Mixed D 2/5-HT 2 Antagonism Differentially Affects Apomorphine- and Amphetamine-Induced Stereotyped Behavior

Abstract

Evidence supports the hypothesis that psychostimulant stereotypy is mediated through postsynaptic dopamine receptors. Given the recent findings of behavioral, neurochemical and electrophysiological studies showing 5-HT 2 modulation of dopamine systems, a series of experiments were undertaken to assess the ability of D 2 and 5-HT 2 antagonists to reverse apomorphine and amphetamine stereotypy in the rat. Haloperidol reduced stereotyped behavior induced by d-amphetamine (50% reduction with 0.162 mg/kg) and apomorphine (50% reduction with 0.112 mg/kg) MDL 28,133A, a mixed D 2/5-HT 2 antagonist, also reduced stereotypy in the apomorphine group (50% reduction with 3.89 mg/kg) but was much less effective in antagonizing the effects of d-amphetamine (not even a 25% reduction with 9.0 mg/kg). MDL 100,907, a selective 5-HT 2 antagonist, was ineffective at reducing stereotyped behavior induced by either stimulant. Thus, 5-HT 2 modulation of dopaminergic activity was not demonstrated in the case of psychostimulant stereotypy. Furthermore, 5-HT 2 antagonism did not induce stereotypy, as has been proposed in some models. These findings provide further support for the hypothesis that antipsychotic medications with high affinity for 5-HT 2 receptors do not interfere with the regulation of the nigrostriatal dopaminergic system and, therefore, would be less likely to produce extrapyramidal side effects.