Brain Research, 552 (1991) 141-152 0 1991 Elsevier Science Publishers B.V. 0006-&X993/91/$03.50 ADONIS OC06899391166973 141 BRES 16697 The amphetamine conditioned place preference: differential involvement of dopamine receptor subtypes and two dopaminergic terminal areas Noboru Hiroi and Norman M. White Department of Psychology, McGill University, Montreal, Que. (Canada) (Accepted 15 January 1991) Key words: Conditioned place preference; o-Amphetamine; Neuroleptic; Dl; D2; SCH23390; a-Flupenthixol; Metoclopramide; Sulpiride; Nucleus accumbens; Striatum; Primary reward; Conditioned reward; Conditioned reinforcement; Conditioning; Dopamine We investigated involvement of dopamine receptor subtypes and two dopaminergic terminal areas in the acquisition and the expression of the amphetamine conditioned place preference (CPP). When injected systemically before conditioning, both Dl and D2 dopamine antagonists blocked acquisition in a dose-dependent manner. When injected systemically before testing, the effects of the same Dl and D2 antagonists differed. The selective Dl antagonist SCH23390 dose-dependently blocked expression of the previously established conditioned behavior within the dose range that also blocked acquisition. In contrast, D2 antagonists failed to block expression of the amphetamine CPP at doses which blocked acquisition. Expression was, however, blocked by higher doses of D2 antagonists, which may have lost their selectivity for the D2 dopamine receptor. The expression of the CPP was also blocked by microinjections of SCH23390 or sulpiride into nucleus accumbens, but not into striatum. In a control experiment, sodium pentobarbital, which significantly reduced spontaneous locomotor activity in a manner similar to the higher doses of the dopamine antagonists, had no effect on the expression of the amphetamine CPP when given before testing. Finally, electrolytic lesions of the dorsal striatum potentiated the amphetamine CPP. These findings indicate that the dopamine released by amphetamine interacts with both Dl and D2 dopamine receptors to establish a CPP, but that the expression of the CPP may involve activation of the Dl dopamine receptor in the nucleus accumbens. INTRODUCTION Activation of dopamine systems causes acute behav- ioral changes in animals52~s3~s4 and humans3v26 and long- lasting behavioral modifications. Food9,27,35,50, sti- mulants11*40,47,70,73, and medial forebrain bundle sti- mulation’9~23*36,38*43,64*65 unconditionally evoke dopalsine release and establish incentive learning such as that measured in the conditioned place preference (CPP) paradigm 18,45,55,58,61,62 It is most likely that activation of the mesolimbic dopamine pathway is the basis of this incentive learning. Microinjections of amphetamine into nucleus ac- cumbens4*‘3T’4, but not other dopamine terminal areas13, 14, establish CPPs. The establishment of the amphet- amine CPP is impaired by 6-OHDA lesions of the nucleus accumbens61. A dopamine receptor antagonist injected into nucleus accumbens blocks acquisition of the CPP by stimulation of the medial forebrain bundle”. Another property of the mesolimbic dopamine system is that it is activated by conditioned stimuli. These are originally neutral stimuli that have been paired with events that unconditionally evoke dopamine release. When a conditioned stimulus is presented, cell bodies in VTA and medial substantia nigra fireM and concentra- tions of dopamine metabolites increase in the nucleus accumbens’0,35. The importance of dopamine release for the expression of incentive learning was demonstrated by the finding that the expression of the amphetamine CPP was blocked by a-flupenthixol injected into the nucleus accumbens or by reserpine, a vesicle deplete?‘. Studies have shown that the acquisition of the am- phetamine CPP is blocked by both selective D134.39 and D234*61 dopamine antagonists, and pharmacological stim- ulation of either dopamine receptor subtype in nucleus accumbens establishes CPPs, probably provided that the other subtype is tonically activated by endogenous dopamine release 68 However, little is known about how . the two types of dopamine receptors are involved in the expression of the amphetamine CPP during testing. Also unknown is the involvement of the striatal dopamine system in CPP expression during testing. The findings that dopamine depletion in the nucleus accumbens attenuates the amphetamine CPP61 and microinjections Correspondence: N. Hiroi. Present address: MIT, Department of Brain and Cognitive Sciences, E25-618, Cambridge, MA 02139, U.S.A.