Δ9-Tetrahydrocannabinol acts as a partial agonist to modulate glutamatergic synaptic transmission between rat hippocampal neurons in culture

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) is the principal psychoactive ingredient in marijuana. We examined the effects of Delta(9)-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 Ga concentration spikes that were measured by indo-1-based microfluorimetry. Delta(9)-THC produced a concentration; dependent inhibition of spike frequency with an EC50 of 20 +/- 4 nM and a maximal inhibition of 41 +/- 3%. Thus, Delta(9) -THC was potent, but had low intrinsic activity, Delta(9)-THC (100 nM) inhibition of spiking was reversed by 300 nM N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716), indicating that the inhibition was mediated by CBI cannabinoid receptors. Delta(9)-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 Delta(9)-THC is a partial agonist. The effect of Delta(9)-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 Delta(9)-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 Delta(9)-THC is a partial agonist. The psychotropic effects of Delta(9)-THC may result from inhibition of glutamatergic synaptic transmission. The modest physical dependence produced by Delta(9)-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.