Alpha-2A but not 2B/C noradrenergic receptors in ventral tegmental area regulate phasic dopamine release in nucleus accumbens core.

Adrenergic receptors (AR) in the ventral tegmental area (VTA) modulate local neuronal activity and, as a consequence, dopamine (DA) release in the mesolimbic forebrain. Such modulation has functional significance: intra-VTA blockade of α-AR attenuates behavioral responses to salient environmental stimuli in rat models of drug seeking and conditioned fear as well as phasic DA release in the nucleus accumbens (NAc). In contrast, α-AR in the VTA has been suggested to act primarily as autoreceptors, limiting local noradrenergic input. The regulation of noradrenaline efflux by α-AR could be of clinical interest, as α-AR agonists are proposed as promising pharmacological tools in the treatment of PTSD and substance use disorder. Thus, the aim of our study was to determine the subtype-specificity of α-ARs in the VTA capable of modulating phasic DA release. We used fast scan cyclic voltammetry (FSCV) in anaesthetized male rats to measure DA release in the NAc after combined electrical stimulation and infusion of selected α-AR antagonists into the VTA. Intra-VTA microinfusion of idazoxan - a non-subtype-specific α-AR antagonist, as well as BRL-44408 - a selective α-AR antagonist, attenuated electrically-evoked DA in the NAc. In contrast, local administration of JP-1302 or imiloxan (α- and α-AR antagonists, respectively) had no effect. The effect of BRL-44408 on DA release was attenuated by intra-VTA DA D antagonist (raclopride) pre-administration. Finally, we confirmed the presence of α-AR protein in the VTA using western blotting. In conclusion, these data specify α-, but not α- or α-AR as the receptor subtype controlling NA release in the VTA.