TY - JOUR T1 - Δ<sup>9</sup>-Tetrahydrocannabinol Acts as a Partial Agonist to Modulate Glutamatergic Synaptic Transmission between Rat Hippocampal Neurons in Culture JF - Molecular Pharmacology JO - Mol Pharmacol SP - 8 LP - 13 DO - 10.1124/mol.55.1.8 VL - 55 IS - 1 AU - Maoxing Shen AU - Stanley A. Thayer Y1 - 1999/01/01 UR - http://molpharm.aspetjournals.org/content/55/1/8.abstract N2 - 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. ER -