day, there is a circadian variation in task engagement. A time of consistently high task engagement in the midafternoon was selected for manipulation in the present study. Subjects were stabilized on performance on the “easy” task for two weeks prior to the first administration of the drug. They continued on the easy task for six additional days after drug administration. They were then switched to the “hard task” for seven days prior to the second administration of the yohimbine. Procedure

On treatment days, subjects were administered .25 mg/kg yohimbine in an orange slice. Analysis focused upon the number of games played in the 60-minute time period from 30 to 90 minutes after administration of the orange on treatment days. This time sequence was chosen because it allows time for the absorption of the drug, and was most reflective of a drug effect in our prior work (Rosenblum et al., 1991). This one-hour period was compared to the same time period 24 hours before and 24 hours after drug administration for each task; previous research (Rosenblum et al., 1991) has shown that response to yohimbine was unaffected by repeated exposure to the drug. In light of the stable levels of performance and the innocuous procedure of drug presentation, no explicit placebo trials were conducted. The data were analyzed by condition (pre-drug, drug, and postdrug) and task (easy versus hard).

RESULTS The overall frequency of engagement in the two levels of task on days in which the yohimbine was not administered did not differ significantly [Mean number of games on pre/post days for “easy” = 107.0 (SD = 49.0); mean for hard game = 166.7 (SE = 113.9); F = .Ol, df= l/4; n.s.1. The ANOVA did reveal a significant task by condition interaction effect (F = 14.7; df = 218; p c .Ol). As reflected in Figs. 1 and 2, although administration of yohimbine did not significantly affect performance on the “easy” game (mean on drug day = 128.6 (SD = 73.2); F = 1.31, n.s.), performance on the “hard” task was dramatically decreased by the drug (mean on drug day = 15.8 (SD = 27.9); F = 8.3, df = 218, p < .Ol). It is noteworthy that in all instances in which games were played under the drug condition, all food pellets were readily removed from the food cup, reflecting subject’s continued capacity for this degree of fine motor control under yohimbine. Moreover, an analysis of the average latency to complete a game indicated that although under the “hard” condition, subjects generally played far fewer games during yohimbine challenge, if they did initiate a game, they were able to complete it successfully within a very brief time: latency to completion under yohimbine ranged from .6 to 1.0 second, which was not significantly different from the normal time to complete a game, and indicated that motor behavior was not adversely affected by yohimbine.

306

SFRIEDMANETAL.

EASY GAME DRUG = .25 mg/kg Yohimbine m

Subject 1

m

Subject 2

Esil

Subject4

m

Subject 5

=

Subject3

300 E

250

M E

200

s

150

P L A Y E

100

D

0

50

PRE-DRUG

POST-DRUG

DRUG DAY

DAY

DAY

HARD GAME DRUG = .25 mg/kg Yohimbine

G

350

2

300

E S

250

P L A Y E D

m

Subject 1

m

Subject2

69

Subject 4

m

Subject 5

m

Subject 3

200 150 loo 50 o

PRE-DRUG

DAY

FIG.~. NU!+~BEROF%ARD"GAMES

DRUG DAY

POST-DRUG

DAY

PLAYEDWKHANDWITHOUTYOHIMBINEPROVOCATION.

YOHIMEIINE AND PRIMATES

307

DISCUSSION Results of this study demonstrate the usefulness of the Rumbaugh VCT technique in assessing disturbance in perceptual-motor performance during yohimbine provocation. The .25 mg/kg dose did not affect subjects’ performance on the “easy” task, indicating that this dosage did not physically debilitate the animals nor directly impede either the visual or motor capacities involved in seeing the screen or manipulating the joystick, especially since subjects were also able to demonstrate manual dexterity in removing the food pellets from a small dispenser. As a consequence, when the cognitive demand of the task was relatively “simple,” they were able to overcome the psychophysiological changes brought on by the yohimbine and perform on the VCT. However, when a more cognitively demanding task was presented, requiring sustained attention and coordination for successful completion, subjects’ readiness to initiate a task during the challenge was greatly diminished. In fact, under the influence of yohimbine, performance was almost completely eliminated with the “hard’ task, although the few trials that they did initiate were completed quickly and accurately. As reflected in Figs. 1 and 2, and as evidenced by the fact that the low total of games played was not the result of frequent errors following initiation of games, it is clear that readiness to engage the games was interfered with by the drug; several subjects failed even to try to play the “hard” task. It is possible that when animals were faced with the requirements of a complex cognitive task, the distraction of their disturbingly altered internal sensations interfered with their capacity to initiate engagement. After a 24-hour period had passed, when the drug presumably was no longer active, performance returned to predrug level for both the “easy” and “hard” tasks. The cognitive effects of yohimbine can also be considered from a neurobiological perspective. Extensive rodent work by Weiss and Simson (1985) and Minor, Pelleymounter, & Maier (1988) have explored the effects of inescapable shock on noradrenergic function and subsequent test-task performance. Weiss and Simson (1985) showed that the amount of time spent floating in a swim task by rats who had previously received inescapable shock (reflective of “learned helplessness”) was negatively correlated with NE concentrations in the locus cemleus (LC). Because reductions of NE concentrations in the LC were associated with increased activity in the ascending dorsal tegmental bundle and increases in forebrain NE, the behavioral depression observed was hypothesized to result from stress-induced NE depletion in the LC and a functional blockade of inhibitory presynaptic alpha-2 autoreceptors. In a similar context, Minor et al. (1988) found that stress-induced depletion of the LC by inescabable shock contributed to an increase in latency to task initiation, especially when irrelevant cues were present. The effects of yohimbine in nonhuman primates may parallel the effects of inescapable shock or “learned helplessness” observed in rats. Like inescapable shock, yohimbine produces blockade, albeit pharmacological, of the alpha-2 autoreceptors and, thus, increases forebrain NE. It is conceivable, therefore, that yohimbine induced a state of “helplessness” or noninitiation in our primate subjects when the complexity of the task exceeded a certain threshhold.

