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Vol. 55, Issue 1, 8-13, January 1999
9-Tetrahydrocannabinol Acts as a Partial Agonist
to Modulate Glutamatergic Synaptic Transmission between Rat Hippocampal
Neurons in Culture
Department of Pharmacology, University of Minnesota Medical School,
Minneapolis, Minnesota
9-Tetrahydrocannabinol (9-THC) is the
principal psychoactive ingredient in marijuana. We examined the effects
of 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
Ca++ concentration spikes that were measured by
indo-1-based microfluorimetry. 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, 9-THC was potent, but had low intrinsic
activity. 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 CB1 cannabinoid receptors. 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
9-THC is a partial agonist. The effect of
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
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 9-THC
is a partial agonist. The psychotropic effects of 9-THC
may result from inhibition of glutamatergic synaptic transmission. The
modest physical dependence produced by 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.
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