ACS chemical neuroscienceJun 1, 2026

Glucose-Dependent Insulinotropic Polypeptide Receptors in the Emotion System Reduce Dopamine Release and Cocaine's Effect on Dopamine

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

In mice, GIPR signaling in the lateral septum may help dampen dopamine release and cocaine-related dopamine increases.

Evidence

A laboratory mouse study used receptor-expression mapping and fast-scan cyclic voltammetry to show lateral septum GIPR/GLP-1R coexpression and reduced electrically evoked and cocaine-boosted dopamine after GLP-1R or GIPR agonists.

Caveat

The work is preclinical, and systemic agonist dosing plus dopamine readouts do not establish the exact lateral septum circuit mechanism or human relevance.

Simplified

Tirzepatide, a dual agonist of the glucagon-like peptide 1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), represents a new class of medication for obesity and type II diabetes treatment. Using laboratory mice, we show that GIPRs are present in the lateral septum (LS) in cells also expressing GLP-1R, particularly in the dorsolateral LS. Likewise, we show the coexpression of the dopamine (DA) D2 receptor (DRD2) in LS cells with GLP-1R in both the dorsolateral and intermediate portions of the LS. Using fast-scan cyclic voltammetry, we demonstrate that systemic GLP-1R or GIPR agonist treatment reduces both electrically evoked DA release in the LS and the ability of cocaine to increase extracellular DA levels. These data unveil a new central role for GIPR signaling and identify a potentially important cell type expressing both GLP-1R and GIPR upon which tirzepatide or other dual agonists may modulate DA homeostasis in the brain.