Modulation of excitatory synaptic transmission by Δ ⁹- tetrahydrocannabinol switches from agonist to antagonist depending on firing rate

Δ 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 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 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]-(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 Ca ²⁺ 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 I _Ca, 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 Ca ²⁺ 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.