GIPR and GLP-1R Agonists Reduce Dopamine Release and Cocaine-Induced Dopamine Increase in Mouse Lateral Septum
Background
Cocaine use disorder (CUD) remains a highly treatment-resistant addiction with significant relapse rates. Dopamine signaling in mesocorticolimbic circuits is central to cocaine's reinforcing effects, making it a critical therapeutic target. While GLP-1R agonists like liraglutide have shown promise in addiction models, the role of GIPR signaling, particularly in brain regions like the lateral septum (LS) involved in reward and motivation, has been less explored. This study investigates how GIPR and GLP-1R activation might modulate dopamine homeostasis in the context of addiction.
Study Design
Researchers utilized laboratory mice to investigate the expression and functional impact of GIPRs and GLP-1Rs in the lateral septum (LS). They performed immunohistochemistry to map receptor coexpression with dopamine D2 receptor (DRD2). To assess functional effects, mice received systemic treatment with GLP-1R or GIPR agonists. Dopamine release was measured using fast-scan cyclic voltammetry in the LS, evaluating both electrically evoked dopamine release and the increase in extracellular dopamine levels induced by cocaine administration. The study aimed to determine if agonist treatment could reduce these dopamine responses.
Results
The study revealed that GIPRs are indeed present in the lateral septum (LS), specifically coexpressed with GLP-1R in cells within the dorsolateral LS. Furthermore, DRD2 was found to be coexpressed with GLP-1R in LS cells across both dorsolateral and intermediate regions. These anatomical findings set the stage for functional observations. Systemic treatment with either a GLP-1R agonist or a GIPR agonist significantly modulated dopamine dynamics in the LS. > Both agonists reduced electrically evoked dopamine release in the LS. Critically, both GLP-1R and GIPR agonist treatments also reduced the ability of cocaine to increase extracellular dopamine levels. These data highlight a novel central role for GIPR signaling and identify a cell type expressing both GLP-1R and GIPR that could be targeted by dual agonists like tirzepatide to modulate dopamine homeostasis.
Key Findings
- GIPRs are expressed in the mouse lateral septum (LS), co-localizing with GLP-1Rs.
- Dopamine D2 receptors (DRD2) coexpress with GLP-1R in the dorsolateral and intermediate LS.
- Systemic GLP-1R agonist treatment reduces electrically evoked dopamine release in the LS.
- Systemic GIPR agonist treatment reduces electrically evoked dopamine release in the LS.
- Both GLP-1R and GIPR agonists reduce cocaine's ability to increase extracellular dopamine in the LS.
Why It Matters
This research unveils a novel mechanism by which GIPR and GLP-1R agonists, including dual agonists like tirzepatide, could modulate dopamine signaling in brain regions critical for reward and addiction. The findings suggest a potential therapeutic avenue for cocaine use disorder (CUD), where current treatments are severely lacking. By reducing both baseline dopamine release and cocaine-induced dopamine surges, these agonists might mitigate the reinforcing effects of cocaine and reduce craving. While preclinical, this work provides a strong rationale for further investigating tirzepatide's utility in addiction, potentially moving towards human trials for CUD. It expands the known therapeutic scope of these metabolic peptides into neuropsychiatric disorders, suggesting that existing protocols for metabolic conditions might eventually be adapted for addiction treatment.
gipr
glp-1r
dopamine
cocaine-use-disorder
lateral-septum
addiction