The potent α2-adrenoceptor antagonist RS 79948 also inhibits dopamine D2 -receptors: Comparison with atipamezole and raclopride. (1st October 2022)

• Record Type: Journal Article
• Authors: Frau, Roberto; Devoto, Paola; Aroni, Sonia; Saba, Pierluigi; Sagheddu, Claudia; Siddi, Carlotta; Santoni, Michele; Carli, Marco; Gessa, Gian Luigi
• Is Part Of: Neuropharmacology. Volume 217(2022)
• Publication Date: 2022-10-01
• Subjects: Anti-dopamine beta-hydroxylase saporin -- Behavior -- Catecholamines -- In vivo electrophysiology -- Microdialysis; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109192
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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. Highlights: RS 79948 is not only an α2 -adrenergic- but also a dopamine D2 -receptor antagonist. These two properties result in opposite actions on dopaminergic function. The simultaneous α2 -and D2 antagonism, peculiar of atypical antipsychotics, might be of interest for psychiatric disorders.