d-Amphetamine Fails to Increase Extracellular Dopamine Levels in Mice Lacking α1b-Adrenergic Receptors: Relationship between Functional and Nonfunctional Dopamine Release

Abstract

It was found recently that locomotor and rewarding effects of psychostimulants and opiates were dramatically decreased or suppressed in mice lacking α1b-adrenergic receptors [α1b-adrenergic receptor knock-outs (α1bAR-KOs)] (Drouin et al., 2002). Here we show that blunted locomotor responses induced by 3 and 6 mg/kgd-amphetamine in α1bAR-KO mice [−84 and −74%, respectively, when compared with wild-type (WT) mice] are correlated with an absence of d-amphetamine-induced increase in extracellular dopamine (DA) levels in the nucleus accumbens of α1bAR-KO mice. Moreover, basal extracellular DA levels in the nucleus accumbens are lower in α1bAR-KO than in WT littermates (−28%;p < 0.001). In rats however, prazosin, an α1-adrenergic antagonist, decreasesd-amphetamine-induced locomotor hyperactivity without affecting extracellular DA levels in the nucleus accumbens, a finding related to the presence of an important nonfunctional release of DA (Darracq et al., 1998). We show here that locald-amphetamine releases nonfunctional DA with the same affinity but a more than threefold lower amplitude in C57BL6/J mice than in Sprague Dawley rats. Altogether, this suggests that a trans-synaptic mechanism amplifies functional DA into nonfunctional DA release. Our data confirm the presence of a powerful coupling between noradrenergic and dopaminergic neurons through the stimulation of α1b-adrenergic receptors and indicate that nonfunctional DA release is critical in the interpretation of changes in extracellular DA levels. These results suggest that α1b-adrenergic receptors may be important therapeutic pharmacological targets not only in addiction but also in psychosis because most neuroleptics possess anti-α1-adrenergic properties.