The inhibitory effects of a variety of established and putative antipsychotic compounds on the hypermotility induced by D-amphetamine at two dose levels (0.5 and 2.0 mg/kg) have been studied. Classical antipsychotics (haloperidol, fluphenazine and cis(Z)-flupentixol) and the selective dopamine D-2 receptor antagonist remoxipride inhibit hypermotility in the two conditions with similar potencies, whereas sertindole, clozapine, risperidone, ziprasidone and olanzapine preferentially inhibit the effect of the low dose of D-amphetamine (selectivity ratios between 6.5 and 18). Seroquel, amperozide and the selective 5-HT2A receptor antagonist MDL 100.151 ((+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol) have no effect on D-amphetamine 2.0 mg/kg, but inhibit the response to D-amphetamine 0.5 mg/kg. The alpha(1)-adrenoceptor antagonist prazosin inhibits the motility response to D-amphetamine 0.5 mg/kg with slightly higher potency than that to D-amphetamine 2.0 mg/kg, whereas the 5-HT2A/2C receptor antagonist ritanserin selectively inhibits the effect of D-amphetamine 0.5 mg/kg. The histamine H-1 receptor antagonist mepyramine is ineffective in both models. All compounds, except remoxipride, MDL 100.151 and ritanserin (which are ineffective) inhibit spontaneous locomotor activity at dose levels close to those inhibiting the response to D-amphetamine 2.0 mg/kg. Prazosin has partial inhibitory effect. In conclusion, dopamine antagonism has similar inhibitory effect on hyperactivity induced by low and high D-amphetamine dosages, alpha(1)-adrenoceptor antagonism also contributes to both effects, whereas 5-HT2 receptor antagonism selectively interacts with the low D-amphetamine dose. This indicates that the responses to D-amphetamine 0.5 and 2.0 mg/kg are differently modulated by these neurotransmitters. These results indicate that the dose level of D-amphetamine inducing hyperactivity is important for the pharmacology of this response and indicate that different neuronal interactions are involved. The implications of these observations for the improved ratio between efficacy and neurological side-effects of newer antipsychotics are discussed.