308

S. FRIEDMAN

ET AL.

Recent models of PD (Barlow, 1988; Clark, 1986; Beck & Emery, 1985) have highlighted the role that cognitive misinterpretations of presumably harmless physical sensations play in the development and maintenance of the disorder. It is clinically well known that panic/anxiety in and of itself can also interfere with cognitions and the performance of complex tasks. It is therefore surprising that performance on specific cognitive and perceptual-motor tasks such as those used in our study [e.g., the Stroop Test (Stroop, 1935)] have not been used as dependent measures in human pharmacological challenge studies. One recent study (Albus et al., 1992), however, found that requiring subjects to perform two mental tasks reduced patients reports of panic attacks under a 20-mg yohimbine challenge, but did not alter performance on the task. These controlled, quantitative techniques may avoid some of the methodological limitations cited by Margraf, Ehlers, & Roth (1986) as inherent in laboratory provocation studies. They may also be useful in providing more specific data regarding the location of central sites of activity involved in the panic process. Use of the VCT technique with nonhuman primates in the current study demonstrated the efficacy of detailed quantitative assessment in differentiating levels of cognitive performance when a subject is confronted with an appropriate psychopharmacological challenge. The fact that subjects carried out all aspects of the task when the cognitive demand was relatively easy, but did not engage the cognitively more demanding task appears to confirm the direct impact of yohimbine. The behavior of the monkeys also reflects the affective sequelae of its administration on cognitive performance in animal subjects who are apparently unable to modulate the physiological effects of yohimbine by cognitive strategies. The use of this technique clearly warrants further exploration of the cognitive/motivational or attentional effects of other putatively anxiogenic compounds in our nonhuman primate model. Availability of the Rumbaugh VCT techniques should also facilitate exploration of the possible therapeutic role of learning experiences prior to the pharmacological challenges. Presence of previously learned abilities might be used to lessen the sense of “loss of control” seen as important in the provocation of the panic attack (Barlow, 1988). For example, it has been shown that providing PD patients with an illusion of control during CO, challenge, by making them believe they could control the flow of the CO,, appeared to protect some PD subjects from experiencing a panic attack (Sanderson, Rapee, & Barlow; 1989). In keeping with the recent work of Albus et al. (1992) discussed above, a previous study in our laboratory, using pigtail macaques, provided a demonstration of the possible ameliorative effects of learned-task engagement during psychological challenge (Plimpton & Rosenblum, 1983). That study showed that if infant monkeys had the opportunity to engage in a previously learned, readily accomplished digging task for food rewards while experimentally separated from their mothers, there was a significant amelioration of the depressive symptoms that usually accompany the loss experience in that species. In the current study, it is possible that our highly experienced primate subjects were buffered somewhat from the full disruptive effects of the yohimbine by the availability of their well-practiced, relatively “easy” task. Thus, the current study points to several future lines of research with both human subjects and their nonhuman primate counterparts. Consideration

Y0HlMBINEANDPRlMATFs

309

should be given to the further systematic assessment of cognitive capacities during the course of panic provocation and the interactions of cognitive diffrculty and task requirements with the level of affective disturbance tbat is provoked. In addition, the potential role of specific learned performance possibilities in alleviating initiation or prolongation of evoked panic patterns also warrants further exploration, both as a possible therapeutic intervention strategy and as a means of furthering our understanding of the relationship between cognitive and affective factors in panic attacks.

