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

Alan M Roloff, Stanley A Thayer

Molecular Pharmacology April 2009 DOI: 10.1124/mol.108.051482 (opens in new tab)

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AI-extracted from the abstract
Characteristics Basic science laboratory study Peer reviewed
Population Cultured rat hippocampal neurons
Interventions THC Win55212-2 2-arachidonylglycerol
Dose THC 1 microM, Win55212-2 100 nM, 2-arachidonylglycerol 1 microM
Topics Cannabis
Key points THC inhibited excitatory neurotransmission and calcium currents in cultured rat hippocampal neurons at 0.1 Hz stimulation but not at 0.5 Hz, while full cannabinoid agonists Win55212-2 and 2-arachidonylglycerol inhibited at both rates. At 0.5 Hz, THC occupied CB1 receptors without coupling to presynaptic calcium channels and blocked Win55212-2's inhibition. The authors propose THC displays state-dependent switching from agonist to antagonist, which may explain its complex in vivo actions.

Abstract

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 neurotransmission between cultured rat hippocampal neurons in a manner highly sensitive to stimulus rate. THC (1 microM) 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 microM) 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 microM 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 Gbetagamma 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.

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