There has been a dramatic increase in illicit fentanyl use in the United States over the last decade. In 2018, more than 31,000 overdose deaths involved fentanyl or fentanyl analogs, highlighting an urgent need to identify effective treatments for fentanyl use disorder. An emerging literature shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the reinforcing efficacy of drugs of abuse. However, the effects of GLP-1R agonists on fentanyl-mediated behaviors are unknown. The first goal of this study was to determine if the GLP-1R agonist exendin-4 reduced fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, an animal model of relapse, in rats. We found that systemic exendin-4 attenuated fentanyl taking and seeking at doses that also produced malaise-like effects in rats. To overcome these adverse effects and enhance the clinical potential of GLP-1R agonists, we recently developed a novel dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs), GEP44, that does not produced nausea-like behavior in drug-naïve rats or emesis in drug-naïve shrews. The second goal of this study was to determine if GEP44 reduced fentanyl self-administration and reinstatement with fewer adverse effects compared to exendin-4 alone. In contrast to exendin-4, GEP44 attenuated opioid taking and seeking at a dose that did not suppress food intake or produce adverse malaise-like effects in fentanyl-experienced rats. Taken together, these findings indicate a novel role for GLP-1Rs and Y2Rs in fentanyl reinforcement and highlight a potential new therapeutic approach to treating opioid use disorders.

An emerging preclinical literature suggests that targeting central glucagon-like peptide-1 receptors (GLP-1Rs) may represent a novel approach to treating cocaine use disorder. However, the exact neural circuits and cell types that mediate the suppressive effects of GLP-1R agonists on cocaine-seeking behavior are largely unknown. The laterodorsal tegmental nucleus (LDTg) expresses GLP-1Rs and functions as a neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the primary source of central GLP-1, with midbrain and forebrain nuclei known to regulate cocaine-seeking behavior. The goal of this study was to characterize the role of LDTg GLP-1R-expressing neurons and their projections to the ventral tegmental area (VTA) in the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we showed that administration of the GLP-1R agonist exendin-4 (Ex-4) directly into the LDTg significantly attenuated cocaine seeking at a dose that did not affect sucrose seeking, ad libitum food intake, or body weight. In addition, our studies revealed that selectively activating NTS-to-LDTg circuits attenuated cocaine seeking via a GLP-1R-dependent mechanism. We also demonstrated, for the first time, that GLP-1Rs are expressed primarily on GABAergic neurons in the LDTg and that the efficacy of Ex-4 to reduce cocaine seeking depends, in part, on activation of LDTg-to-VTA GABAergic projections. Taken together, these studies identify a central mechanism by which Ex-4 attenuates cocaine seeking and highlight GABAergic GLP-1R-expressing circuits in the midbrain as important anti-craving pathways in regulating cocaine craving-induced relapse.

We congratulate Dr. Hernandez on the publication of the final portion of her thesis research at University of Pennsylvania!

Find the abstract below:

Despite the effectiveness of current medications to treat opioid use disorder, there is still a high rate of relapse following detoxification. Thus, there is critical need for innovative studies aimed at identifying novel neurobiological mechanisms that could be targeted to treat opioid use disorder. A growing body of preclinical evidence indicates that glucagon-like peptide-1 (GLP-1) receptor agonists reduce drug reinforcement. However, the efficacy of GLP-1 receptor agonists in attenuating opioid-mediated behaviors has not been thoroughly investigated. Using recently established models of opioid-taking and -seeking behaviors, we showed that systemic administration of the GLP-1 receptor agonist exendin-4 reduced oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats. We also identified behaviorally selective doses of exendin-4 that reduced opioid-taking and -seeking behaviors and did not produce adverse feeding effects in oxycodone-experienced rats. To identify a central site of action, we showed that systemic exendin-4 penetrated the brain and bound putative GLP-1 receptors on dopamine D1 receptor- and dopamine D2 receptor-expressing medium spiny neurons in the nucleus accumbens shell. Consistent with our systemic studies, infusions of exendin-4 directly into the accumbens shell attenuated oxycodone self-administration and the reinstatement of oxycodone-seeking behavior without affecting ad libitum food intake. Finally, exendin-4 did not alter the analgesic effects of oxycodone, suggesting that activation of GLP-1 receptors attenuated opioid reinforcement without reducing the thermal antinociceptive effects of oxycodone. Taken together, these findings suggest that GLP-1 receptors could serve as potential molecular targets for pharmacotherapies aimed at reducing opioid use disorder.

The University of Pennsylvania School of Nursing also highlighted our research on opioids and satiety factors in a news article . Find the full paper in Neuropsychopharmacology published here.