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.