title: Behavioural and gene transcription alterations induced by spontaneous cannabinoid withdrawal in mice.
abstract: This study examined behavioural signs that occur during tolerance development to cannabinoid treatment and hormonal and gene expression alterations induced by spontaneous cannabinoid withdrawal in mice. Tolerance to CP-55,940 treatment developed for hypothermia, ambulatory and exploratory locomotor activity. Cessation of cannabinoid treatment resulted in a behavioural withdrawal syndrome characterized by a pronounced increase in ambulatory activity and rearings. Corticosterone plasma concentrations dramatically increased 24 and 72 h after cessation of cannabinoid treatment. Similarly, an increase (40%) in cannabinoid [35S]GTPgammaS binding autoradiography was detected on days 1 and 3 of abstinence. Spontaneous cannabinoid withdrawal produced time-related significant alterations in gene transcription: (i) decreased (20%) tyrosine hydroxylase (TH) mRNA levels in the ventral tegmental area and increased (50%) in substantia nigra; (ii) increased proenkephalin (PENK) gene expression more than 100% in caudate-putamen, nucleus accumbens, olfactory tubercle and piriform cortex; (iii) increased (20-40%) pro-opiomelanocortin (POMC) gene expression in the arcuate nucleus of the hypothalamus. These results suggest that spontaneous cannabinoid withdrawal occur after cessation of CP-55,940 treatment. This 'syndrome' includes behavioural, hormonal and gene transcription alterations that seems to be part of the regulation of neuronal plasticity induced by spontaneous cannabinoid withdrawal.
authors.affiliation: Servicio de Psiquiatría y Unidad de Investigación, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Oliva
authors.forename: Sergio
authors.initials: S
authors.lastname: Ortiz
authors.forename: Tomás
authors.initials: T
authors.lastname: Palomo
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
mesh_terms: D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002186:Cannabinoids / Q000009:adverse effects* / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D003511:Cyclohexanols / Q000009:adverse effects*; D004195:Disease Models, Animal; D004361:Drug Tolerance; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D004745:Enkephalins; D009025:Morpholines; D009281:Naphthalenes; D011498:Protein Precursors; D012333:RNA, Messenger; C029992:proenkephalin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D011333:Pro-Opiomelanocortin; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D014446:Tyrosine 3-Monooxygenase; D003345:Corticosterone