Cannabinoid CB1 and Cholecystokinin CCK2 Receptors Modulate, in an Opposing Way, Electrically Evoked [3H] GABA Efflux from Rat Cerebral Cortex Cell Cultures: Possible Relevance for Cortical GABA Transmission and Anxiety

The effects of treatments with cannabinoid (CB)(1) and cholecystokinin (CCK)(2) receptor agonists and antagonists, as well as compounds that enhance endocannabinoid signaling by inhibiting degradation, e. g., the fatty acid amide hydrolase inhibitor 3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate (URB597) or the endocannabinoid reuptake inhibitor (5Z, 8Z, 11Z, 14Z)-N-(3-furanylmethyl)-5,8,11,14-eicosatetraenamide (UCM707), were studied both on spontaneous and electrically evoked [H-3] GABA efflux from rat cerebral cortex cell cultures. The CCK2 receptor agonist CCK-8S, the CB1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2), URB597, UCM707, the CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR141716A), and the CCK2 receptor antagonist 2-[2-(5-Br-1H-indol-3-yl)ethyl]-3-[3-(1-methylethoxy)phenyl]-4-(3H)-quinazolinone (LY225910) did not affect spontaneous [H-3] GABA efflux. CCK-8S concentration-dependently increased electrically evoked [H-3] GABA overflow, and this effect was prevented by LY225910. WIN55,212-2, URB597, and UCM707 induced a reduction of electrically evoked [H-3]GABA overflow. This reduction was counteracted by SR141716A. When CCK-8S and one of cannabinoid-interfering compounds were simultaneously added, at concentrations by themselves ineffective, to the superfusion medium, an enhancement in electrically evoked [H-3] GABA efflux was observed. This increase was counteracted by either SR141716A or LY225910 as well as by the inhibitor of protein kinase C, (1R)-2-[12-[(2R)-2(benzoyloxy)propyl]-3,10-dihydro-4,9-dihydroxy-2,6,7,11-tetramethoxy-3,10-dioxo-1-perylenyl]-1-methylethylcarbonic acid 4-hydroxyphenyl ester (calphostin C). These results indicate that CB1 and CCK2 receptors modulate, in an opposing way, electrically evoked [H-3] GABA efflux from rat cerebral cortex cell cultures. The existence of a CB1/CCK2 receptor heteromer on cortical GABA terminals, with a possible relevance for cortical GABA transmission and anxiety, is postulated.