Activation of a locus coeruleus to ventral tegmental area noradrenergic pathway blunts binge-like ethanol intake and promotes aversive unconditioned responses in TH-ires-Cre mice

Ethanol comprises innately aversive properties that may act as a deterrent to overconsumption. We have previously found that chemogenetic activation or inhibition of a noradrenergic locus coeruleus (LC) to rostromedial tegmental nucleus (RMTg) pathway bidirectionally modulates binge-like ethanol intake and aversive reactivity in male and female TH-ires-Cre mice. We previously hypothesized that noradrenergic RMTg circuitry may modulate ethanol intake and aversion through inhibitory inputs to the ventral tegmental area (VTA), a region that is both densely innervated by the RMTg and proposed to coordinate the balance between the rewarding and aversive properties of ethanol. Here, we build upon this work by providing evidence for a direct role of noradrenergic signaling in the VTA in the modulation of binge-like ethanol intake and unconditioned aversive responses. Using "drinking-in-the-dark" procedures, we reveal that site-directed administration of an α-1 adrenergic receptor (AR) agonist into the VTA blunts binge-like ethanol intake and associated blood ethanol concentrations (BECs) without altering sucrose consumption or locomotion. Next, we demonstrate that chemogenetic activation of noradrenergic LC to VTA projection neurons blunts binge-like ethanol intake and BECs in male and female mice without altering sucrose intake or locomotion. Further, we demonstrate that chemogenetic activation of LC to VTA projection neurons induces mid-frequency vocalizations consistent with an aversion- or malaise-like state in mice. The present findings indicate an important involvement of noradrenergic LC to VTA circuitry in the modulation of ethanol intake and aversion.