The potent α 2 -adrenoceptor antagonist RS 79948 also inhibits dopamine D 2 -receptors: Comparison with atipamezole and raclopride.

Neurochemical, electrophysiological and behavioral evidence indicate that the potent α ₂ -adrenoceptor antagonist RS 79948 is also a dopamine (DA) D ₂ receptor antagonist. Thus, results from ligand binding and adenylate cyclase activity indicate that RS 79948 binds to D ₂ receptors and antagonized D ₂ receptor-mediated inhibition of cAMP synthesis at nanomolar concentrations. Results from microdialysis indicated that RS 79948 shared with the selective α ₂ -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 D ₂ 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 α ₂ -and D ₂ receptors. Thus, RS 79948, but not atipamezole, prevented D ₂ -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 α ₂ -adrenoceptor- and D ₂ -receptor antagonistic action might endow RS 79948 with potential therapeutic relevance in the treatment of schizophrenia, drug dependence, depression and Parkinson's disease.
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