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

Abstract

BACKGROUND:

Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB1 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 CB1 neutral antagonist AM4113 on the abuse-related effects of nicotine and its effects on anxiety and depressive-like behavior in rats.

METHODS:

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).

RESULTS:

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.

CONCLUSION:

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.

• Authors: Aliou B Gueye, Yaroslaw Pryslawsky, Jose M Trigo, Nafsika Poulia, Foteini Delis, Katerina Antoniou, Michael Loureiro, Steve R Laviolette, Kiran Vemuri, Alexandros Makriyannis, Bernard Le Foll
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 19 Issue 12 (12 2016) ISSN: 1469-5111 [Electronic] England
• PMID: 27493155 (Publication Type: Journal Article)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of CINP.

Chemical References

• AM4113
• Cannabinoid Receptor Antagonists
• Cnr1 protein, rat
• Piperidines
• Pyrazoles
• Receptor, Cannabinoid, CB1
• Rimonabant

Topics

• Animals
• Anxiety (chemically induced, psychology)
• Behavior, Addictive (drug therapy, metabolism, physiopathology, psychology)
• Behavior, Animal (drug effects)
• Cannabinoid Receptor Antagonists (pharmacology, toxicity)
• Cues
• Depression (chemically induced, psychology)
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Drug Inverse Agonism
• Drug-Seeking Behavior (drug effects)
• Male
• Maze Learning (drug effects)
• Mesencephalon (drug effects, metabolism, physiopathology)
• Motivation (drug effects)
• Motor Activity (drug effects)
• Piperidines (pharmacology, toxicity)
• Pyrazoles (pharmacology, toxicity)
• Rats, Long-Evans
• Rats, Wistar
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, metabolism)
• Rimonabant
• Signal Transduction (drug effects)
• Swimming
• Time Factors
• Tobacco Use Cessation Devices
• Tobacco Use Disorder (drug therapy, metabolism, physiopathology, psychology)
• Weight Loss (drug effects)