Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats

Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we...

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Autores principales:	Margaret A. Minnig, Tayun Park, Maria Echeveste Sanchez, Pietro Cottone, Valentina Sabino
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	ethanol self-administration alcohol use disorder (AUD) PAC1R pituitary adenylate cyclase activating polypeptide (PACAP) compulsive Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/34c447b7c60e486dba3323c352fb8631
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spelling	oai:doaj.org-article:34c447b7c60e486dba3323c352fb86312021-12-03T06:25:59ZViral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats1662-515310.3389/fnbeh.2021.787362https://doaj.org/article/34c447b7c60e486dba3323c352fb86312021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnbeh.2021.787362/fullhttps://doaj.org/toc/1662-5153Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.Margaret A. MinnigTayun ParkMaria Echeveste SanchezPietro CottoneValentina SabinoFrontiers Media S.A.articleethanolself-administrationalcohol use disorder (AUD)PAC1Rpituitary adenylate cyclase activating polypeptide (PACAP)compulsiveNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Behavioral Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ethanol self-administration alcohol use disorder (AUD) PAC1R pituitary adenylate cyclase activating polypeptide (PACAP) compulsive Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	ethanol self-administration alcohol use disorder (AUD) PAC1R pituitary adenylate cyclase activating polypeptide (PACAP) compulsive Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Margaret A. Minnig Tayun Park Maria Echeveste Sanchez Pietro Cottone Valentina Sabino Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats
description	Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.
format	article
author	Margaret A. Minnig Tayun Park Maria Echeveste Sanchez Pietro Cottone Valentina Sabino
author_facet	Margaret A. Minnig Tayun Park Maria Echeveste Sanchez Pietro Cottone Valentina Sabino
author_sort	Margaret A. Minnig
title	Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats
title_short	Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats
title_full	Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats
title_fullStr	Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats
title_full_unstemmed	Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats
title_sort	viral-mediated knockdown of nucleus accumbens shell pac1 receptor promotes excessive alcohol drinking in alcohol-preferring rats
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/34c447b7c60e486dba3323c352fb8631
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Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats

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