Abstract
Preclinical and clinical evidence suggests that exogenous administration of oxytocin (OT) may hold promise as a therapeutic strategy for reducing heavy alcohol drinking. However, it remains unknown whether these effects are mediated by stimulation of endogenous sources of OT and signaling at oxytocin receptors (OTR) in brain or in the periphery. To address this question, we employed a targeted chemogenetic approach to examine whether selective activation of OT-containing neurons in the paraventricular nucleus of the hypothalamus (PVN) alters alcohol consumption in a binge-like drinking (“Drinking-in-the-Dark”; DID) model. Adult male Oxt-IRES-Cre mice received bilateral infusion of a Cre-dependent virus containing an excitatory DREADD (AAV8-hSyn-DIO-hM3Dq-mCherry) or control virus (AAV8-hSyn-DIO-mCherry) into the PVN. Chemogenetic activation of PVNOT+ neurons following clozapine-N-oxide injection reduced binge-like alcohol drinking in a similar manner as systemic administration of the neuropeptide. Pretreatment with a brain-penetrant OTR antagonist (L-368,899) reversed this effect while systemic administration of a peripherally restricted OTR antagonist (Atosiban) did not alter reduced alcohol drinking following chemogenetic activation of PVNOT+ neurons. Altogether, these data are the first to demonstrate that targeted activation of hypothalamic (endogenous) OT reduces alcohol consumption, providing further evidence that this neuropeptide plays a role in regulation of alcohol self-administration behavior. Further, results indicate that the ability OT to reduce alcohol drinking is mediated by signaling at OTR in the brain.
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CEK conducted all surgical and behavioral work, assisted in histological and data analyses, and wrote main portions of the manuscript. WCG conducted immunohistochemical and confocal microscopy procedures and assisted in data interpretation and editing manuscript drafts. MFL assisted in experimental design and statistical analyses, along with data interpretation and editing manuscript drafts. HCB conceived of the project, acquired funding, guided all aspects of experimental work, and edited final draft of manuscript. All authors reviewed and approved the final manuscript.
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King, C.E., Griffin, W.C., Lopez, M.F. et al. Activation of hypothalamic oxytocin neurons reduces binge-like alcohol drinking through signaling at central oxytocin receptors. Neuropsychopharmacol. 46, 1950–1957 (2021). https://doi.org/10.1038/s41386-021-01046-x
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DOI: https://doi.org/10.1038/s41386-021-01046-x
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