Mechanisms of rostrocaudal differences in accumbal kappa opioid receptor effects on ethanol drinking

PROJECT SUMMARY In alcohol use disorder (AUD), alcohol consumption is driven, in part, by negative reinforcement: the removal of the negative affective state. This negative reinforcement is governed, in part, by the dynorphin/kappa opioid receptor (KOR) system and involves the monoamines, serotonin (5-HT) and dopamine (DA). Across multiple brain regions, activation of KORs has been found to elicit a state of aversion, and this is also the case for the nucleus accumbens (NAc) shell, in the caudal subregion. Paradoxically, however, KOR activation in the rostral NAc shell has been found to be rewarding. Our preliminary data, using a model of ethanol drinking that reflects the transition to dependence, show that KOR activation in the rostral NAc shell promotes approach behavior and attenuates ethanol drinking, while activation in the caudal shell instead promotes avoidance behavior and ethanol drinking. Moreover, while DA and 5-HT afferents terminate in both the rostral and caudal shell, KORs have far greater inhibitory effects on DA release in the caudal shell. We hypothesize that activation of KORs in the rostral NAc shell elicits a hedonic state and inhibits ethanol drinking, by preferentially modulating 5-HT vs. DA; in contrast, KOR activation in the caudal NAc shell drives a dysphoric state and increases ethanol drinking, by preferentially modulating DA vs. 5-HT. Aim 1 investigates the specific hypothesis that KOR activation in the rostral shell reduces ethanol drinking and induces positive affect, with the balance of KOR control over monoamine release tipped towards 5-HT. To accomplish this, the proposed experiments, in the rostral NAc shell, will use pharmacology to determine effects of KOR activation on (1) ethanol drinking and (2) approach/avoidance behavior, molecular biology to (3) examine the distribution of KORs on DA and 5-HT terminals, and electrochemical techniques to measure effects of KOR activation on optically stimulated (4) DA and (5) 5-HT. Aim 2 investigates the specific hypothesis that KOR activation in the caudal shell potentiates ethanol drinking and negative affect, with KORs having their major effects on DA. To accomplish this, the proposed experiments, in the caudal NAc shell, will determine effects of KOR activation on (1) ethanol drinking and (2) approach/avoidance behavior, (3) examine the distribution of KORs on DA and 5-HT terminals, and measure effects of KOR activation on optically stimulated (4) DA and (5) 5-HT. Aim 3 clarifies the mechanism driving these paradoxical effects on behavior. It investigates the specific hypothesis that KOR-mediated inhibition of 5- HT activity in the NAc shell inhibits ethanol consumption, while inhibition of DA activity does the opposite, and that these effects of 5-HT and DA inhibition are most apparent in the rostral and caudal shell, respectively. Thus, the proposed experiments will examine behavioral effects of viral KOR expression selectively on (1) DA and (2) 5-HT terminals in the rostral and caudal shell, and chemogenetic inhibition of (3) DA and (4) 5-HT projections to these subregions. Understanding the diverse functions of the KOR system could ultimately facilitate the design of pathway-specific therapeutics, revolutionizing treatment for AUD.