Cocaine is a widely abused illicit drug and cocaine use disorder is a major public health concern as ~1 million American adults met the diagnostic criteria for the disorder in 2018.  Furthermore, recent data from the National Institute of Drug Abuse identifies substance use disorder as a risk factor for developing severe COVID-19 related symptoms that require hospitalization. Preventing relapse and promoting long-term abstinence remain the greatest challenges for successfully treating cocaine use disorder. Unfortunately, there are currently no FDA-approved pharmacotherapies to reduce the rate of cocaine relapse. Thus, further exploration of the neurological mechanisms underlying relapse is imperative to fill this gap in knowledge.

An emerging literature indicates that activation of central glucagon-like peptide-1 receptors (GLP-1Rs) reduces the rewarding effects of drugs of abuse and attenuates drug-seeking behavior during abstinence. In contrast, our preliminary data show that acute activation of GLP-1Rs in the central nucleus of the amygdala (CeA) augments the ability of a priming injection of cocaine to reinstate drug-seeking behavior during abstinence. These unexpected findings suggest that central GLP-1 signaling has differential roles in motivated behaviors depending on the circuits studied and thus opens a vast new area of research in addiction neuroscience.

The overarching goal of this study is to further examine the role of CeA GLP-1R signaling in cocaine-mediated behaviors. To verify out preliminary data, we intend to selectively activate GLP-1Rs in the CeA via a GLP-1R agonist and hypothesize that it will potentiate drug-seeking behavior. To determine if inhibiting endogenous GLP-1-producing projections from the nucleus tractus solitarus (NTS) to the CeA is sufficient to reduce cocaine seeking, chemogenetic techniques will be used to selectively inhibit this neural circuit prior to reinstatement tests sessions. We hypothesize that inhibition of endogenous NTS-to-CeA projections will attenuate drug seeking. To date, GLP-1R-expressing circuits in the amygdala have not been characterized. Neural tracing and fluorescent in situ hybridization techniques will be used to determine whether the bed nucleus of the stria terminalis (BNST) receives projections from GLP-1R-expressing neurons in the CeA. We hypothesize that the BNST is a primary downstream target of GLP-1R-expressing neurons in the CeA due to its role in withdrawal-mediated behaviors including drug seeking. The role of CeA GLP-1Rs in regulating motivated behaviors, including drug seeking, is largely unknown and understanding this circuitry is critical toward developing a therapeutic intervention that targets the central GLP-1 circuits to reduce cocaine craving-induced relapse. Perhaps a mixed agonist drug or one that takes advantage of the GLP-1Rs biased-agonism and diverging cellular cascade experienced is the key to treating cocaine-use disorder. 

Future directions will further examine this circuitry and investigate how stress may play a role. GLP-1 and cocaine are both anxiogenic and anxiety promotes cocaine-seeking behavior. Furthermore, CeA GLP-1 signaling promotes anxiety and these preliminary data suggest that CeA GLP-1 signaling promotes cocaine seeking as well. Thus, it is possible that CeA GLP-1 signaling mediates stress-induced cocaine seeking. 

*Due to COVID-19 the results of this study were hindered, however, we are currently increasing our n for experiment 1 and in the process of characterizing the CeA projections to the BNST as outlined in experiment 3.