The kappa-opioid receptor (KOR) has been a target of recent interest in the treatment of alcohol use disorder, due to its role in negatively reinforced ethanol drinking, whereby aversive stimuli can promote ethanol intake. The KOR is densely expressed in the nucleus accumbens (NAc) on terminals of afferent neurons from the ventral tegmental area (VTA), where their activation has been found to suppress dopamine release such as is observed during alcohol withdrawal. We have previously found that KOR agonism differs along the rostro-caudal axis of the NAc shell, and that there may be a sex-related difference in baseline levels of ethanol intake. In the present study, we sought to determine if KOR stimulation in the rostral NAc shell could reverse effects of dopamine afferent activation on ethanol drinking. In Experiments 1 and 2, we used Long-Evans rats, as well as female transgenic tyrosine hydroxylase (TH)-Cre rats on a Long-Evans background in Experiment 3, which have a TH promoter directing expression of Cre recombinase in dopamine-containing cells, and we allowed them to drink under an intermittent access model, which establishes binge-like ethanol drinking. After the establishment of stable drinking, we bilaterally infused an excitatory designer receptors exclusively activated by designer drugs (DREADD) virus in the VTA of Experiment 2 groups, and a Cre-dependent excitatory DREADD in the VTA of the Experiment 3 group. After time for transduction, we injected into the NAc shell (1) the DREADD agonist, clozapine-N-oxide (CNO) (Experiments 2-3), (2) the KOR agonist, U50,488H (Experiments 1-3), (3) CNO + U50,488H (Experiments 2-3), and (4) saline vehicle (Experiments 1-3), counterbalanced in a Latin-Square design, and measured subsequent ethanol drinking. Surprisingly, we found that both U50,488H and CNO, independently and combined, enhanced ethanol drinking in high-level drinkers, and that these effects were not additive. Furthermore, the opposite trend was seen in low-level drinkers, suggesting a phenotype-dependent effect. These results suggest that both the DREADD activation and the KOR agonist microinjection have a similar net effect on dopamine release into the NAc shell, and that these effects depended on the phenotype of the drinker. The findings support the use of KOR antagonism as a therapy for alcohol use disorder, despite its potential unconventional effects on the dopamine system, and the overall use of individualized medication that considers an individual’s sex and phenotype.

Effects of Dopamine and Kappa Opioid Receptor Activity in the Rostral Nucleus Accumbens Shell on Ethanol Drinking in Rats

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