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 high affinity for the D4 (dopaminergic), and the 5‐HT1c and 5‐HT2 (serotonergic) receptor subtypes on locomotor activity in an animal model of Parkinson's disease showing a bimodal response curve to increasing doses of a D2 agonist. Sulpiride (D2 antagonist) and ritanserin (5‐HT1c and 5‐HT2 antagonist) were used for comparison. The D1 agonist SKF 38393 at a dose of 8 mg/kg significantly reversed the akinesia induced by 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 low dose of a D2 agonist, LY 171555 (quinpirole, 1 μg/kg), inhibited the effects of SKF 38393, whereas the same drug at higher doses (5–50 μg/kg) restored and potentiated the stimulatory response to D1 stimulation. Clozapine inhibited the inhibitory phase and potentiated the stimulatory phase of the curve. Sulpiride inhibited both phases of the dose‐response curve (inhibitory/stimulatory), whereas ritanserin had no effect. We believe these results may reflect a disinhibition phenomenon possibly mediated by the blockade by clozapine of a subpopulation of inhibitory dopa‐mine (DA) receptors belonging to the D2 “family”.