Neural circuit engagement within the nucleus accumbens (NAc) shell is implicated in the regulation of both negative and positive affect. Classically, the dynorphin/kappa opioid receptor (KOR) system in the NAc was believed to promote dysphoric behavior, while dopamine was viewed as interacting with reward behavior, and KOR activation was known to inhibit dopamine release. Recently, however, both the KOR and dopamine systems have, separately, been shown to have differential effects across the rostro-caudal axis of the NAc shell on hedonic responses. Whether or not this is due to interactions between KORs and dopamine, and if it extends to other affective behaviors, remains to be determined. In this study, we examined in rats the relationship between the KOR and dopamine systems in both the rostral and caudal NAc shell using ex vivo fast scan cyclic voltammetry and the impact of KOR activation on affective behavior using approach-avoidance assays. We report here that activation of KORs in the caudal NAc shell significantly inhibits dopamine release, stimulates novelty-induced rearing behavior, increases avoidance behavior, and reduces locomotor activity. In contrast, activation of KORs in the rostral NAc shell inhibits dopamine release to a lesser extent and instead increases approach behavior. Taken together, these results indicate that there is heterogeneity across the rostro-caudal axis of the NAc shell in the effects of KOR stimulation on affective behaviors, and they suggest that this might be due to differences in KOR control over dopamine release.

While limited research has implicated the neuropeptide, pituitary adenylate cyclase‐activating polypeptide (PACAP), in problematic alcohol use, the brain regions and isoforms involved in this effect remain to be determined. One region that has been found both to exhibit PACAP binding and, separately, to be involved in ethanol drinking is the nucleus accumbens (NAc). Thus, this study sought to characterize the effect of the PACAP isoforms in the NAc on ethanol drinking under the intermittent‐access two‐bottle‐choice paradigm, in male and female Long–Evans rats. With microinjection into the medial NAc shell, PACAP‐27 but not PACAP‐38 was found to dose‐dependently reduce binge‐like ethanol drinking. In contrast, the PACAP receptor antagonist, PACAP (6‐27), but not PACAP (6‐38), enhanced ethanol drinking. This effect of PACAP was substance specific, as neither isoform in the NAc shell affected binge‐like sucrose drinking. It was also anatomically specific, as PACAP‐38 rather than PACAP‐27 suppressed ethanol drinking when injected into the NAc core, and PACAP‐27 instead enhanced drinking when injected into the caudal third of the medial NAc shell. Finally, while PACAP‐38 in the NAc shell affected stress‐related exploratory behavior, reducing time spent in the light chamber of a light–dark box, PACAP‐27 did not significantly affect behavior in a light–dark box or open field. Together, these results, showing that PACAP‐27 in the NAc shell attenuates binge‐like ethanol drinking without affecting select stress‐related behaviors, suggest that compounds related to this PACAP isoform should be investigated as potential novel therapeutics for the treatment of alcohol use disorder.

Background While men in the United States consume more alcohol than women, rates of drinking are converging. Nevertheless, females remain underrepresented in preclinical alcohol research. Here, we examined rats' sex‐related differences in patterns of ethanol (EtOH) drinking and the effects of this drinking on exploratory and anxiety‐like behavior. Methods Adult male and female Long‐Evans rats were given 20% ethanol under the intermittent‐access two‐bottle‐choice paradigm. Their intake was measured daily for the first 7 weeks. During the eighth week, intake was measured over the 24 h of daily access. During the ninth week, they, along with EtOH‐naive controls, were tested prior to daily access in a novel chamber, light–dark box, and hole board apparatus. During the tenth week, blood ethanol concentration (BEC) was assessed after 30 to 40 min of access. Results Females overall demonstrated higher ethanol intake and preference across all access weeks than males, although only half of females drank significantly more than males. Across 24 h of daily access, both sexes had their highest intake in the first 30 min and their lowest in the middle of the light phase of the light/dark cycle. Despite their greater ethanol intake, females did not show significantly different BECs than males. In behavioral tests, females showed less vertical time in a novel activity chamber, more movement between chambers in a light–dark box, and more nose pokes in a hole‐board apparatus than males. While a history of ethanol drinking led to a trend for lower vertical time in the activity chamber and greater chamber entries in the light–dark box, the effects were not sex‐dependent. Conclusions These results suggest that female and male rats could both be tested for acute effects of ethanol after 30 min of daily access, but that nuanced considerations are needed in the design of these experiments and the interpretation of their findings.

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The dynorphin (DYN)/kappa opioid receptor (KOR) system has increasingly been investigated as a possible pharmacotherapeutic target for alcohol use disorder, but findings on the direction of its effects have been mixed. Activation of KORs by DYN has been shown to elicit dysphoric effects, and the DYN/KOR system has canonically been considered particularly important in driving alcohol intake through negative reinforcement in dependent states. However, this review also highlights its activity in opposing the positive reinforcement that drives alcohol intake at earlier stages. Both DYN and KORs are concentrated in the extended amygdala, a set of interconnected regions that includes the bed nucleus of the stria terminalis, central nucleus of the amygdala, and nucleus accumbens shell. This review focuses on the role of the DYN/KOR system in the extended amygdala in ethanol use. It begins by examining the effects of ethanol on the expression of DYN/KOR in the extended amygdala, expression of DYN/KOR in alcohol‐preferring and alcohol‐avoiding animals, and the effects of knocking out DYN/KOR genes on ethanol intake. Then, it examines the effects on ethanol use in both dependent and nondependent states from systemic pharmacological manipulations of DYN/KOR and from specific manipulation of this system in regions of the extended amygdala. We propose that greater expression and binding of DYN/KOR, by reducing the positive reinforcement that drives early stages of intake, initially acts to prevent the escalation of ethanol drinking. However, prolonged, binge‐like, or intermittent ethanol intake enhances levels of DYN/KOR in the extended amygdala such that the system ultimately facilitates the negative reinforcement that drives later stages of ethanol drinking. This review highlights the potential of the DYN/KOR system as a target that can affect different outcomes across different stages of ethanol drinking and the development of alcohol use disorder.

Neural activity in the nucleus accumbens (NAc) shell has long been implicated in the regulation of negative and positive affect. Classically, the dynorphin/kappa opioid receptor (KOR) system in the NAc was believed to promote dysphoric behaviors, while dopamine release was viewed as interacting with reinforcing stimuli, and KOR-activation was known to inhibit dopamine release. Recently, however, both the KOR and dopamine systems have been shown to have differential effects across the rostro-caudal axis of the NAc shell on hedonic responses. Whether or not this is due to interactions between KORs and dopamine, and if it extends to other affective behaviors, remains to be determined. In this study, we examined in rats the relationship between the KOR and dopamine systems in both the rostral and caudal NAc shell using ex vivo fast scan cyclic voltammetry and the impact of KOR activation on affective behaviors using various assays.We found that activation of KORs in the caudal NAc shell resulted in greater dopamine inhibition, and stimulated novelty-induced rearing behavior and anxiety-like and avoidance behaviors while reducing locomotor activity. In contrast, activation of KORs in the rostral NAc shell resulted in less dopamine inhibition and actually reduced anxiety-like and avoidance behaviors. These results demonstrate that there is heterogeneity across the rostro-caudal axis of the NAc shell in the effects of KOR stimulation on affective behavior and they suggest that this might be due to differences in KOR control over dopamine inhibition.