Enhanced stereotyped response to amphetamine after pretreatment with small doses of molindone

Pretreatment of rats with small doses of the antipsychotic drug, molindone, enhanced the stereotyped behavioral response to amphetamine. In order to determine whether molindone enhanced amphetamine-induced stereotypy by the same mechanism as chronic administration of amphetamine or drugs that inhibit central noradrenergic transmission, the effect of these drugs on the stereotyped behavior produced by beta-phenethylamine (PEA) was compared. Following the administration of phenoxybenzamine, reserpine and diethyldithiocarbamate, the stereotyped response produced by beta-phenethylamine was intensified. In contrast, neither molindone nor chronic pretreatment with amphetamine altered beta-phenethylamine-induced stereotypy. As shown previously with chronic amphetamine pretreatment, molindone also failed to enhance the stereotyped response produced by apomorphine. However, in contrast to the effects of chronic administration of amphetamine, molindone both increased the striatal concentration of dihydroxyphenylacetic acid (DOPAC) and blocked the ability of small doses of apomorphine to decrease this dopamine (DA) metabolite. The doses of molindone that blocked the apomorphine-induced reduction in the concentration of DOPAC in the striatum correlated with the doses that enhanced amphetamine-induced stereotypy. Since the decrease in DOPAC in the striatum produced by apomorphine is thought to be mediated through the stimulation of striatal DA autoreceptors, these results suggest that molindone enhances amphetamine-induced stereotypy by selectively inhibiting DA autoreceptors.