Effect of CCK 1 and CCK 2 receptor blockade on amphetamine-stimulated exploratory behavior and sensitization to amphetamine Aet Alttoa, Jaanus Harro * Department of Psychology, Centerof Behavioral and Health Sciences, Tartu University, Tiigi 78, 50410 Tartu, Estonia Received 21 January 2003; received in revised form 17 June 2003; accepted 30 September 2003 Abstract Interactions between dopaminergic neurotransmission and cholecystokinin (CCK) in the CNS may be important in the pathogenesis of psychotic disorders and substance abuse. In this study, the effect of coadministration of the selective CCK receptor antagonists devazepide and L-365,260 (for selectively blocking CCK 1 and CCK 2 receptors, respectively), on the effect of amphetamine on the rat exploratory behavior, and on sensitization of locomotor response to amphetamine, were studied. Amphetamine (0.5 mg/kg) increased exploratory activity in the exploration box for 5 consecutive testing days, while devazepide (10 Ag/kg) blocked and L-365,260 (10 Ag/kg) enhanced amphetamine-induced stimulation of activity. Devazepide coadministration prevented the development of sensitization to amphetamine, while coadministration of L-365,260 with amphetamine potentiated the locomotor effect of a challenge dose of amphetamine. These results suggest that endogenous CCK, released during exploratory activity, shapes behavioral responses to amphetamine by acting on both receptor subtypes, and modulates the development of sensitization to amphetamine. D 2003 Elsevier B.V./ECNP. All rights reserved. Keywords: Amphetamine; CCK; Devazepide; L-365,260; Exploratory behavior; Sensitization 1. Introduction Cholecystokinin (CCK) is a gut–brain peptide, which acts via CCK 1 and CCK 2 receptor subtypes (Noble et al., 1999). CCK is involved in the regulation of feeding, pain perception, and learning and memory (Crawley and Corwin, 1994; Moran and Schwartz, 1994), and possibly in the pathogenesis of anxiety and psychosis (see Bourin et al., 1996; Harro et al., 1993 for review). A subpopulation of the dopaminergic neurons in the ventral tegmental area projecting to the nucleus accumbens contains CCK as a cotransmitter (Ho ¨ kfelt et al., 1980). It has been demonstrated that CCK modulates dopaminergic ac- tivity depending on the CCK receptor subtype involved. For example, CCK acting via CCK 1 receptors in the medial posterior nucleus accumbens potentiates dopaminergic ac- tivity while CCK acting on CCK 2 receptors in the anterior nucleus accumbens either has no effect or inhibits dopami- nergic activity (Crawley, 1991; Marshall et al., 1991). Similarly, behavioral studies have demonstrated that intra- cerebrally administered CCK potentiates dopamine-depen- dent behavior in a CCK 1 receptor-mediated manner while inhibits it via CCK 2 receptors (Crawley, 1991, 1992, 1994; Vaccarino and Rankin, 1989). Dopaminergic activity in the nucleus accumbens is increased in response to natural rewards and drugs of abuse (Heffner et al., 1980; Di Chiara and Imperato, 1988; Pfaus et al., 1990; Young et al., 1992) and novelty (Rebec et al., 1997). Given the dopamine involvement in drug reward (Wise and Bozarth, 1985) or attribution of incentive salience to stimuli (Berridge and Robinson, 1998; Ikemoto and Panksepp, 1999) as well as in psychotic disorders (Davis et al., 1991 for review), CCK may contribute to the development or expression of drug abuse or psychosis. The selective CCK receptor antagonists have been shown to be ineffective in modulating baseline locomotor behavior, but they alter the behavioral changes induced by dopamine or dopamine agonists, e.g. the indirect agonist amphetamine (Josselyn and Vaccarino, 1995; Philips et al., 1993; Tieppo et al., 2000). CCK receptors also seem to contribute to the development and expression of behavioral sensitization to amphetamine (DeSousa et al., 1999; Wunderlich et al., 2000), a phenomenon known to occur after repeated expo- sure to psychostimulants (Segal and Mandell, 1974; Pierce 0924-977X/$ - see front matter D 2003 Elsevier B.V./ECNP. All rights reserved. doi:10.1016/j.euroneuro.2003.09.006 * Corresponding author. Tel.: +372-7-375-911; fax: +372-7-375-900. E-mail address: jharro@psych.ut.ee (J. Harro). www.elsevier.com/locate/euroneuro European Neuropsychopharmacology 14 (2004) 324 – 331