PACAP Signaling Network in the Nucleus Accumbens Core Regulates Reinstatement Behavior in Rat

Area of Science:

• Neuroscience
• Gut-Brain Axis Research
• Pharmacology

Background:

• Cocaine use disorder (CUD) lacks effective treatments due to challenges in targeting neural circuits.
• The gut-brain axis, including GLP-1 receptors, shows promise for modulating neural circuits with minimal CNS impact.
• Pituitary adenylate cyclase polypeptide (PACAP) is a gut-brain axis peptide influencing behavior.

Purpose of the Study:

• To investigate the presence and function of an endogenous PACAP signaling network in the rat nucleus accumbens core (NAcc).
• To explore PACAP's potential role in modulating cocaine-seeking behavior.

Main Methods:

• Examined endogenous expression of PACAP and its receptor (PAC1R) in the rat NAcc.
• Investigated the effect of intra-NAcc PACAP infusions on cocaine-primed reinstatement.
• Assessed PACAP's interaction with D1 and D2 receptor agonists in blocking reinstatement.

Main Results:

• PACAP and PAC1R were found to be endogenously expressed in the rat NAcc.
• Intra-NAcc PACAP administration blocked cocaine-primed reinstatement behavior.
• PACAP inhibited reinstatement mediated by D1 receptor agonism but not D2 receptor agonism.

Conclusions:

• Endogenous PACAP signaling exists within the NAcc and can inhibit cocaine-seeking behavior.
• PACAP's action appears precise, differentiating between D1 and D2 receptor pathways.
• Targeting NAcc PACAP signaling via the gut-brain axis presents a potential novel therapeutic strategy for CUD.