Mu-opioid receptor activation in the medial shell of nucleus accumbens promotes alcohol consumption, self-administration and cue-induced reinstatement

Abstract

Endogenous opioid signaling in ventral cortico-striatal-pallidal circuitry is implicated in elevated alcohol consumption and relapse to alcohol seeking. Mu-opioid receptor activation in the medial shell of the nucleus accumbens (NAc), a region implicated in multiple aspects of reward processing, elevates alcohol consumption while NAc opioid antagonists reduce it. However, the precise nature of the increases in alcohol consumption, and the effects of mu-opioid agonists on alcohol seeking and relapse are not clear. Here, we tested the effects of the mu-opioid agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) in rat NAc shell on lick microstructure in a free-drinking test, alcohol seeking during operant self-administration, extinction learning and expression, and cue-reinforced reinstatement of alcohol seeking. DAMGO enhanced the number, but not the size of drinking bouts. DAMGO also enhanced operant alcohol self-administration and cue-induced reinstatement, but did not affect extinction learning or elicit reinstatement in the absence of cues. Our results suggest that mu-opioid agonism in NAc shell elevates alcohol consumption, seeking and conditioned reinforcement primarily by enhancing the incentive motivational properties of alcohol and alcohol-paired cues, rather than by modulating palatability, satiety, or reinforcement.

Mammalian target of rapamycin complex 1 and its downstream effector collapsin response mediator protein‐2 drive reinstatement of alcohol reward seeking

“…These findings are in line with previous data showing that different signaling cascades are induced by alcohol in discrete brain regions and subpopulations of neurons (Ron & Barak ). These findings are also in line with previous studies showing that the NAc shell is critical for cue‐ (Richard & Fields ) and context‐ (Perry & McNally ) induced reinstatement of extinguished drug‐seeking behavior. Additionally, context‐induced reinstatement of operant responding for a beer solution was shown to be correlated with increased expression of c‐Fos in the ventral part of the NAc shell (Hamlin et al .…”

Optogenetic activation of amygdala projections to nucleus accumbens can arrest conditioned and unconditioned alcohol consummatory behavior

“…These findings suggest that photoactivation of BLA terminals in the AcbSh can interfere with the behavioral impact of Pavlovian conditioned reward cues and also the execution of unconditioned consummatory action, in agreement with the proposed permissive role of AcbSh neuronal inhibition in consummatory behavior (Kelley, 2004; Krause et al, 2010; Nicola et al, 2004; Taha and Fields, 2006) and in agreement with recent studies using optogenetics in the AcbSh to control feeding (O’Connor et al, 2015; Prado et al, 2016). The current findings confirm that alcohol consummatory behavior is under control of feeding circuits in the accumbens, as shown previously using opioid agonists (Richard and Fields, 2016; Zhang and Kelley, 2011) and GABA A receptor subunit knockdown (Nie et al, 2011), and extend these findings to show that this control can be recruited by activation of BLA terminals.…”

“…Importantly, the observed effects on cued alcohol seeking were generalizable to sucrose-conditioned cues. It is not clear how our findings relate to a prior report of pharmacological inactivation of the AcbSh; this study found that muscimol into the AcbSh increased sucrose intake but decreased alcohol intake (Stratford and Wirtshafter, 2011); of note other studies find opioids increase both sucrose and alcohol intake (Richard and Fields, 2016; Zhang and Kelley, 2002). In general, the present findings are consistent with a long-recognized account of AcbSh as a locus of control over feeding (Kelley, 2004; O’Connor et al, 2015; Stratford and Kelley, 1997) and orofacial function (Koshikawa et al, 2011; Prinssen et al, 1994; Roitman et al, 2005), and are consistent with previous reports of interrupted sucrose licking following electrical stimulation of the AcbSh (Krause et al, 2010), and, conversely, elevated licking following photoinhibition of AcbSh (O’Connor et al, 2015).…”

Role of mu, but not delta or kappa, opioid receptors in context‐induced reinstatement of oxycodone seeking

“…A question for future research is what are the brain sites and circuits that play a role in naltrexone's effect on context‐induced reinstatement. We speculate that likely brain areas are the nucleus accumbens shell, ventral pallidum and basolateral amygdala where MOR plays a role in cue‐ and context‐induced reinstatement of alcohol seeking (Marinelli et al ., ; Perry & McNally, ; Richard & Fields, ).…”