title: CB1Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.
abstract: Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans.
  
  
  
  We investigated in mice the role of CB1cannabinoid receptors (CB1Rs) in memory impairment and spine density changes induced by nicotine withdrawal precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the endocannabinoid system and genetically modified mice were used.
  
  
  
  Memory impairment during nicotine withdrawal was blocked by the CB1R antagonist rimonabant or the genetic deletion of CB1R in forebrain gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CB1R). An increase of 2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG enzymatic degradation JZL184 did not produce any effect in cognitive impairment. Moreover, memory impairment was prevented by the selective mammalian target of rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin. Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days after the precipitation of nicotine withdrawal, when the cognitive deficits were still present. Indeed, a correlation between memory performance and mature spine density was found. Interestingly, these structural plasticity alterations were normalized in GABA-CB1R conditional knockout mice and after subchronic treatment with rimonabant.
  
  
  
  These findings underline the interest of CB1R as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk.
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Saravia
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: África
authors.initials: Á
authors.lastname: Flores
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Plaza-Zabala
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Busquets-Garcia
authors.affiliation: Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición (AP, RdlT), Instituto Salud Carlos III, Madrid, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Pastor
authors.affiliation: Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain; CIBER Fisiopatología Obesidad y Nutrición (AP, RdlT), Instituto Salud Carlos III, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U862 NeuroCentre Magendie, Group Endocannabinoids and Neuroadaptation, Bordeaux, France; University of Bordeaux, Bordeaux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Ozaita
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: fernando.berrendero@upf.edu.
authors.forename: Fernando
authors.initials: F
authors.lastname: Berrendero
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage; D063388:Endocannabinoids / Q000378:metabolism; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology; D005989:Glycerides / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects*; D009538:Nicotine / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000008:administration & dosage; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018079:Receptors, GABA / Q000235:genetics / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D000077285:Rimonabant; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D018079:Receptors, GABA; D009538:Nicotine; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide
keywords: CB(1)R; Cognition; Knockout mice; Nicotine; Plasticity; Withdrawal