Antistereotypic effects of dopamine D-1 and D-2 antagonists after intrastriatal injection in rats. pharmacological and regional specificity

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Abstract
Apomorphine antagonistic effects of a range of dopamine (DA) antagonists were studied after intracerebral and after peripheral injection. Inhibitory activity was found selectively within the ventral striatum with a D-1 antagonist (SCH 23390), D-2 antagonists (benzamides, butyrophenones) and mixed D-1/D-2 antagonists (thioxanthenes, phenothiazines), whereas α-adrenoceptor antagonists, muscarinic- and serotonin S2-antagonists were ineffective. Great differences in absolute potencies and in peripheral versus intrastriatal potency ratios were observed. High peripheral versus central selectivity ratios and high intrastriatal potencies were found with the hydrophilic compounds (-)-sulpiride, veralipride and domperidone which do not readily cross the blood-brain barrier. High intrastriatal potency was also observed for the benzamide, YM 09151-2, haloperidol and spiroperidol although these compounds had lower peripheral versus intrastriatal selectivity ratios. Neuroleptic potency after intracerebral administration did not depend solely on DA receptor affinity but additionally on physicochemical properties. On the basis of the peripheral vs. intrastriatal potency ratios, it is concluded that only few of the neuroleptics tested in this study are suited for topographical studies of DA receptor function using intracerebral injection but that (-)-sulpiride is one example combining high potency, high central selectivity, high DA D-2 receptor specificity stereoselectivity and long duration of action. The siteselectivity of apomorphine-antagonistic effects was further studied using (-)-sulpiride as a model compound. Inhibitory activity against oral stereotypy was preferentially found after injection into the ventral striatum, whereas the lowcomponent patterns of apomorphine stereotypy (sniffing, rearing, motility) were blocked equally well in the ventral striatum and nucleus accumbens. In contrast, a facilitation of oral stereotypy was induced by (-)-sulpiride in the dorsal striatum. No effect on apomorphine-stereotypy was found after injection into frontal cortex, supragenual cortex, septum, amygdala, substantia nigra or thalamus. These results support data obtained in lesion studies indicating the ventral striatum as the important site mediating inhibition of oral stereotypy after DA receptor blockade. However, the differentiation between striatum and accumbens in medition of stereotypy and hyperactivity was not as absolute as has been suggested by lesion studies