Chronic Effects of Indirect and Direct Cannabinoid Receptor Agonists on Addiction-Related Behaviors and Dopamine Release

A major problem with current anxiolytic medications is abuse liability; thus, new pharmaceutical targets are being explored. The cannabinoid system is one potential target. The current paper examined behavioral and neurochemical changes related to abuse liability following chronic administration of the indirect cannabinoid agonist arachidonoyl serotonin (AA-5-HT) and the direct cannabinoid type 1 receptor (CB1R) agonist arachidonyl-2-chloro-ethylamide (ACEA). AA-5-HT indirectly agonizes the cannabinoid system via inhibition of the dual fatty acid amide hydrolase (FAAH) while also inhibiting transient vanilloid type 1 (TRPV1) channels. Neither AA-5-HT nor ACEA induced conditioned place preference (CPP) or altered behaviors during open field (OF) or saccharin preference testing. AA-5-HT did not alter phasic dopamine release in the nucleus accumbens, as measured with in vivo fixed potential amperometry; however, ACEA decreased dopamine release and enhanced the dopaminergic effect of cocaine. Overall, neither AA-5-HT nor ACEA induced behavioral or neurochemical changes associated with abuse liability; however, indirect mechanisms of agonizing the cannabinoid system may be a better alternative than direct mechanisms if concerned with disrupting dopamine function.