GLP-1 is also produced by a small population of neurons in the brainstem that are activated during feeding. The release of GLP-1 in the brain suppresses appetite and, if released at high levels, contributes to feelings of discomfort or sickness after overeating. These combined insulinotropic and anorexigenic effects provided the scientific rationale for developing long-lasting GLP-1 receptor (GLP1R) agonists such as semaglutide, the active ingredient in Ozempic®, used for blood glucose management in type 2 diabetes, and Wegovy®, used for weight loss in obesity.
Emerging evidence suggests that GLP1R agonists have other unexpected health benefits. Risk of death from cardiovascular events was reduced in overweight patients who were treated with GLP1R agonists. The incidence of nonfatal heart attacks and stroke was similarly reduced in these individuals. Data from a small number of human clinical trials suggest that GLP1R agonists may protect against age-related neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Larger-scale human clinical trials have been initiated to determine whether GLP1R agonists represent novel treatments for these devastating brain disorders.
Semaglutide and related drugs are also gaining attention as promising anti-craving medications that may help prevent relapse in individuals with substance use disorders (SUDs), chronic conditions defined by compulsive drug-seeking behaviors. Existing pharmacotherapies for SUDs typically target the same receptor systems in the brain that are activated by drugs of abuse.
For instance, opioids such as fentanyl and heroin can fully activate μ opioid receptors (μORs), producing intense euphoria that drives the development of opioid use disorder (OUD). The frontline treatment for OUD, buprenorphine, is an opioid itself that can only partially activate μORs; it does not induce the same level of euphoria as full agonists but sufficiently activates μORs to relieve withdrawal symptoms and reduce the intense cravings associated with abstinence.
GLP1R agonists could represent an entirely new frontier in managing relapse risk by targeting mechanisms beyond the traditional receptor systems involved in addiction.
Still, the risk of relapse remains significant, and improved treatments are urgently needed. GLP1R agonists could represent an entirely new frontier in managing relapse risk by targeting mechanisms beyond the traditional receptor systems involved in addiction.
The early promise of GLP1R agonists in alleviating drug craving has sparked considerable interest in their mechanisms of action. Opioids, alcohol, and other addictive substances increase dopamine release in the nucleus accumbens (NAc), a key brain region involved in reward processing. This dopamine surge is believed to underlie the reinforcing properties of these substances, and a desire to obtain this effect may contribute to drug craving that promotes relapse. GLP1R agonists have been shown to attenuate dopamine signaling in the NAc and other brain regions, an action that may explain their anti-craving effects.
Surveys of GLP1R levels in the brain have revealed only modest expression by the dopamine neurons in the midbrain or their target neurons in the NAc that are primarily affected by addictive drugs. This has raised suspicion that other brain regions with higher GLP1R levels contribute to their anti-craving effects.
The interpeduncular nucleus (IPN) contains some of the highest concentrations of GLP1Rs in the brain. The IPN also contains high levels of μORs, nicotinic acetylcholine receptors (nAChRs), CB1 cannabinoid receptors, and other receptors that regulate the actions of addictive drugs.
The laboratory of Paul J. Kenny, PhD, has shown that stimulation of GLP1Rs in the IPN completely abolishes the rewarding effects of nicotine (see Nature Neuroscience). Activation of the IPN decreases dopamine signaling, perhaps explaining the inhibitory effect of GLP1Rs on dopamine transmission. Whether GLP1Rs in the IPN regulate the motivational properties of opioids, alcohol, and other addictive drugs is currently unknown.
Activation of GLP1Rs by semaglutide and similar drugs initiates a signaling cascade that triggers the activation of a protein called TCF7L2. This protein, in turn, regulates the expression of genes responsible for mediating cellular responses to GLP1R agonists. The Kenny laboratory has found that TCF7L2 is expressed in the IPN. It is also densely expressed in the medial habenula (MHb), which provides the major source of excitatory synaptic input to IPN neurons. Findings revealed that genetic disruption of TCF7L2 expression in MHb and IPN neurons decreases their sensitivity to GLP1R agonists and dramatically increases the rewarding effects of nicotine. Identifying the TCF7L2-regulated genes that control the actions of GLP1R agonists on MHb and IPN neurons may provide further opportunities for developing new SUD pharmacotherapeutics. (See Figure.)
Figure. Left panel: GLP1R stimulates the activity of the transcription factor TCF7L2 in the medial habenula. Blue-stained neurons are those in which TCF7L2 is actively regulating gene expression. Right panel: GLP1R signaling and TCF7L2 interact in a reciprocal manner to regulate the expression of genes involved in drug craving and the development of type 2 diabetes.
The risk of type 2 diabetes is known to be significantly higher in tobacco smokers compared to nonsmokers. Likewise, alcohol, opioid, and cocaine dependence are each associated with an increased risk of diabetes. The Kenny lab has found that nicotine elevates blood glucose levels in rats and mice through a mechanism involving GLP1Rs and TCF7L2 in the MHb and IPN. Repeated exposure to this effect of nicotine precipitates diabetes-related abnormalities in blood glucose homeostasis, suggesting that GLP1R signaling in the brain may contribute to the development of diabetes and other metabolic disturbances in cigarette smokers and those with other SUDs.
The link between GLP1Rs and the motivational and physiological properties of addictive drugs hints at deeper interactions between reward-related circuits in the brain and peripheral metabolic processes.
GLP1R agonists such as semaglutide have emerged as powerful tools for managing type 2 diabetes and obesity. Beyond their established metabolic benefits, ongoing human clinical trials will soon reveal whether GLP1R agonists also represent novel treatments for SUDs. The link between GLP1Rs and the motivational and physiological properties of addictive drugs hints at deeper interactions between reward-related circuits in the brain and peripheral metabolic processes. Understanding how GLP1Rs exert their anti-craving effects may reveal important new insights into the mechanisms of SUDs and how the use of addictive drugs and the risk of developing diabetes and other metabolic disturbances intersect.
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Paul J. Kenny, PhD
Ward-Coleman Professor of Neuroscience and Chair, Nash Family Department of Neuroscience, and Director, Marie-Josée and Henry R. Kravis Drug Discovery Institute, Icahn School of Medicine at Mount Sinai @PaulKennyPhD