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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. Copyright © 2022 Elsevier Ltd. All rights reserved.


Roberto Frau, Paola Devoto, Sonia Aroni, Pierluigi Saba, Claudia Sagheddu, Carlotta Siddi, Michele Santoni, Marco Carli, Gian Luigi Gessa. The potent α2-adrenoceptor antagonist RS 79948 also inhibits dopamine D2 -receptors: Comparison with atipamezole and raclopride. Neuropharmacology. 2022 Oct 01;217:109192

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PMID: 35850212

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