Δ9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus

Marijuana impairs learning and memory through actions of its psychoactive constituent, delta-9-tetrahydrocannabinol (Δ9-THC), in the hippocampus, through activation of cannabinoid CB1 receptors (CB1R). CB1Rs are found on glutamate and GABA neuron axon terminals in the hippocampus where they control neurotransmitter release. Previous studies suggest that Δ9-THC is a partial agonist of CB1Rs on glutamate axon terminals in the hippocampus, whereas its effects on GABA terminals have not been described. Using whole-cell electrophysiology in brain slices from C57BL6/J mice, we examined Δ9-THC effects on synaptic GABA IPSCs and postsynaptic GABA currents elicited by laser-induced photo-uncaging (photolysis) of α-carboxy-2-nitrobenzyl (CNB) caged GABA. Despite robust inhibition of synaptic IPSCs in wildtype mice by the full synthetic agonist WIN55,212-2, using a Tween-80 and DMSO vehicle, Δ9-THC had no effects on IPSCs in this, or in a low concentration of another vehicle, randomly-methylated β-cyclodextrin (RAMEB, 0.023%). However, IPSCs were inhibited by Δ9-THC in 0.1% RAMEB, but not in neurons from CB1R knockout mice. Whereas Δ9-THC did not affect photolysis-evoked GABA currents, these responses were prolonged by a GABA uptake inhibitor. Concentration-response curves revealed that the maximal effects of Δ9-THC and WIN55,212-2 were similar, indicating that Δ9-THC is a full agonist at CB1Rs on GABA axon terminals. These results suggest that Δ9-THC inhibits GABA release, but does not directly alter GABAA receptors or GABA uptake in the hippocampus. Furthermore, full agonist effects of Δ9-THC on IPSCs likely result from a much higher expression of CB1Rs on GABA versus glutamate axon terminals in the hippocampus.