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 α1-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, α2-AR in the VTA has been suggested to act primarily as autoreceptors, limiting local noradrenergic input. The regulation of noradrenaline efflux by α2-AR could be of clinical interest, as α2-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 α2-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 α2-AR antagonists into the VTA. Intra-VTA microinfusion of idazoxan - a non-subtype-specific α2-AR antagonist, as well as BRL-44408 - a selective α2A-AR antagonist, attenuated electrically-evoked DA in the NAc. In contrast, local administration of JP-1302 or imiloxan (α2B- and α2C-AR antagonists, respectively) had no effect. The effect of BRL-44408 on DA release was attenuated by intra-VTA DA D2 antagonist (raclopride) pre-administration. Finally, we confirmed the presence of α2A-AR protein in the VTA using western blotting. In conclusion, these data specify α2A-, but not α2B- or α2C-AR as the receptor subtype controlling NA release in the VTA.

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent.

Substance use disorder is linked to impairments in the ventral tegmental area (VTA) dopamine (DA) reward system. Noradrenergic (NA) inputs from locus coeruleus (LC) into VTA have been shown to modulate VTA neuronal activity, and are implicated in psychostimulant effects. Phasic LC activity controls time- and context-sensitive processes: decision making, cognitive flexibility, motivation and attention. However, it is not yet known how such temporally-distinct LC activity contributes to cocaine seeking. In a previous study we demonstrated that pharmacological inhibition of NA signaling in VTA specifically attenuates cocaine-seeking. Here, we used virally-delivered opsins to target LC neurons for inhibition or excitation, delivered onto afferents in VTA of male rats seeking cocaine under extinction conditions. Optogenetic stimulation or inhibition was delivered in distinct conditions: upon active lever press, contingently with discreet cues; or non-contingently, i.e., throughout the cocaine seeking session. Non-contingent inhibition of LC noradrenergic terminals in VTA attenuated cocaine seeking under extinction conditions. In contrast, contingent inhibition increased, while contingent stimulation reduced cocaine seeking. These findings were specific for cocaine, but not natural reward (food) seeking. Our results show that NA release in VTA drives behavior depending on timing and contingency between stimuli - context, discreet conditioned cues and reinforcer availability. We show that, depending on those factors, noradrenergic signaling in VTA has opposing roles, either driving CS-induced drug seeking, or contributing to behavioral flexibility and thus extinction.