The effects of delta9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors.
The effects of chronic Delta(9)-tetrahydrocannabinol on cannabinoid receptor levels and receptor-G-protein coupling were investigated. Male Sprague-Dawley rats were infused continuously with low or high dose regimens of Delta(9)-tetrahydrocannabinol or vehicle for 4 days. Following treatment, rats were sacrificed for cannabinoid CB(1) receptor binding analysis or challenged with the cannabinoid CB(1) receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). The rats receiving Delta(9)-tetrahydrocannabinol exhibited antagonist-precipitated withdrawal signs. Each brain region (cerebellum, cortex, hippocampus and basal ganglia) from high-dose rats showed 30-70% decreases in [3H] (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxyphenyl)cyclohexanol (WIN55212-2) B(max) values, indicating receptor down-regulation. Most regions showed decreased WIN55212-2-stimulated [35S]guanosine-5'-O-3-thiotriphosphate (GTPgammaS) binding, indicating desensitization of cannabinoid CB(1) receptors. Additional receptor binding assays in cerebellar membranes showed a significantly greater decrease in agonist than in antagonist B(max) values, indicating a lower fraction of coupled receptors after treatment. Concentration-effect analysis of five agonists revealed that the treatment resulted in greater decreases in the efficacy of low-efficacy agonists.
Breivogel
Christopher S
CS
Department of Pharmaceutical Sciences, Campbell University School of Pharmacy, P.O. Box 1090, Buies Creek, NC 27506, USA. breivogel@mailcenter.campbell.edu
Scates
Susan M
SM
Beletskaya
Irina O
IO
Lowery
Olivia B
OB
Aceto
Mario D
MD
Martin
Billy R
BR
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002186:Cannabinoids / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D013759:Dronabinol / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D002189:Marijuana Abuse / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism*
D002186:Cannabinoids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol