Phurmacology Biochemistry & Behavior, Vol. 23, pp. 173-183, 1985. c Ankho International Inc. Printed in the U.S.A. 0091-3057185 $3.00 + .OO Stressor Invoked Exacerbation of Amphetamine-Elicited Perseveration’ HYMIE ANISMAN, BRENDA HAHN, DAVID HOFFMAN AND ROBERT M. ZACHARKO Unit for Behavioral Medicine and Pharmacology, Department of Psychology, Carleton University Ottawa, Onturio KIS 5B6, Canada Received 13 October 1983 ANISMAN, H., B. HAHN, D. HOFFMAN AND R. M. ZACHARKO. Stressor inrolied r.wcrrbarion of antphrtamin~- rlicitrd prrsweration. PHARMACOL BIOCHEM BEHAV 23(2) 173-183, 1985.-The provocation of stimulus preserva- tion induced by amphetamine in a Y-maze was appreciably enhanced in animals that had been exposed to uncontrollable shock, whereas controllable shock did not influence performance. The enhancement of the stimulus perseveration was evident irrespective of whether the stressor was applied immediately or 72 hr prior to the perseveration test, provided that the stimulus complex in which shock was delivered was similar to that in which the perseveration test was conducted. When the two environments were distinctively different from one another the enhancement of stimulus perseveration was evident immediately after shock exposure, but not 72 hr after shock. It is suggested that stressors may have long-term effects of amphetamine-elicited perseveration, but the expression of such an effect is dependent upon the stimulus context in which the behavior is examined. Moreover, it is suggested that evaluation of amphetamine-induced behavioral changes, and possibly amphetamine-elicited and idiopathic psychosis, should consider the stress history of the organism. Stress Amphetamine Perseveration EXPOSURE to aversive stimulation may induce neurochem- ical alterations which are fundamental to the induction or exacerbation of various forms of behavioral and physical pathology [3,28]. Although the central neurochemical changes provoked by stressors of moderate severity are fairly transient, it seems that traumatic aversive events may result in the sensitization or conditioning of neurochemical changes. In particular, presentation of cues that had previ- ously been paired with uncontrollable footshock will result in a marked increase in the utilization of norepinephrine (NE) [13] and in some brain regions dopamine (DA) neuronal ac- tivity will be increased as well [17]. Likewise, it has been demonstrated that among mice exposed to traumatic shock which reduces brain NE concentrations, subsequent reexpo- sure to even a limited amount of shock will result in a rapid reinduction of the amine reduction [2]. As in the case of stressors, it has been demonstrated that sensitization effects may occur in response to catecholamine stimulants such as amphetamine. In particular, among animals treated with am- phetamine, subsequent administration of the drug provoked increased DA release from striatal tissue ([26,27], see also [8]), as well as increased unilateral circling [27], stereotypy and polydipsia [8]. amphetamine have additive effects may be related to the fact that the two treatments induce similar neurochemical conse- quences. Stressors, like amphetamine, are known to provoke increased turnover of NE and in some regions DA (see [4]). Indeed, it has been demonstrated that the neuro- chemical consequences of a stressor may be augmented among amphetamine treated animals [4,34]. Thus, it has been suggested that administration of amphetamine or a stressor results in the sensitization of the substrate for the neurochemical change, thereby enhancing the subsequent behavioral response to the same or to the alternative treat- ment [8]. Not only will amphetamine and stress exposure result in an enhanced response to subsequent treatment of a similar nature, but cross-treatment sensitization effects have been reported as well. Exposure to a stressor may result in a subsequent enhancement of the stereotyped response pat- terns ordinarily exerted by amphetamine [8, 9, 221 and vice versa [8,9]. The finding that catecholamine stimulants and Inasmuch as the stereotypy elicited by amphetamine has been assumed to represent an animal model of amphetamine-induced as well as idiopathic psychosis in hu- mans [ 191, these findings were taken to suggest that stressful events may be a fundamental variable in provoking or exacerbating psychotic behaviors [8]. Stereotypy, however, is largely influenced by motoric factors, and likely does not tap changes of attentional processes or the response to en- vironmental stimuli, which may be essential factors in psychotic disorders. Accordingly, it was suggested that in evaluating the effects of amphetamine and in drawing paral- lels to human idiopathic disorders, it would be propitious to assess behaviors in addition to stereotypy, particularly those which involve the response to environmental stimuli [ 191. The purpose of the present investigation was to determine whether stressful events would enhance the effects of am- phetamine on stimulus perseveration in a Y-maze spontane- ous alternation task, a behavior thought to involve variations ‘Supported by grants A9845 and UOO58from the Natural Sciences and Engineering Research Council of Canada, and MT-6486 from the Medical Research Council of Canada. 173