Hypothesizing glucagon-like peptide 1 (GLP-1), agonists promote hypodopaminergia, resulting in heightened addictive reward-seeking and altered mood: Breaking the bubble and adding salt to a wound

Recent articles have suggested that the agonistic effects of GLP-1 in alcohol use disorder and substance use disorder are mediated centrally, partly through the downregulation of dopamine signaling. This hypothesis, from a consortium of multidisciplinary scientists and clinicians, explores the role of GLP-1 receptor agonists as compounds with broad antiaddiction properties. Short-term dopamine downregulation is relevant in treating metabolic disorders to reduce hyperdopaminergia, which increases insulin resistance and decreases insulin secretion. Single-nuclei transcriptomics and Fluorescent in situ Hybridization (FISH) studies revealed that GLP-1Rs are expressed primarily on GABA neurons in the VTA. Scientists using in-vivo fiber photometry found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. However, to our knowledge, this is the first hypothesis to expose the potential of GLP-1 receptor agonists for heightened addictive reward-seeking behavior. Therefore, we caution against promoting chronic stimulation via GLP-1 agonists. Indeed, basic research findings have linked GLP-1 receptor agonists and several genes within the dopaminergic reward pathway. Therefore, stimulation of GLP-1 receptor agonists, especially chronically, can lead to the dysregulation of the dopaminergic pathway, which in turn can putatively cause depression, suicidality, and other mood disturbances. We therefore hypothesize that while employing GLP-1 agonism offers therapeutic benefits in instances of recognized hyperdopaminergia, it could be detrimemtal in patients with hypodopaminergia at risk for SUD.