title: 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: Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB1inverse 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 CB1neutral 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.
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Aliou B
authors: AB
authors: Gueye
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Yaroslaw
authors: Y
authors: Pryslawsky
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Jose M
authors: JM
authors: Trigo
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Nafsika
authors: N
authors: Poulia
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Foteini
authors: F
authors: Delis
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Katerina
authors: K
authors: Antoniou
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Michael
authors: M
authors: Loureiro
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Steve R
authors: SR
authors: Laviolette
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Kiran
authors: K
authors: Vemuri
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis).
authors: Alexandros
authors: A
authors: Makriyannis
authors: Translational Addiction Research Laboratory (Dr Gueye, Mr Pryslawsky, Dr Trigo, and Dr Le Foll), Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments (Dr Le Foll), and Campbell Family Mental Health Research Institute (Dr Le Foll), Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Department of Pharmacology, and Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (Dr Le Foll); Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Ms Poulia and Drs Delis and Antoniou); Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (Drs Loureiro and Laviolette); Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA (Drs Vemuri and Makriyannis). Bernard.LeFoll@camh.ca.
authors: Bernard
authors: B
authors: Le Foll
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000523:psychology; D016739:Behavior, Addictive / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology* / Q000633:toxicity; D003463:Cues; D003863:Depression / Q000139:chemically induced / Q000523:psychology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D058999:Drug-Seeking Behavior / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009042:Motivation / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology* / Q000633:toxicity; D011720:Pyrazoles / Q000494:pharmacology* / Q000633:toxicity; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects; D013550:Swimming; D013997:Time Factors; D061485:Tobacco Use Cessation Devices; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D015431:Weight Loss / Q000187:drug effects*
chemical_list: C529765:AM4113; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant
keywords: CB1 antagonism; anxiety; depression; dopamine; nicotine reward