Research report Effects of repeated treatment with amphetamine or phencyclidine on working memory in the rat Mark Renato Stefani *, Bita Moghaddam Department of Psychiatry, Yale University School of Medicine, V.A. Medical Center, Mail Slot 116A/2, West Haven, CT 06516, USA Received 12 December 2001; received in revised form 1 February 2002; accepted 2 February 2002 Abstract Repeated exposure to psychomotor stimulants produces long-lasting molecular, cellular and locomotor behavioral changes. Such changes are likely to contribute to the development of drug addiction and psychosis. It is not clear whether these durable changes are accompanied by lasting changes in cognition. We examined the long-term effects of repeated treatment with phencyclidine (PCP) or amphetamine on working memory, using a discrete, paired-trials, delayed-alternation task sensitive to the acute effects of PCP and amphetamine, and to the integrity of the prefrontal cortex. Twice daily treatment with PCP (5.0 mg/kg) or amphetamine (2.5 mg/kg) for 5 days did not produce lasting, significant impairments in alternation performance in comparison to either pre-treatment baseline performance or to the vehicle-treated group. Subsequent challenge doses of PCP (1, 3 and 5 mg/kg) produced alternation deficits in vehicle, PCP, and amphetamine pre-treated groups that were dependent on dose, but not on pre-treatment regimen. However, rats pre-treated with PCP showed a trend towards sensitization in response to PCP challenge. The present data suggest that psychostimulant treatment regimens that are reported to produce long-lasting changes in neural morphology and locomotor behavior may not produce equally durable changes in working memory. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Phencyclidine; Psychosis; Working memory; Schizophrenia; Sensitization; Behavior 1. Introduction Repeated, intermittent exposure to a psychomotor stimulant produces long-lasting molecular, cellular and behavioral changes, including alterations in receptor expression, neuronal excitability and morphology, and motoric hyper-responsiveness to subsequent stimulant administration [26,28,30,33,34,36 /38,43]. Such effects appear to involve durable neuronal changes, particularly in the meso-accumbal and meso-prefrontal dopaminer- gic [13,17,20,34,36,37] and the prefrontal glutamatergic systems [26,30,36,37]. These long-term morphological and behavioral changes very likely contribute to the development of drug addiction [28,35] and other adverse conditions such as psychosis [7,25,32]. In addition to characterizing changes at the molecular and cellular levels, comprehensive models of addiction and psychosis must also replicate the cognitive impair- ments, such as deficits in working memory, attention and behavioral flexibility, that are associated with these conditions [9,10,29]. To date, most behavioral studies of psychostimulant effects have characterized long-term effects on motor behaviors such as locomotion and stereotypy rather than on cognition [13,17  /19,21,42,43]; for reviews see [25,35,39]. Furthermore, the few experi- ments in which the cognitive effects of repeated psycho- motor stimulant administration have been studied have generally examined behavior within a few days following the cessation of drug treatment (e.g. [18]). Thus, it is not clear whether such cognitive impairments are as durable as the more thoroughly studied motoric effects. The prefrontal cortex, a region strongly implicated in working memory and attention, among other cognitive processes [3,11], has been found to be an integral component of the circuitry displaying plasticity asso- ciated with repeated exposure to psychostimulants. Cellular and molecular abnormalities have been re- ported in the prefrontal cortex of animals that have received repeated treatment with psychostimulants [26,30,36,37]. Moreover, lesions of the prefrontal cortex * Corresponding author. Tel.: 1-203-932-5711x3500; fax: 1-203- 937-3897 E-mail address: mark.stefani@yale.edu (M.R. Stefani). Behavioural Brain Research 134 (2002) 267 /274 www.elsevier.com/locate/bbr 0166-4328/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII:S0166-4328(02)00040-2