Cippitelli, AndreaAstarita, GiuseppeDuranti, AndreaCaprioli, GiovanniUbaldi, MassimoStopponi, SerenaKallupi, MarsidaSagratini, GianniRodríguez de Fonseca, FernandoPiomelli, DanieleCiccocioppo, Roberto2012-12-112012-12-112011-11-30Cippitelli A, Astarita G, Duranti A, Caprioli G, Ubaldi M, Stopponi S, et al. Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition. PLoS ONE.2011; 6(11):e28142WOS000298168100040http://hdl.handle.net/10668/704Journal Article; Research Support, Non-U.S. Gov't;Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use.enEnfermedad agudaAmidohidrolasasAnimalesAnsiedadÁcidos araquidónicosBenzamidasEncéfaloCarbamatosCotininaEndocanabinoidesGlicéridosImplantes experimentalesLocomociónMasculinoAprendizaje por laberintoNicotinaAlcamidas poliinsaturadasRatasSíndrome de abstinencia a sustanciasProductos para dejar de fumar tabacoAumento de pesoMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::AmidohydrolasesMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::AnxietyMedical Subject Headings::Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Arachidonic AcidsMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::BenzamidesMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::BrainMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Acids, Acyclic::CarbamatesMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrrolidines::Pyrrolidinones::CotinineMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Neurotransmitter Agents::EndocannabinoidsMedical Subject Headings::Chemicals and Drugs::Lipids::GlyceridesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Equipment and Supplies::Prostheses and Implants::Implants, ExperimentalMedical Subject Headings::Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Movement::LocomotionMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Learning::Maze LearningMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Alkaloids::Solanaceous Alkaloids::NicotineMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::Polyunsaturated AlkamidesMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::RatsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, WistarMedical Subject Headings::Diseases::Substance-Related Disorders::Substance Withdrawal SyndromeMedical Subject Headings::Technology, Industry, Agriculture::Technology, Industry, and Agriculture::Manufactured Materials::Tobacco Use Cessation ProductsMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development::Growth::Body Size::Body Weight::Body Weight Changes::Weight GainMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Acute Diseaseresearch article22140525open access10.1371/journal.pone.00281421932-6203PMC3227620