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Effects of mosapramine (Y-516), a new dopamine D2 antagonist, on reverse tolerance (sensitization) after repeated administration of methamphetamine (MAP; 2 mg/kg, s.c.) were investigated by means of ambulatory activity in mice; and they were compared with those of clocapramine (CCP), bromperidol (BPD) and chlorpromazine (CPZ). Y-516 (0.3, 1, 3 and 10 mg/kg, p.o.), CCP (3, 10 and 30 mg/kg, p.o.), BPD (0.1, 0.3 and 1 mg/kg, p.o.), CPZ (1, 3 and 10 mg/kg, p.o.) or 0.5% methylcellulose (MC; solvent, p.o.) were given to mice 30 min before MAP administration. The ambulatory activity was measured by tilting-type activity changes for 3 hr after MAP. These treatments were repeated 5 times at 3-4 day intervals. Then MAP alone was challenge-administered to all of these mice 3-4 days after the final administration. Marked reverse tolerance was produced after repeated administration of MC plus MAP. On the other hand, the ambulation-increasing effect of MAP was suppressed dose-dependently in groups pretreated with Y-516 or comparison-drugs, although the development of reverse tolerance was not completely inhibited after the repeated administration. In the challenge-administration of MAP, the ambulation-increasing effect was dose-dependently suppressed in the Y-516 group or the comparison-drug plus MAP group as compared with that in the MC plus MAP group.

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Effects of mosapramine (Y-516), a new dopamine D2 antagonist, on reverse tolerance after repeated administration of methamphetamine by means of the ambulation-increasing effect in mice.