Olanzapine, a novel atypical antipsychotic, reverses d-amphetamine-induced inhibition of midbrain dopamine cells.

This study compared the ability of the novel atypical antipsychotic olanzapine with that of clozapine to reverse the d-amphetamine-induced inhibition of substantia nigra (A9) and ventral tegmental area (A10) dopamine (DA) cells. Extracellular single-unit recordings were made from A9 and A10 DA cells in anesthetized rats. When administered alone, neither olanzapine nor clozapine altered the firing rate of A9 or A10 DA cells. Administration of d-amphetamine (0.5, 1.0 and 2.0 mg/kg, IV, decreased the firing rate of A9 and A10 DA cells. Olanzapine completely reversed the inhibitory effects of d-amphetamine on A10 DA cells (ED100 = 0.18 mg/kg, IV) and on A9 DA cells (ED100 = 1.0 mg/mg, IV). Clozapine completely reversed the inhibitory effects of d-amphetamine on A10 DA cells (ED100 = 3.8 mg/kg, IV), but only partially reversed the effects of d-amphetamine on A9 DA cells at the highest dose tested (8.0 mg/kg, IV). Thus, olanzapine, like clozapine, was more potent in reversing the effects of d-amphetamine on A10 than A9 DA cells. In addition, olanzapine was more potent than clozapine in the reversal of d-amphetamine effects on A9 and A10 DA cells. These results indicate that olanzapine and clozapine have similar effects on DA unit activity and predict that olanzapine should have an atypical antipsychotic profile in man.