MECHANISM OF ACTION OF CLOZAPINE-INDUCED MODIFICATION OF MOTOR BEHAVIOR IN AN ANIMAL-MODEL OF THE SUPER-OFF PHENOMENON

We tested the effects of clozapine, an ''atypical'' neuroleptic with h igh affinity for the D4 (dopaminergic), and the 5-HT1c and 5-HT2 (sero tonergic) receptor subtypes on locomotor activity in an animal model o f Parkinson's disease showing a bimodal response curve to increasing d oses of a D2 agonist. Sulpiride (D2 antagonist) add ritanserin (5-HT1c and 5-HT2 antagonist) were used for comparison. The D1 agonist SKF 38 393 at a dose of 8 mg/kg significantly reversed the akinesia induced b y chronic reserpine treatment (1 mg/kg for 5 days) and alpha-methyl-p- tyrosine pretreatment (300 mg/kg). In this model, the addition of a lo w dose of a D2 agonist, LY 171555 (quinpirole, 1 mu g/kg), inhibited t he effects of SKF 38393, whereas the same drug at higher doses (5-50 m u g/kg) restored and potentiated the stimulatory response to D1 stimul ation. Clozapine inhibited the inhibitory phase and potentiated the st imulatory phase of the curve. Sulpiride inhibited both phases of the d ose-response curve (inhibitory/stimulatory), whereas ritanserin had no effect. We believe these results may reflect a disinhibition phenomen on possibly mediated by the blockade by clozapine of a subpopulation o f inhibitory dopamine (DA) receptors belonging to the D2 ''family.''