Effects of glucagon-like peptide 1 receptor signaling in the dorsolateral septum on ethanol operant self-administration and relapse behaviors

Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting more than 400 million people globally. Glucagon-like peptide-1 (GLP-1) has recently shown promise as a treatment for AUD but the underlying neural mechanisms are unclear. Given that dorsolateral septum (dLS) highly expresses GLP-1 receptors and is implicated in reward processing, this study investigated whether GLP-1 reduces ethanol intake and relapse behaviors via dLS. Long Evans rats were given intermittent access to 20 % ethanol solution before receiving training for ethanol operant self-administration. To examine relapse, operant self-administration was extinguished and two relapse tests were conducted: reacquisition of ethanol self-administration and prime + context-induced reinstatement of ethanol seeking. On self-administration test days, rats received intra-dLS injections of GLP-1 receptor agonist Exendin 4 (Ex4; 5 ng, 25 ng) or vehicle. During relapse tests, rats received intra-dLS infusion of either vehicle or 25 ng Ex4. Food intake and body weight were also measured. Results showed that intra-dLS Ex4 (25 ng) reduced ethanol self-administration in male high responders, but not in male low responders or females. Thus, only male rats were included in subsequent relapse tests. Intra-dLS Ex4 also reduced reacquisition of ethanol self-administration but had no impact on prime + context-induced reinstatement. No sustained changes in 24-h food intake or body weight were observed following intra-dLS Ex4 infusions. Finally, retrograde tracing results showed that dLS receive input from NTS GLP-1-expressing neurons. Together, these findings support the dLS as a key region in mediating the effects of GLP-1 receptor signaling on ethanol self-administration and reacquisition but suggest different contributing mechanisms in reinstatement of ethanol seeking.