Behavioural and gene transcription alterations induced by spontaneous cannabinoid withdrawal in mice.
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.
Oliva
José M
JM
Servicio de Psiquiatría y Unidad de Investigación, Hospital Universitario 12 de Octubre, Madrid, Spain.
Ortiz
Sergio
S
Palomo
Tomás
T
Manzanares
Jorge
J
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
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