Inhibition of monoacylglycerol lipase reduces nicotine withdrawal.
- Authors
- Muldoon, P P; Chen, J; Harenza, J L; Abdullah, R A; Sim-Selley, L J; Cravatt, B F; Miles, M F; Chen, X; Lichtman, A H; Damaj, M I
- Year
- 2015
- Journal
- British journal of pharmacology
- PMID
- 25258021
- DOI
- 10.1111/bph.12948
- PMCID
- PMC4301695
BACKGROUND AND PURPOSE: Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored. EXPERIMENTAL APPROACH: To evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets. KEY RESULTS: BXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB1 receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans. CONCLUSIONS AND IMPLICATIONS: Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.
No figures extracted from this document.
No chunks β full text not yet ingested.
No entities extracted from this document yet.
No uploaded files.
No citations found.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| FAAH and MAGL inhibition: Evolving approaches to treating substance use disorders. | Maddox CJ et al. | β | 2026 | β |
| A multi-site study examining the tobacco withdrawal trajectory in people with tobacco and cannabis co-use. | Rabin RA et al. | β | 2025 | β |
| Maternal Obesity and Excessive Gestational Weight Gain Influence Endocannabinoid Levels in Human Milk Across Breastfeeding: Potential Implications for Offspring Development. | Pontes TF et al. | β | 2025 | β |
| The Role of Fatty Acid Binding Proteins in Neuropsychiatric Diseases: A Narrative Review. | Powell A et al. | β | 2025 | β |
| Association of <i>MGLL</i> Intronic C>T Single Nucleotide Polymorphism (rs782440) with Borderline Personality Disorder: A Case-Control Study. | Hatami Bavarsad N et al. | β | 2023 | β |
| Differential roles of diacylglycerol lipase (DAGL) enzymes in nicotine withdrawal. | Buzzi B et al. | β | 2023 | β |
| Maternal high-fat diet decreases milk endocannabinoids with sex-specific changes in the cannabinoid and dopamine signaling and food preference in rat offspring. | Dias-Rocha CP et al. | β | 2023 | β |
| Addiction-related neuroadaptations following chronic nicotine exposure. | Wills L et al. | β | 2021 | β |
| Chronic Augmentation of Endocannabinoid Levels Persistently Increases Dopaminergic Encoding of Reward Cost and Motivation. | Covey DP et al. | β | 2021 | β |
| Endocannabinoid Gene Γ Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts. | Elkrief L et al. | β | 2021 | β |
| New Insights in the Involvement of the Endocannabinoid System and Natural Cannabinoids in Nicotine Dependence. | Saravia R et al. | β | 2021 | β |
| Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases. | Zanfirescu A et al. | β | 2021 | β |
| Druggable Targets in Endocannabinoid Signaling. | Gregus AM et al. | β | 2020 | β |
| Inhibition of monoacylglycerol lipase reduces nicotine reward in the conditioned place preference test in male mice. | Muldoon PP et al. | β | 2020 | β |
| Novel therapeutic and drug development strategies for tobacco use disorder: endocannabinoid modulation. | Butler K et al. | β | 2020 | β |
| The novel MAGL inhibitor MJN110 enhances responding to reward-predictive incentive cues by activation of CB1 receptors. | Feja M et al. | β | 2020 | β |
| Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice. | Saravia R et al. | β | 2019 | β |
| Effects of Fatty Acid Amide Hydrolase Inhibitors Acute Administration on the Positive and Cognitive Symptoms of Schizophrenia in Mice. | Kruk-Slomka M et al. | β | 2019 | β |
| Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders. | Galaj E et al. | β | 2019 | β |
| 2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain. | Baggelaar MP et al. | β | 2018 | β |
| Inhibition of endocannabinoid degradation rectifies motivational and dopaminergic deficits in the Q175 mouse model of Huntington's disease. | Covey DP et al. | β | 2018 | β |
| Loren Parsons' contribution to addiction neurobiology. | De Luca MA et al. | β | 2018 | β |
| Monoacylglycerol lipase (MAGL) as a promising therapeutic target. | Gil-OrdΓ³Γ±ez A et al. | β | 2018 | β |
| Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study. | Cecil CAM et al. | β | 2018 | β |
| CB<sub>1</sub> Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal. | Saravia R et al. | β | 2017 | β |
| InΒ vivo interactions between Ξ±7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-Ξ±: Implication for nicotine dependence. | Jackson A et al. | β | 2017 | β |
| Monoglyceride lipase as a drug target: At the crossroads of arachidonic acid metabolism and endocannabinoid signaling. | Grabner GF et al. | β | 2017 | β |
| The endocannabinoid system as a target for addiction treatment: Trials and tribulations. | Sloan ME et al. | β | 2017 | β |
| Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism. | Doler C et al. | β | 2016 | β |
| Inhibition of monoacylglycerol lipase (MAGL) enhances cue-induced reinstatement of nicotine-seeking behavior in mice. | Trigo JM et al. | β | 2016 | β |
| Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives. | Scherma M et al. | β | 2016 | β |
| Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis. | Carey CE et al. | β | 2015 | β |