Δ⁹-Tetrahydrocannabinol antagonizes endocannabinoid modulation of synaptic transmission between hippocampal neurons in culture

Cannabinoids inhibit excitatory synaptic transmission between hippocampal neurons in culture. Δ⁹-tetrahydrocannabinol (THC), the principal psychoactive component in marijuana, acts as a partial agonist at these synapses. Thus, THC inhibited but did not block synaptic transmission when applied alone and, when applied in combination with WIN552212-2, it partially reversed the effects of this full agonist. Here, we address the question of how THC might interact with endocannabinoid signaling. Reducing the extracellular Mg²⁺ concentration to 0.1 mM elicited a repetitive pattern of glutamatergic synaptic activity that produced intracellular Ca ²⁺ concentration spikes that were measured by indo-1-based microfluorimetry. The endocannabinoid, 2-arachidonyl glycerol (2-AG) produced a concentration-dependent and complete inhibition of spike frequency with an EC₅₀ of 63±13 nM. 2-AG (1 μM) inhibition of spiking was blocked by SR141716A (1 μM). THC (100 nM) antagonized the actions of 2-AG producing a parallel shift in the concentration-response relationship for 2-AG (EC₅₀ of 1430±254 nM). The attenuation of 2-AG (1 μM) inhibition of synaptic activity by THC was concentration-dependent with an IC₅₀ of 42±9 nM. These results demonstrate that THC can antagonize endocannabinoid signaling. Thus, the effects of THC on synaptic transmission are predicted to depend on the level of endocannabinoid tone.