title: Delta(9)-Tetrahydrocannabinol-induced desensitization of cannabinoid-mediated inhibition of synaptic transmission between hippocampal neurons in culture.
abstract: Prolonged exposure to cannabinoids results in desensitization of cannabinoid receptors. Here, we compared the desensitization produced by the partial agonist, Delta(9)-tetrahydrocannabinol (THC) to that produced by the full agonist Win55,212-2 on cannabinoid-mediated inhibition of glutamatergic synaptic transmission. Synaptic activity between rat hippocampal neurons was determined from network-driven increases in the intracellular Ca(2+) concentration ([Ca(2+)](i) spikes). To assess the effects of prolonged treatment, cultures were incubated with cannabinoids, washed in 0.5% fatty-acid-free bovine serum albumin to ensure the removal of the lipophilic drug and then tested for inhibition of [Ca(2+)](i) spiking by Win55,212-2. In control experiments, 0.1 microM Win55,212-2 inhibited [Ca(2+)](i) spiking by 93 +/- 5%. Win55,212-2 produced significantly less inhibition of [Ca(2+)](i) spiking following 18-24h treatment with 1 microM THC (48 +/- 5%) or treatment with 1 microM Win55,212-2 (29 +/- 6%). Thus, THC produced significantly less functional desensitization than Win55,212-2. The desensitization produced by THC was maximal at 0.3 microM, remained stable between 1 and 7 days of preincubation and shifted the EC(50) of acute inhibition by Win55,212-2 from 27 to 251 nM. Differences in the long-term effects of cannabinoid receptor agonists on synaptic transmission may prove important for evaluating their therapeutic and abuse potential.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street, Minneapolis, MN 55455-0217, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lundberg
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Daniel
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Thayer
mesh_terms: D000818:Animals; D048588:Benzoxazines; D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002478:Cells, Cultured; D013759:Dronabinol / Q000494:pharmacology*; D006213:Hallucinogens / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D006213:Hallucinogens; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D002118:Calcium