EFFECTS OF SULPIRIDE AND NEMONAPRIDE, BENZAMIDE DERIVATIVES HAVING DISTINCT POTENCIES OF ANTAGONISTIC ACTION ON DOPAMINE D-2 RECEPTORS, ON SENSITIZATION TO METHAMPHETAMINE IN MICE

The acute ambulatory stimulation by methamphetamine (2 mg kg(-1) s.c.) was dose-dependently reduced by 3-h pretreatment or combined treatmen t with sulpiride (1-100 mg kg(-1) s.c.), and combined treatment with n emonapride (0.003-0.03 mg kg(-1) s.c.), benzamide derivatives having s elective antagonistic action on dopamine D-2 receptors. The repeated ( 5 times) administrations of methamphetamine at 3-day intervals induced a sensitization to its ambulation-increasing effect, and the sensitiz ation was significantly inhibited by 3-h pretreatment with either sulp iride (10-100 mg kg(-1)), or combined treatment with either sulpiride (3 or 10 mg kg(-1)) or nemonapride (0.01 or 0.03 mg kg(-1)) at each me thamphetamine administration. Although the ambulation-increasing effec t of methamphetamine disappeared by 3 h after the administration, the 3-h post-treatment with sulpiride (3 mg kg(-1)) or nemonapride (0.03 m g kg(-1)) after each methamphetamine administration was effective for a significant inhibition of the Induction of methamphetamine sensitiza tion, whereas, the comparatively higher doses of sulpiride (30 and met hamphetamine sensitization. On the other hand, the repeated administra tions of sulpiride (30 and 100 mg kg(-1)) alone, but not any doses of nemonapride, at 3-day intervals elicited a significant increase in the sensitivity to methamphetamine. These results suggest that, although the potencies of the anti-methamphetamine effects of sulpiride and nem onapride differ by a factor of 3000, they inhibit the induction of sen sitization to methamphetamine in the pretreatment, combined treatment and early post-treatment schedules. However, it is also suggested that the repeated treatment with comparatively higher doses of sulpiride m ay produce a denervation supersensitivity of dopamine D-2 receptors, a nd resultant increase in the sensitivity to methamphetamine.