Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for learning and memory, the consequences of prolonged exposure to ⌬ 9 -THC for hippocampal function are poorly understood. Rats were injected with ⌬ 9 -THC (10 mg/kg, i.p., q.d.) for 1, 3, or 7 d, and electrophysiological recordings were performed in hippocampal slices 1d after the final injection. At this time, ⌬ 9 -THC was undetectable in hippocampus using liquid chromatography-mass spectrometry (LC-MS). Hippocampal LTP generated using high-frequency (HFS) or theta burst stimulation was not observed in brain slices from the 7-d ⌬ -THC also produced tolerance to the inhibition of synaptic GABA, but not glutamate release by the agonist WIN55,212-2. These data define consequences of repeated ⌬ 9 -THC exposure for synaptic plasticity in the hippocampus that may help explain memory impairments in humans following chronic marijuana use.

As the amount of CBD found in most marijuana strains in the US is considerably less than that of THC, these results suggest that CBD concentrations relevant to what is normally found in marijuana exert very little, if any, modulatory effects on CB(1)-receptor-mediated pharmacological effects of marijuana smoke.