Regulation of hippocampal cannabinoid CB receptor actions by adenosine A receptors and chronic caffeine administration: implications for the effects of ∆-tetrahydrocannabinol on spatial memory

Vasco C. Sousa (1) , Natália Assaife-Lopes (1) , Joaquim Alexandre Ribeiro (1) , Judith A Pratt (1) , Ros R Brett (1) , Ana Maria Sebastião (1)

1 Institute of Pharmacology and Neurosciences and Unit of Neurosciences

The cannabinoid CB receptor-mediated modulation of γ-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A receptors localized in GABAergic cells do not directly influence GABA release. CB and A receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: Δ-tetrahydrocannabinol (THC, a CB receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A-CB interaction influences GABA and glutamate release in the hippocampus. We found that A receptor activation attenuated the CB-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 (i.p., 3 mg/kg/day, for 15 days, >12h before trials) led to an A-mediated enhancement of the CB-dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB receptor number and an attenuation of CB coupling with G-protein. A receptor levels were increased following chronic caffeine administration. This study demonstrates that A receptors exert a negative modulatory effect on CB-mediated inhibition of GABA release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in cortex and hippocampus, with functional implications in spatial memory.

Mots clés: Receptor Pharmacology; GABA; Learning & Memory; Neuropharmacology; adenosine; cannabinoid; hippocampus; caffeine; THC

Vasco C. Sousa, Natália Assaife-Lopes, Joaquim Alexandre Ribeiro, Judith A Pratt, Ros R Brett, et al.. Regulation of hippocampal cannabinoid CB receptor actions by adenosine A receptors and chronic caffeine administration: implications for the effects of ∆-tetrahydrocannabinol on spatial memory. Neuropsychopharmacology, 2010, ⟨10.1038/npp.2010.179⟩. ⟨hal-00583532⟩