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

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 36; no. 2; pp. 472 - 487
• Main Authors: SOUSA, Vasco C, ASSAIFE-LOPES, Natália, RIBEIRO, Joaquim A, PRATT, Judith A, BRETT, Ros R, SEBASTIAO, Ana M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 06.10.2010
• Subjects: Adenosine A1 Receptor Antagonists - toxicity; Animals; Biological and medical sciences; Caffeine - toxicity; Chronic Disease; Dronabinol - toxicity; Hippocampus - drug effects; Hippocampus - metabolism; Male; Medical sciences; Memory - drug effects; Memory - physiology; Memory Disorders - chemically induced; Memory Disorders - metabolism; Mice; Mice, Inbred C57BL; Neuropharmacology; Original; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Psychotropic Drugs - pharmacology; Rats; Rats, Wistar; Receptor, Adenosine A1 - metabolism; Receptor, Cannabinoid, CB1 - metabolism; CB1 cannabinoid receptor; Purine nucleoside; Adenosine; memory; CNS stimulant; Psychotropic; Central nervous system; A1 Adenosine receptor; Cannabinoid; THC; Encephalon; Respiratory analeptic; Chronic; Xanthine derivatives; Drug of abuse; Hippocampus; Caffeine; Spatial memory
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2010.179

The cannabinoid CB(1) 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(1) receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A(1) receptors localized in GABAergic cells do not directly influence GABA release. CB(1) and A(1) receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: Δ(9)-tetrahydrocannabinol (THC, a CB(1) receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A(1)-CB(1) interaction influences GABA and glutamate release in the hippocampus. We found that A(1) receptor activation attenuated the CB(1)-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 A(1)-mediated enhancement of the CB(1)-dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB(1) receptor number and an attenuation of CB(1) coupling with G protein. A(1) receptor levels were increased following chronic caffeine administration. This study shows that A(1) receptors exert a negative modulatory effect on CB(1)-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.