Acute and subchronic effects of MJ-13859, a potential antipsychotic drug, on rat brain dopaminergic function

The potential antipsychotic drug, MJ-13859, was tested for its acute and subchronic effects on rat brain dopaminergic neurotransmission and function. This drug exhibited an IC50 for displacement of [3H]spiperone binding of 6.35 nM which was similar to trifluoperazine, a potent classical antipsychotic drug. In female rats, MJ-13859 was slightly less potent than trifluoperazine for induction of catalepsy, inhibition of stimulant-induced hyperactivity and for increasing striatal, frontal cortical and olfactory tubercule dopamine metabolism. Both drugs also blocked dopamine autoreceptors on striatal dopamine nerve endings. When administered i.p., rather than s.c., the effect of MJ-13859 on dopamine metabolism was reduced significantly. When administered to male rats, the response of dopamine metabolism to drug was reduced, but a similar inhibition of stimulated activity occurred as in female rats. These results suggest a rapid first pass metabolism of MJ-13859 in the rat and that the antistimulant effect may be partly independent of the antidopaminergic effects. Osmotic minipumps were implanted s.c. for 2 week continuous infusion of MJ-13859 at doses of 1.0 or 3.0 mg/kg/day. Unlike classical antipsychotic drugs, MJ-13859 did not cause a subsensitivity to the ability of acute haloperidol challenge (0.1 mg/kg s.c.) to increase dopamine metabolism. After allowing a 4-day drug washout period before [3H]spiperone binding assay for D2 receptors, neither the maximum binding nor Kd were altered in rats treated for 2 weeks with 3.0 mg/kg/day of MJ-13859. Haloperidol at 1.0 mg/kg/day for 2 weeks caused a 57% increase in D2 receptor maximum binding.(ABSTRACT TRUNCATED AT 250 WORDS)