Buzzi_2023_Brain.Res_1817_148483

Nicotine and tobacco-related deaths remains a leading cause of preventable death and disease in the United States. Several studies indicate that modulation of the endocannabinoid system, primarily of the endocannabinoid 2-Arachidonoylglycerol (2-AG), alters nicotinic dependence behaviors in rodents. This study, using transgenic knock-out (KO) mice, evaluated the role of the two 2-AG biosynthesis enzymes, (Diacylglycerol lipase-alpha) DAGL-alpha and DAGL-beta in spontaneous nicotine withdrawal. DAGL-alpha deletion prevents somatic and affective signs of nicotine withdrawal, while DAGL-beta deletion plays a role in hyperalgesia due to nicotine withdrawal. These results suggest a differential role of these enzymes in the various signs of nicotine withdrawal. Our behavioral findings relate to the distribution of these enzymes with DAGL-beta being highly expressed in macrophages and DAGL-alpha in neurons. This study offers new potential targets for smoking cessation therapies.