The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D1 or D2 selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D1 dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D2 dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D1 or D2 dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor.

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The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by high doses of the dopamine receptor antagonists haloperidol and SCH 23390. In two experiments, male Wistar rats were injected daily for 4 days with either cocaine (15 mg/kg, IP) or vehicle in combination with haloperidol (1.0 mg/kg, IP), SCH 23390 (0.5 mg/kg, SC), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. At 24 h after the last preexposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure compared to vehicle treatments (i.e., sensitization). Moreover, the acute activating effects of cocaine over days were blocked by both haloperidol and SCH 23390. The coadministration of haloperidol, but not SCH 23390, blocked the development of behavioral sensitization to cocaine. That is, after the cocaine challenge injection, rats pretreated with SCH 23390 and cocaine did not differ from rats preexposed only to cocaine, whereas rats pretreated with haloperidol and cocaine did not differ from rats pretreated only with vehicle. Pretreatment with haloperidol or SCH 23390 without cocaine enhanced the locomotor-activating effects of the subsequent cocaine challenge injection. These findings suggest that cocaine-induced behavioral sensitization may develop as a result of repeated dopamine D1- or D2-type receptor stimulation, and that brief dopamine antagonist treatments enhance subsequent behavioral sensitivity to cocaine.

In three experiments, male Wistar rats (250-350 g) were injected (SC) daily with the D1-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D2-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D1-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8-10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D1 receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D2 receptor stimulation also contributes to the effect.

Rats exposed to 1 of 2 different stimulus compartments showed a preference for the novel compartment. The novelty-maintained place preference was eliminated by the DI agonist SKF 38393 and the D 2 agonist quinpirole, but only at doses that also produced an impairment in locomotor activity. The novelty-maintained place preference was also eliminated by the DI antagonist SCH 23390, but not by the D 2 antagonist eticlopride. Both of the antagonist drugs tested produced a dose-dependent depression in locomotor activity. However, SCH 23390 was shown to block novelty-maintained place preference at a dose that had no significant effect on locomotor activity. These results indicate that DI receptors may play a role in the incentive value of novel stimuli.Although multiple neurotransmitter systems are undoubtedly involved in the rewarding effects of various stimuli such as food, water, electrical brain stimulation, and drugs of abuse, there is now strong evidence implicating a critical role for the mesolimbic dopamine (DA) system (Wise & Rompre, 1989). This brain reward system consists of cell bodies in the midbrain ventral tegmental area that project rostrally to the limbic forebrain, primarily the nucleus accumbens and olfactory tubercles (Oades & Halliday, 1987). In general, the increased operant response rate that is maintained by a rewarding stimulus is blocked when DA antagonists are administered peripherally or directly into the nucleus accumbens. The ratedecreasing effect of DA antagonists may reflect a decrease in the relative incentive value of the rewarding stimulus rather than a motoric impair-