The Role of The Central GLP-1 System in Cocaine-Seeking Behavior

Cocaine use disorder continues be a significant public health concern with no available FDA-approved pharmacotherapies despite decades of research focused on treatment and the neurobiological mechanisms underlying drug addiction. Thus, there remains a critical need for conceptually innovative approaches toward identifying new medications to treat this disease. Current preclinical literature show that analogs of the neuroendocrine hormone glucagon-like peptide-1 (GLP-1) have promising clinical potential, as GLP-1 receptor (GLP-1R) activation reduces the rewarding and reinforcing effects of cocaine in animal models of drug addiction. To expand our knowledge of the neural circuitry and neurobiological mechanisms that underly the effects of GLP-1 on cocaine addiction, the research presented in this doctoral dissertation studies the role of the central GLP-1 system in regulating the reinstatement of cocaine-seeking behavior, an animal model of relapse. In Chapter 2, I establish that the GLP-1R agonist exendin-4 reduces cocaine seeking at doses that do not cause adverse side effects and acts on GLP-1Rs in the ventral tegmental area (VTA). Second, I show that the endogenous central GLP-1 system is dynamically changed by cocaine self-administration and abstinence. Chapter 3 demonstrates that GLP-1R activation in the nucleus accumbens (NAc) was sufficient to reduce cocaine seeking. To determine the effects of NAc GLP-1R activation on neuronal excitability in cocaine-experienced rats, electrophysiological studies were conducted and found that exendin-4 increased the intrinsic excitability of NAc medium spiny neurons. Chapter 4 continues to investigate the mechanism of exendin-4 to reduce cocaine seeking and the involvement of GLP-1R signaling in hindbrain nuclei. Administration of exendin-4 into the laterodorsal tegmental nucleus (LDTg) was found to decrease cocaine seeking by activating GLP-1Rs on GABAergic neurons that project to the VTA. Additionally, the ability of GLP-1-producing neurons in the nucleus tractus solitarius (NTS) to reduce cocaine seeking was examined. Activation of NTS-to-LDTg projections significantly attenuated cocaine seeking through a GLP-1-mediated mechanism without effecting food intake or body weight in cocaine-experienced animals. Collectively, this dissertation broadens our understanding of the neurobiological mechanisms that regulate cocaine seeking and also provides further evidence for the use of GLP-1 system-targeted therapeutics for treating cocaine use disorder