Delta 9-tetrahydrocannabinol antagonizes endocannabinoid modulation of synaptic transmission between hippocampal neurons in culture.
Cannabinoids inhibit excitatory synaptic transmission between hippocampal neurons in culture. Delta9-tetrahydrocannabinol (THC), the principal psychoactive component in marijuana, acts as a partial agonist at these synapses. Thus, THC inhibited but did not block synaptic transmission when applied alone and, when applied in combination with WIN552212-2, it partially reversed the effects of this full agonist. Here, we address the question of how THC might interact with endocannabinoid signaling. Reducing the extracellular Mg2+ concentration to 0.1 mM elicited a repetitive pattern of glutamatergic synaptic activity that produced intracellular Ca2+ concentration spikes that were measured by indo-1-based microfluorimetry. The endocannabinoid, 2-arachidonyl glycerol (2-AG) produced a concentration-dependent and complete inhibition of spike frequency with an EC50 of 63 +/- 13 nM. 2-AG (1 microM) inhibition of spiking was blocked by SR141716A (1 microM). THC (100 nM) antagonized the actions of 2-AG producing a parallel shift in the concentration-response relationship for 2-AG (EC50 of 1430 +/- 254 nM). The attenuation of 2-AG (1 microM) inhibition of synaptic activity by THC was concentration-dependent with an IC50 of 42 +/- 9 nM. These results demonstrate that THC can antagonize endocannabinoid signaling. Thus, the effects of THC on synaptic transmission are predicted to depend on the level of endocannabinoid tone.
Kelley
Brooke G
BG
Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455-0217, USA.
Thayer
Stanley A
SA
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D013759:Dronabinol