Mu-opioid receptor knockout on Foxp2-expressing neurons reduces aversion-resistant alcohol drinking

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2024-12, Vol.247, p.173932, Article 173932
• Main Authors: Carvour, Harrison M., Roemer, Charlotte A.E.G., Underwood, D'Erick P., Padilla, Edith S., Sandoval, Oscar, Robertson, Megan, Miller, Mallory, Parsadanyan, Natella, Perry, Thomas W., Radke, Anna K.
• Format: Article
• Language: English
• Subjects: Alcohol; Aversion-resistance; FoxP2; Knockout mouse; Mu-opioid receptor
• ISSN: 0091-3057; 1873-5177; 1873-5177
• DOI: 10.1016/j.pbb.2024.173932

Mu-opioid receptors (MORs) in the amygdala and striatum are important in addictive and rewarding behaviors. The transcription factor Foxp2 is a genetic marker of intercalated (ITC) cells in the amygdala and a subset of striatal medium spiny neurons (MSNs), both of which express MORs in wild-type mice and are neuronal subpopulations of potential relevance to alcohol-drinking behaviors. For the current series of studies, we characterized the behavior of mice with genetic deletion of the MOR gene Oprm1 in Foxp2-expressing neurons (Foxp2-Cre/Oprm1fl/fl). Male and female Foxp2-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and homozygous Cre− (control) animals were tested for aversion-resistant alcohol consumption using an intermittent access (IA) task, operant responding for a sucrose reward, conditioned place aversion (CPA) to morphine withdrawal, and locomotor sensitization to morphine. The results demonstrate that deletion of MOR on Foxp2-expressing neurons renders mice more sensitive to quinine-adulterated alcohol. Mice with the deletion (vs. Cre− controls) also consumed less alcohol during the final sessions of the IA task, were less active at baseline and following morphine injection, and there was a trend toward less responding for sucrose under an FR3 schedule. Foxp2-MOR deletion did not impair the ability to learn to respond for reward or develop a conditioned aversion to morphine withdrawal. Together, these investigations demonstrate that Foxp2-expressing neurons may be involved in escalation of alcohol consumption and the development of compulsive-like alcohol drinking. •It is not known how specific MOR populations contribute to alcohol drinking.•FoxP2-Cre/Oprm1fl/fl mice have MOR deletion on FoxP2 neurons.•FoxP2-MOR deletion reduced escalation of alcohol consumption.•FoxP2-MOR deletion reduced quinine-resistant alcohol drinking.•FoxP2-MOR deletion decreased locomotor activity at baseline and following morphine.