Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

Phasic dopamine (DA) release from the ventral tegmental area (VTA) into forebrain structures is implicated in associative learning and conditional stimulus (CS)-evoked behavioral responses. Mounting evidence points to noradrenaline signaling in the VTA as an important regulatory input. Accordingly, adrenergic receptor (AR) blockade in the VTA has been shown to modulate CS-dependent behaviors. Here, we hypothesized that α₁ - and α₂ -AR (but not β-AR) activity preferentially modulates phasic, in contrast to tonic, DA release. In addition, these effects could differ between forebrain targets. We used fast-scan cyclic voltammetric measurements in rats to assess the effects of intra-VTA microinfusion of terazosin, a selective α₁ -AR antagonist, on electrically evoked phasic DA release in the nucleus accumbens (NAc) core and medial prefrontal cortex (mPFC). Terazosin dose-dependently attenuated phasic, but not tonic, DA release in the NAc core, but not in the mPFC. Next, we measured the effects of intra-VTA administration of the α₂ -AR selective antagonist RX-821002 on evoked DA in the NAc core. Similar to the effects of α₁ -AR blockade, intra-VTA α₂ -AR blockade with RX-0821002 strongly and dose-dependently attenuated phasic, but not tonic, DA release. In contrast, no regulation by RX-821002 was observed in the mPFC. This effect was sensitive to intra-VTA blockade of D2 receptors with raclopride. Finally, the β-AR antagonist propranolol ineffectively modulated DA release in the NAc core. These findings revealed both α₁ - and α₂ -ARs in the VTA as selective regulators of phasic DA release. Importantly, we demonstrated that AR blockade modulated mesolimbic, in contrast to mesocortical, DA release in previously unstudied heterogeneity in AR regulation of forebrain phasic DA.