Modulation of Excitatory Synaptic Transmission by Δ9-Tetrahydrocannabinol Switches from Agonist to Antagonist Depending on Firing Rate

Delta(9)-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 neuro-transmission between cultured rat hippocampal neurons in a manner highly sensitive to stimulus rate. THC (1 mu M) inhibited excitatory postsynaptic currents (EPSCs) and whole-cell I-Ca 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]-(1naphthalenyl)methanone mesylate salt] (Win55212-2) (100 nM) and 2-arachidonylglycerol (1 mu M) 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 mu M 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 I-Ca, but reversal of the inhibition produced by Win55212-2 required a pulse to +80 mV, suggesting that the voltage-dependent reversal of G beta gamma 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.