AM11101

Despite being the most prevalently abused illicit drug class, the neurochemical effects of cannabinoids (CBs) in key reward-related brain regions are not fully understood. Here, we used in vivo microdialysis combined with liquid chromatograph mass spectrometry to delineate how single, intraperitoneal injections of delta-9-tetrahydrocannabinol (Δ⁹-THC), and synthetic partial (AM11101) and full (AM8936) CB₁ agonists, impacted dopamine (DA), glutamate (Glu), and γ-aminobutyric acid (GABA) balance in the nucleus accumbens (nAcc) shell of male mice for 5 h post-administration, as well as conditioned place preference to determine their rewarding effects. Low doses of Δ⁹-THC increased DA and GABA, whereas AM8936 increased all three neurotransmitters. High doses of Δ⁹-THC and AM8936 decreased DA, while only high doses of AM8936 decreased GABA. AM11101 failed to substantially alter all three neurotransmitters. Correlation analysis revealed a significant DA-GABA and Glu-GABA relationship for Δ⁹-THC at early time points. Though their effects differed in timing, both AM11101 and AM8936 produced significant relationships between all three neurotransmitters. In conditioned place preference (CPP) studies, Δ⁹-THC and AM8936, but not AM11101, significantly increased CPP score. Together, these data demonstrate that CB₁ agonists differentially impact DA, GABA, and Glu levels in the nAcc shell, which directly correlate to reward-related behavioral effects. The lack of reward-related neurochemical or behavioral effects of AM11101, coupled with its superior biochemical profile, suggests that this partial CB₁ agonist is unique and warrants further studies on its potential as a CB₁-based pharmacotherapeutic for clinical indications.