Inhibitory effects on the discriminative stimulus properties of D-amphetamine by classical and newer antipsychotics do not correlate with antipsychotic activity. Relation to effects on the reward system?

Classical antipsychotics exemplified by haloperidol (0.30), fluphenazine (0.070) and cis(Z)-flupentixol (0.088; ED(50) values in mu mol/kg are given in parentheses for all compounds) potently block the discriminative stimulus properties of D-amphetamine (1.0 mg/kg, IP) in rats. Newer antipsychotics have very different profiles: clozapine (7.2) and olanzapine (5.9) induce dose-dependent inhibition, while risperidone (>6.1) and remoxipride (>47) show weak inhibitory effects and sertindole (>23), seroquel (>20), amperozide (>2.9) and the putative antipsychotic MDL 100151 (>13; racemate with MDL 100907 as the active enantiomer) are ineffective. Antagonists of alpha(1)-adrenoceptors (prazosin; >6.0), 5HT(2A/2C) (ritanserin; >2.6) and histamine H-1 receptors (mepyramine; >50) are ineffective. Sertindole (0.076), risperidone (0.23), clozapine (0.39), olanzapine (0.088), MDL 100151 (0.0082), fluphenazine (0.13) and ritanserin (0.12) are potent inhibitors of the discriminative stimulus induced by the 5-HT2A/2C agonist DOI (0.63 mg/kg, IP), while haloperidol (similar to 0.4) cis(Z)-flupentixol(similar to 0.04), amperozide (similar to 0.5) and prazosin (>12) show partial inhibition and remoxipride (>23) and mepyramine (>25) are ineffective. The results indicate that inhibition of D-amphetamine discrimination does not correlate with antipsychotic activity of newer antipsychotics, as has previously been suggested in the literature. Furthermore, the inhibitory potencies against D-amphetamine-induced discrimination (present study) and hypermotility (previous study in the same strain of rats) do not correlate either for several of the newer antipsychotics (e.g. for sertindole, risperidone, seroquel and remoxipride). The discrepancies cannot solely be explained by additional pharmacological effects of these compounds, e.g. 5-HT2 receptor blockade. The D-amphetamine discrimination is documented to depend on increased limbic dopamine function which in humans is associated with increased euphoria. Based on these results, it is hypothesized that D-amphetamine discrimination rather than a model for antipsychotic activity may reflect dysphoric or anhedonic activity.