REFERENCES Albus, M.. Zahn, T. P, & Breier, A. (1992). Anxiogenic properties of yohimbine: II. Influence of experimental set and setting. European Archives of Psychiatry and Clinical Neuroscience, 241,345-35 1. Andrews,M. W. (1993). Vtdeo-task paradigm extended to Saimiri. Perceptual ana’ Motor Shills, 76, 183-191. Andrews, M. W., & Rosenblum, L. A. (in press). Joy-stick use by bonnet macaques under different motivational conditions. Proceedings of the 14th Congress of the International Primatological Society. Barlow, D. H. (1988). Anxiety and its disorders: The nature and treatment of anxiety and panic. New York: The Guilford Press. Beck, A. T., & Emery, G. (1985). Anxiety disorders and phobias: A cognitive perspective. New York: Basic Books. BOM, J. A., Harrison, J., & Rces, W. (1971). Lactate-induced anxiety: Therapeutic applications. British Journal of Psychiatry, 119,468-470. Chambless, D. L. & Goldstein, A. J. (1986). Agoraphobia: Multiple perspectives on theory ana’ treatment. New York: John Wiley & Sons. Chamey, D. S., Heninger, G. R., & Breier, A. (1984). Noradrcnergic function in panic anxiety. Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Archives of General Psychiatry, 43, 1042-1055. Chantey, D. S., Woods, S. W., Goodman, W. K., & Heninger, G. R. (1987). Neurobiological correlates of panic anxiety: Biochemical and behavioral correlates of yohimbine induced panic attacks. American Journal of Psychiatry, 144,1030-1036. Chopin, P., Pellow, S., & File, S. E. (1986). Tbe effects of yohimbine on exploratory and locomotor behavior arc attributable to its effects at noradrenaline and not at benzodiazepine receptors. Neumphannacology, 25.53-57. Cophut, J. D., Rosenblum, L. A., Friedman, S. Bassoff, T. B., & Gorman, J. M. (1992). Behavioral effects of oral yohimbine in differentially rcarcd nonhuman primates. Neuropsychopharrnacology, 6,3 l-37. Clark, D. M. (1986). A cognitive approach to panic. Behavior Research and Therapy, 24, 461-470. Dalgleish, T., & Watts, F. N. (1990). Biases of attention and memory in disorders of anxiety and depression. Clinical Psychology Review, 10.589-604. Friedman, S., Sunderland, G. S., & Rosenblum, L. A. (1988). A nonhuman primate model of panic disorder. Psychiatry Research, 23.65-75. Harris, J. C., & Newman, J. C. (1987). Mediation of separation distress by alpha-2 adrenergic mechanisms in a nonhuman primate. Brain Research, 410.353-356. Kaufman, I., and Rosenblum, L. A. (1966). A behavioral taxonomy for M. nemestrina and M. radiata: Based on longtitudinal observations of family groups in the laboratory. Primates, 7, 205-220. Kenardy, J., Evans, L., & Gei, T. P. (1992). The latent structure of anxiety symptoms in anxiety disorders. American Journal of Psychiatry, 149, 1058-1061.

310

S.

FRIEDMAN

ET Al..

Liebowitz, M. R., Fyer, A. J., Gorman, J. M., Dillon, D., Appleby, I. L., Levy, G., Anderson, S., Levitt, M., Pulij, M., Davies, S. O., & Klein, D. F. (1984). Lactate provocation of panic attacks, 1: clinical and behavioral findings. Archives ofGeneral Psychiatry, 41,764-770. Margraf, J., Ehlers, A., & Roth, W. T. (1986). Sodium lactate infusions and panic attacks: A review and critique. Psychosomatic Medicine, 48,23-S 1. Minor, T. R., Pelleymounter, M. A., & Maier, S. F. (1988) Uncontrollable shock, forebrain norepinephrine, and stimulus selection during choice escape learning. Psychobiology, 16, 135-145. Plimpton, E., and Rosenblum, L. A. (1983). The ecological context of infant maltreatment in primates. In M. Reite (Ed.), Child Abuse: The Non-human Primate Data (pp. 103-117). New York: Alan R. Liss. Redmond, D. E., Jr., & Huang, Y. H. (1979). Current concepts 2. New evidence for a locus coeruleus-norepinephrine connection with anxiety. Life Sciences, 25.2149-2162. Rosenblum, L. A., Coplan, J. D., Friedman, S., & Bassoff, T. (1991). Dose-response effects of oral yobimbine in unrestrained primates. Biological Psychiatry, 29, 647-657. Rumbaugh, D. M., Richardson, W. K., Washburn, D. A., Savage-Rumbaugh, E. S., & Hopkins, W. D. (1989). Rhesus monkeys (Macuca mulana), video tasks, and implications for stimulusresponse spatial contiguity. Journal of Comparative Psychology, 103,32-38. Sanderson, W. C., Rapee, R. M., & Barlow, D. H. (1989). The influence of an illusion of control on panic attacks induced via inhalation of 5.5% carbon dioxide-enriched air. Archives of General Psychiatry, 46, 157-162. Stroop, J. R. (1935). Studies of interference in serial verbal reactions. Journal of Experimental Psychology, 18.643-662. Sunderland, G., Friedman, S., & Rosenblum, L. A. (1989). Imipramine and alprazolam treatment of lactate-induced acute endogenous distress in nonhuman primtes. American Journal of Psychiatry, 146, 10441047. Weiss, J. M., & Simson, P. G. (1985). Neurochemical mechanisms underlying stress-induced depression. In T. Field, P. McCabe, & N. Scheiderman (Eds.), Stress and Coping. Hillsdale, N.J.: Lawrence Erlbaum.