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

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 blockadeof dopamine D2 receptors elicits time-dependent alterations in the Cocaine sensitization.

Abstract

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.