GLP-1 acts on habenular avoidance circuits to control nicotine intake

Tobacco smokers titrate their nicotine intake to avoid its noxious effects, sensitivity to which may influence vulnerability to tobacco dependence, yet mechanisms of nicotine avoidance are poorly understood. Here, we show that nicotine activates glucagon-like peptide-1 (GLP-1) neurons in the nucleus tractus solitarius (NTS). The antidiabetic drugs sitagliptin and exenatide, which inhibit GLP-1 breakdown and stimulate GLP-1 receptors (GLP-1Rs), respectively, decrease nicotine intake in mice. Chemogenetic activation of GLP-1 neurons in NTS similarly decreases nicotine intake. Conversely, Glp1r knockout mice consume greater quantities of nicotine than wild-type mice. Using optogenetic stimulation, we show that GLP-1 excites medial habenular (MHb) projections to interpeduncular nucleus (IPN). Activation of GLP-1Rs in the MHb-IPN circuit abolishes nicotine reward and decreases nicotine intake, whereas their knockdown or pharmacological blockade increases intake. GLP-1 neurons may therefore serve as “satiety sensors” for nicotine that stimulate habenular systems to promote nicotine avoidance before its aversive effects are encountered.