The potent α₂-adrenoceptor antagonist RS 79948 also inhibits dopamine D₂ -receptors: Comparison with atipamezole and raclopride

Neurochemical, electrophysiological and behavioral evidence indicate that the potent α₂-adrenoceptor antagonist RS 79948 is also a dopamine (DA) D₂ receptor antagonist. Thus, results from ligand binding and adenylate cyclase activity indicate that RS 79948 binds to D₂ receptors and antagonized D₂ receptor-mediated inhibition of cAMP synthesis at nanomolar concentrations. Results from microdialysis indicated that RS 79948 shared with the selective α₂-adrenergic antagonist atipamezole the ability to increase the co-release of DA and norepinephrine (NE) from noradrenergic terminals in the medial prefrontal cortex (mPFC), except that RS 79948-induced DA release persisted after noradrenergic denervation, unlike atipamezole effect, indicating that RS 79948 releases DA from dopaminergic terminals as well. Similarly to the D₂ antagonist raclopride, but unlike atipamezole, RS 79948 increased extracellular DA and DOPAC in the caudate nucleus. Electrophysiological results indicate that RS 79948 shared with raclopride the ability to activate the firing of ventral tegmental area (VTA) DA neurons, while atipamezole was ineffective. Results from behavioral studies indicated that RS 79948 exerted effects mediated by independent, cooperative and contrasting inhibition of α₂-and D₂ receptors. Thus, RS 79948, but not atipamezole, prevented D₂-autoreceptor mediated hypomotility produced by a small dose of quinpirole. RS 79948 potentiated, more effectively than atipamezole, quinpirole-induced motor stimulation. RS 79948 antagonized, less effectively than atipamezole, raclopride-induced catalepsy. Future studies should clarify if the dual α₂-adrenoceptor- and D₂-receptor antagonistic action might endow RS 79948 with potential therapeutic relevance in the treatment of schizophrenia, drug dependence, depression and Parkinson's disease.