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

Abstract

The cannabinoid CB 1 receptor-mediated modulation of g-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: D 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, 412 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.

Cannabinoids disrupt hippocampal sharp wave‐ripples via inhibition of glutamate release

“…Recent work has suggested direct interactions of adenosine A1 and CB1 receptors in the hippocampus (Hoffman et al, 2010;Sousa et al, 2011). To exclude a possible interplay between these two systems of neuromodulators in regulating SWRs, we also compared the adenosine-mediated suppression of SWRs in the absence and presence of AM251.…”

The effect of caffeine on working memory load-related brain activation in middle-aged males

“…Caffeine, a non--selective adenosine receptor antagonist (Pelligrino et al, 2010), elicits: 1) neurostimulant effects, primarily via A1 receptors and the dopamine system (Ferre, 2008;Pelligrino et al, 2010); 2) cerebrovascular effects, primarily via A2A and A2B receptors located on blood vessels (Pelligrino et al, 2010); and 3) arousal enhancing effects, via A2A receptors and the histaminergic arousal system (Ferre, 2008); with tolerance thought to arise as the brain regulates its population of adenosine receptors to reach a new state of equilibrium in response to levels of caffeine chronically present in the body (Jacobson et al, 1996;Ralevic and Burnstock, 1998;Sousa et al, 2011). Studies have shown that administration of 200 --250 mg of caffeine results in reduced CBF (Addicott et al, 2009;Field et al, 2003;Laurienti et al, 2003;Liau et al, 2008;Mulderink et al, 2002;Perthen et al, 2008), possibly accompanied by a reduction in the baseline BOLD signal (during simple motor and visual tasks) (Chen and Parrish, 2009b;Perthen et al, 2008) and changes in the magnitude (Griffeth et al, 2011;Laurienti et al, 2002) and temporal dynamics of the BOLD response Liu et al, 2004;Rack--Gomer et al, 2009).…”

A Preliminary Study on the Effects of Self-Reported Dietary Caffeine on Pain Experience and Postoperative Analgesia

“…This may have been an important factor since studies have shown that pain receptors, such as adenosine A1 and cannabinoid CB1, can be altered by chronic caffeine use. 24 However, such findings have been primarily in preclinical samples and it is not known how long-term dietary caffeine intake in humans might influence this antinociceptive action.…”