Dopamine, γ-aminobutyric acid, and glutamate balance in the nucleus accumbens shell: Differential effects of cannabinoid 1 receptor agonists Δ9-Tetrahydrocannabinol, AM11101, and AM8936.

Abstract

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.