Chemogenetic activation of an A2 nucleus of the solitary tract to lateral parabrachial nucleus noradrenergic pathway blunts binge-like ethanol intake and promotes aversive unconditioned responses in male and female mice

While there is strong evidence that the reinforcing effects of ethanol motivate seeking and consumption, ethanol produces aversive effects that limit consumption. We have previously found that in doses that support conditioned taste aversion (CTA) learning ethanol induces activity of noradrenergic (NE+) neurons of the A2 subregion of the nucleus of the solitary tract (NTS) as well as neurons within the lateral parabrachial nucleus (L-PBN), regions that have been implicated in integrating aversive responses. Here we provide evidence of a NE + circuit arising from the A2 and innervating the L-PBN in tyrosine hydroxylase (TH)-ires-cre mice. Next, we used male and female TH-ires-cre mice in tandem with an intersectional chemogenetic approach to assess the role of the NE + A2 to L-BPN circuit in modulating binge-like ethanol intake as well as unconditioned aversive behavior. Using "drinking in the dark" (DID) procedures we found that activating this circuit significantly blunted binge-like ethanol intake and associated blood ethanol concentrations (BECs) without altering sucrose solution intake. Furthermore, silencing this pathway during light cycle drinking revealed a trend of increased ethanol intake and an associated significant increase of BECs with no changes in sucrose intake. Additionally, activation of this circuit, as well as peripheral administration of the emetic agent LiCl, significantly increased the emission of mid-frequency vocalizations (MFVs) in mice, a phenotype reflecting aversive reactivity. The present findings provide novel evidence of a NE + A2 to L-PBN circuit in the modulation of binge-like ethanol intake and aversive responses.