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

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Alcohol use disorder (AUD) is a complex condition with poorly understood genetic and environmental factors.
• Neuropeptide signaling, particularly in the striatum, is implicated in regulating excessive alcohol consumption.

Purpose of the Study:

• To investigate the role of the pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1R) in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking.
• To explore the PACAP/PAC1R system as a potential therapeutic target for AUD.

Main Methods:

• Utilized alcohol-preferring rats, an animal model for alcoholism.
• Administered AAV virus short-hairpin RNA (shRNA) to knockdown PAC1R in the NAcc Shell.
• Assessed ethanol self-administration under Fixed Ratio (FR) 1 and Progressive Ratio (PR) schedules.
• Evaluated the effect of PAC1R knockdown on saccharin self-administration.

Main Results:

• Knockdown of PAC1R in the NAcc Shell significantly reduced PAC1R levels.
• Reduced PAC1R expression led to increased ethanol self-administration, preference, and motivation.
• PAC1R knockdown did not similarly affect saccharin self-administration, indicating selective action on alcohol intake.

Conclusions:

• PAC1R in the NAcc Shell acts as a regulatory mechanism, or "brake," on alcohol consumption.
• Loss of PAC1R function in this brain region contributes to excessive alcohol intake.
• The PACAP/PAC1R signaling pathway presents a promising novel target for AUD treatments.