Regulation of Hippocampal Cannabinoid CB1 Receptor Actions by Adenosine A1 Receptors and Chronic Caffeine Administration: Implications for the Effects of Δ9-Tetrahydrocannabinol on Spatial Memory.

The cannabinoid CB₁ receptor-mediated modulation of γ-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A₁ receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A₁ receptors localized in GABAergic cells do not directly influence GABA release. CB₁ and A₁ receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: Δ⁹-tetrahydrocannabinol (THC, a CB₁ receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A₁-CB₁ interaction influences GABA and glutamate release in the hippocampus. We found that A₁ receptor activation attenuated the CB₁-mediated inhibition of GABA and glutamate release and this interaction was manifested at the level of G-protein activation. Using in vivo and in vitro approaches, we then investigated the functional implications of the adenosine-cannabinoid interplay that may arise following chronic caffeine consumption. Chronic administration of caffeine in mice (intraperitoneally, 3 mg/kg/day, for 15 days, >12 h before trials) led to an A₁-mediated enhancement of the CB₁-dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB₁ receptor number and an attenuation of CB₁ coupling with G protein. A₁ receptor levels were increased following chronic caffeine administration. This study shows that A₁ receptors exert a negative modulatory effect on CB₁-mediated inhibition of GABA and glutamate release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in the cortex and hippocampus, with functional implications in spatial memory. [ABSTRACT FROM AUTHOR]