Abbreviations: 2-AG, 2-arachidonoylglycerol; AA-5-HT, N-arachidonoyl serotonin; ACEA, arachidinoyl-2'chloroethylamide; AEA, arachidonoylethanolamide; B6, C57BL/6J mice; CB1R, cannabinoid type 1 receptor; CB2R, cannabinoid type 2 receptor; CPA, conditioned place aversion; CPP, conditioned place preference; DAR, dopamine autoreceptor; DAT, dopamine transporter; D2R, dopamine receptor D2; D3R, dopamine receptor D3; eCB, endocannabinoid; EPM, elevated plus maze; FAB5, fatty acid binding protein-5; FAB7, fatty acid binding protein 7; FAAH, fatty acid amide hydrolase; LDB, light/dark box; MAGL, monoacylglycerol lipase; NAc, Nucleus accumbens; OF, open field, THC, Δ 9 -tetrahydracannabinol; TRPV1, transient receptor potential vanilloid type 1 channel; VTA, ventral tegmental area anad Highlights • The indirect cannabinoid agonist AA-5-HT did not alter dopamine release or measured behaviors.• The direct cannabinoid receptor agonist ACEA did not alter measured behaviors.• ACEA decreased dopamine release and the dopaminergic response to cocaine.• Neither drug indicated abuse liability, although ACEA did alter dopamine functioning. Abstract 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.