Abstract
Δ9-Tetrahydrocannabinol (THC), the principal psychoactive ingredient in marijuana, acts as a partial agonist on presynaptic cannabinoid type 1 (CB1) receptors to inhibit neurotransmitter release. Here, we report that THC inhibits excitatory neurotransmission between cultured rat hippocampal neurons in a manner highly sensitive to stimulus rate. THC (1 μM) inhibited excitatory postsynaptic currents (EPSCs) and whole-cell ICa evoked at 0.1 Hz but at 0.5 Hz THC had little effect. The cannabinoid receptor full agonists [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate salt] (Win55212-2) (100 nM) and 2-arachidonylglycerol (1 μM) inhibited EPSCs independent of stimulation at 0.1 or 0.5 Hz. THC occupied CB1 receptors at 0.5 Hz, but the receptors failed to couple to presynaptic Ca2+ channels. Consequently, 1 μM THC blocked the inhibition of EPSC amplitude by Win55212-2 when EPSCs were evoked at 0.5 Hz. A depolarizing prepulse to 0 mV reversed THC inhibition of ICa, but reversal of the inhibition produced by Win55212-2 required a pulse to +80 mV, suggesting that the voltage-dependent reversal of Gβγ inhibition of voltage-gated Ca2+ channels accounts for the frequency-dependence of cannabinoid action. THC blocked depolarization-induced suppression of EPSCs evoked at 0.5 Hz, indicating that it inhibited retrograde endocannabinoid signaling in a frequency-dependent manner. Thus, THC displayed a state-dependent switching from agonist to antagonist that may account for its complex actions in vivo.
Footnotes
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This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA07304, DA11806, DA07097] and by the National Science Foundation [Grant IOS0814549].
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ABBREVIATIONS: THC, Δ9-tetrahydrocannabinol; Win55212-2, [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate salt]; CB1, cannabinoid type 1; 2-AG, 2-arachidonylglycerol; EPSC, excitatory postsynaptic current; IPSC, inhibitory postsynaptic current; CB1R, cannabinoid type 1 receptor; VGCC, voltage-gated calcium channel; GPCR, G-protein-coupled receptor; eCB, endocannabinoid; DMEM, Dulbecco's modified Eagle's medium; DSE, depolarization-induced suppression of excitation; AM251, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide; ISI, intersweep interval; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid.
- Received August 19, 2008.
- Accepted December 31, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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