Abstract

Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) is the principal psychoactive ingredient in marijuana. We examined the effects of Δ⁹-THC on glutamatergic synaptic transmission. Reducing the extracellular Mg⁺⁺ concentration bathing rat hippocampal neurons in culture to 0.1 mM elicited a repetitive pattern of glutamatergic synaptic activity that produced intracellular Ca⁺⁺ concentration spikes that were measured by indo-1-based microfluorimetry. Δ⁹-THC produced a concentration-dependent inhibition of spike frequency with an EC₅₀ of 20 ± 4 nM and a maximal inhibition of 41 ± 3%. Thus, Δ⁹-THC was potent, but had low intrinsic activity. Δ⁹-THC (100 nM) inhibition of spiking was reversed by 300 nMN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716), indicating that the inhibition was mediated by CB1 cannabinoid receptors. Δ⁹-THC attenuated the inhibition produced by a full cannabinoid receptor agonist, (+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-napthalenyl)methanone monomethanesulfonate (Win 55212-2), indicating that Δ⁹-THC is a partial agonist. The effect of Δ⁹-THC on synaptic currents was also studied. 6-Cyano-2,3-dihydroxy-7-niroquiinoxaline (CNQX)-sensitive excitatory postsynaptic currents were recorded from cells held at −70 mV in the whole-cell configuration of the patch-clamp and elicited by presynaptic stimulation with an extracellular electrode. Win 55212-2 and Δ⁹-THC inhibited excitatory postsynaptic current (EPSC) amplitude by 96 ± 2% and 57 ± 4%, respectively. Excitatory postsynaptic current amplitude was reduced to 75 ± 5% in the presence of both drugs, demonstrating that Δ⁹-THC is a partial agonist. The psychotropic effects of Δ⁹-THC may result from inhibition of glutamatergic synaptic transmission. The modest physical dependence produced by Δ⁹-THC as well as its lack of acute toxicity may be due to the ability of the drug to reduce, but not block, excitatory neurotransmission.