The CB1 Neutral Antagonist AM4113 Retains the Therapeutic Efficacy of the Inverse Agonist Rimonabant for Nicotine Dependence and Weight Loss with Better Psychiatric Tolerability

Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB inverse agonist found to be effective for smoking cessation, was associated with an increased risk of anxiety and depression. Here we evaluated...

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Bibliographic Details
Published in:The international journal of neuropsychopharmacology 2016-12, Vol.19 (12)
Main Authors: Gueye, Aliou B, Pryslawsky, Yaroslaw, Trigo, Jose M, Poulia, Nafsika, Delis, Foteini, Antoniou, Katerina, Loureiro, Michael, Laviolette, Steve R, Vemuri, Kiran, Makriyannis, Alexandros, Le Foll, Bernard
Format: Article
Language:English
Subjects:
Animals
Anxiety - chemically induced
Anxiety - psychology
Behavior, Addictive - drug therapy
Behavior, Addictive - metabolism
Behavior, Addictive - physiopathology
Behavior, Addictive - psychology
Behavior, Animal - drug effects
Cannabinoid Receptor Antagonists - pharmacology
Cannabinoid Receptor Antagonists - toxicity
Cues
Depression - chemically induced
Depression - psychology
Disease Models, Animal
Dopaminergic Neurons - drug effects
Dopaminergic Neurons - metabolism
Dose-Response Relationship, Drug
Drug Inverse Agonism
Drug-Seeking Behavior - drug effects
Male
Maze Learning - drug effects
Mesencephalon - drug effects
Mesencephalon - metabolism
Mesencephalon - physiopathology
Motivation - drug effects
Motor Activity - drug effects
Piperidines - pharmacology
Piperidines - toxicity
Pyrazoles - pharmacology
Pyrazoles - toxicity
Rats, Long-Evans
Rats, Wistar
Receptor, Cannabinoid, CB1 - antagonists & inhibitors
Receptor, Cannabinoid, CB1 - metabolism
Regular
Signal Transduction - drug effects
Swimming
Time Factors
Tobacco Use Cessation Products
Tobacco Use Disorder - drug therapy
Tobacco Use Disorder - metabolism
Tobacco Use Disorder - physiopathology
Tobacco Use Disorder - psychology
Weight Loss - drug effects
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Summary:Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB inverse agonist found to be effective for smoking cessation, was associated with an increased risk of anxiety and depression. Here we evaluated the effects of the CB neutral antagonist AM4113 on the abuse-related effects of nicotine and its effects on anxiety and depressive-like behavior in rats. Rats were trained to self-administer nicotine under a fixed-ratio 5 or progressive-ratio schedules of reinforcement. A control group was trained to self-administer food. The acute/chronic effects of AM4113 pretreatment were evaluated on nicotine taking, motivation for nicotine, and cue-, nicotine priming- and yohimbine-induced reinstatement of nicotine-seeking. The effects of AM4113 in the basal firing and bursting activity of midbrain dopamine neurons were evaluated in a separate group of animals treated with nicotine. Anxiety/depression-like effects of AM4113 and rimonabant were evaluated 24h after chronic (21 days) pretreatment (0, 1, 3, and 10mg/kg, 1/d). AM4113 significantly attenuated nicotine taking, motivation for nicotine, as well as cue-, priming- and stress-induced reinstatement of nicotine-seeking behavior. These effects were accompanied by a decrease of the firing and burst rates in the ventral tegmental area dopamine neurons in response to nicotine. On the other hand, AM4113 pretreatment did not have effects on operant responding for food. Importantly, AM4113 did not have effects on anxiety and showed antidepressant-like effects. Our results indicate that AM4113 could be a promising therapeutic option for the prevention of relapse to nicotine-seeking while lacking anxiety/depression-like side effects.
ISSN:1461-1457
1469-5111
DOI:10.1093/ijnp/pyw068