Modification of cocaine sensitization by dopamine D1 and D2 receptor antagonists in terms of ambulation in mice.

The progressive enhancement in the ambulation increase caused by the repeated five-time dosings of cocaine (10 mg/kg SC) at 3- to 4-day intervals was dose dependently reduced by simultaneous administration with the selective dopamine D1 and D2 receptor antagonists, SCH 23390; R(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.01, 0.03, and 0.1 mg/kg SC) and YM-09151-2 (nemonapride); cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide (0.01, 0.03, and 0.1 mg/kg SC), respectively. However, the mice given cocaine with SCH 23390 (0.03 mg/kg) or YM-09151-2 (0.03 and 0.1 mg/kg) demonstrated significantly higher sensitivity than the mice given cocaine alone to challenge cocaine. Both 2-h and 24-h posttreatments with SCH 23390 (0.01-0.1 mg/kg) after each cocaine administration, at which the acute stimulant effect of cocaine had disappeared, significantly and dose dependently enhanced the cocaine sensitization. In contrast, 2-h, but not 24-h, posttreatment with YM-09151-2 (0.01-0.1 mg/kg), slightly retarded the induction of cocaine sensitization. The present results suggest that the blockade of dopamine D1 receptors is responsible for a significant enhancement in the cocaine sensitization, independent of the timings of its administration, whereas the blockade of dopamine D2 receptors elicits time-dependent alterations in the cocaine sensitization, a strong enhancement in the simultaneous administration schedule, but a slight retardation in the early posttreatment schedule.