Action of Delta-9-tetrahydrocannabinol on GABA(A) Receptor-mediated Responses in a Grease-gap Recording Preparation of the Rat Hippocampal Slice

We have investigated the effects of delta-9-tetrahydrocannabinol (delta-9-THC) on gamma-aminobutyric acid (GABA) receptor-mediated responses in a grease-gap recording preparation of the rat hippocampus. GABA, and the selective GABA(A) receptor agonist muscimol, evoked depolarizing responses with EC50 values of 8.5 mM and 17.0 microM, respectively. Responses to both of these agonists were selectively reduced by the non-competitive GABA(A) antagonist picrotoxin (5 microM), but were unaffected by the GABA(B) antagonist 2-hydroxysaclofen (500 microM). Responses evoked by the selective GABA(B) receptor agonist baclofen were not sufficiently large to analyse. The GABA uptake inhibitor, nipecotic acid (500 microM), potentiated responses to GABA, but not to muscimol. Similarly, 10-1000 nM delta-9-THC had no significant effect on the response to muscimol, whereas 1000 nM delta-9-THC significantly increased the response to GABA. Since GABA is the substrate of an avid uptake system, but muscimol is not, the results are consistent with the suggestion that delta-9-THC inhibits the uptake of GABA in the hippocampus.