Opioid overdose is a leading cause of preventable death and has been exacerbated by the accessibility of synthetic opioids like fentanyl and the Covid-19 pandemic. Previous studies from the Schmidt lab have shown that centrally administered analogues of the incretin hormone and neuropeptide glucagon-like peptide-1 (GLP-1) attenuate opioid seeking and reinstatement. However, the neurobiological mechanisms underlying this effect remain unknown. 

The interpeduncular nucleus (IPN) is a brain nuclei with an established role in regulating the mesolimbic dopamine system- circuitry that is responsible for mediating drug reward. Because the IPN also contains GLP-1 receptors, we hypothesized that central administration of GLP-1 receptor analogue exendin-4 (Ex-4)  would attenuate opioid seeking. Since GLP-1 receptor analogues are known to decrease feeding behavior, we also measured feeding behavior and body weight change during treatment. 

We began by training male and female rats to self administer fentanyl or oxycodone. Following 21 days of self administration and extinction sessions, cue and drug primed reinstatement tests were done. Rats received either vehicle, low dose, or high dose of Ex-4 into the IPN. 

We found that Ex-4 was successful in attenuating cue and drug primed reinstatement of fentanyl-seeking behavior in male and female rats. Locomotion was not affected. We also found that Ex-4 treatment was effective in attenuating oxycodone seeking behavior in male rats. In all subsets of animals, 24 hour body weight change, water intake, and food intake in male oxycodone experienced rats was not affected. This implies that the doses we used did not produce any non drug-specific effects on feeding behaviors. Fluorescent in situ hybridization (FISH) was performed in slices of the IPN and showed that GLP-1 receptors on GABAergic neurons of the IPN were activated by Ex-4 treatment, providing a potential cell type specific mechanism for the suppressive effects of Ex-4 on opioid taking.