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The conditioned place preference paradigm was used to study the reinforcing properties of D-amphetamine. Rats were injected (i.p.) with D-amphetamine sulphate (0.5, 1.0 or 5.0 mg/kg) and 10 min later confined for 30 min to one side of a shuttle box in which each of the two compartments had distinctive features. On alternate (control) days they received saline injections and were confined for 30 min to the opposite side. At all doses D-amphetamine produced place preference for the distinctive compartment that previously had been associated with the drug. Pretreatment with haloperidol (0.15 or 1.0 mg/kg) antagonized the place preference produced by amphetamine (1.5 mg/kg). By itself, haloperidol (0.15 or 1.0 mg/kg) did not produce place aversion. In separate experiments the D-amphetamine-induced place preference was examined in rats that had received 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens. Animals with the greatest depletion of dopamine did not show preference for the compartment associated with D-amphetamine. Furthermore, the time spent on the amphetamine-reinforced side correlated significantly with the levels of dopamine remaining in the nucleus accumbens but not with the dopamine content in the striatum. Depletion of peripheral catecholamines by systemic injections of 6-OHDA did not affect D-amphetamine-induced place preference conditioning. Other groups of animals that received the dopamine receptor agonist, apomorphine, also developed a conditioned preference for the compartment that had been associated with the drug treatment. These findings support the view that the reinforcing effects of D-amphetamine are mediated by central dopamine-containing neurons, and in particular those of the mesolimbic system.

The conditioned place preference paradigm was used to investigate the reinforcing properties of cocaine. Rats were injected (i.p.) with cocaine hydrochloride (0.625-20 mg/kg) and then immediately confined for 30 min to one side of a shuttle box in which each of the two compartments had distinctive features. On alternate (control) days they received saline injections and were confined for 30 min to the opposite side. Cocaine produced a significant, dose-related preference for the distinctive environment that previously had been paired with the drug. Pretreatment with pimozide (0.5 or 1.0 mg/kg) or haloperidol (1.0 mg/kg), both of which blocked the locomotor stimulant effects of cocaine, failed to influence place preference produced by cocaine (5.0 mg/kg). In addition, neither 6-hydroxydopamine lesions of dopamine terminals in the nucleus accumbens nor 6-hydroxydopamine-induced destruction of central and/or peripheral noradrenergic systems affected cocaine-induced place preference conditioning. In other experiments it was found that injections of the local anaesthetic procaine, at doses that did not affect locomotor activity (25 and 50 mg/kg), also resulted in significant place preference conditioning. It is concluded that cocaine can produce place preference conditioning through a mechanism that is independent of its effects on catecholamine-containing neurons and that may be related to its local anaesthetic properties. It is noted, however, that if cocaine's local anaesthetic properties could be blocked selectively, the drug might still produce place preference conditioning through its enhancement of central dopaminergic function.