Neurochemical and Behavioral Effects of Cannabinoid CB₁Agonist in Male Mice

Abstract ID 92896 Poster Board 304 Despite having many potential therapeutic applications, cannabinoids have multiple undesirable effects limiting their use, such as impaired motor function, sleep disruption, and a notable abuse liability in humans. Like most drugs of abuse, studies have reported cannabinoids to increase extracellular levels of the neurotransmitter dopamine (DA) in key reward-related brain regions, including the nucleus accumbens shell (nAcc shell). However, it is unclear how cannabinoid-induced changes in neurochemical dynamics in the nAcc shell impacts reward-related behavior. Here, we first utilized in vivo microdialysis and liquid chromatography-mass spectrometry to quantify the effects of Δ⁹-THC (0.1–3.2 mg/kg), the synthetic partial CB₁ agonists AM11101 (0.1–3.2 mg/kg), and the full CB₁ agonist AM8936 (0.01–1.0 mg/kg) on extracellular levels of dopamine (DA), glutamate (Glu) and GABA within the nAcc shell of mice. Next, using conditioned place preference (CPP), we determined the relationship between Δ⁹-THC (0.1–1.0 mg/kg), AM11101 (0.1–1.0 mg/kg), and AM8936 (0.01–0.1 mg/kg) induced rewarding properties and changes in DA, GABA, and Glu levels. Results show that lower doses of all three cannabinoids (0.32 mg/kg Δ⁹-THC and AM11101, 0.032 mg/kg AM8936) increase DA in the nAcc shell to 134–161% basal values, whereas administration of higher doses (0.1–1.0 mg/kg AM8936, 1.0–3.2 mg/kg AM11101 and Δ⁹-THC) decrease DA levels to 59-70% basal values. Notably, the onset of these DA changes is immediate (i.e., 20 min) for Δ⁹-THC and AM11101 but delayed by about 140 minutes after AM8936 administration. Interestingly, during the same time period, the doses of Δ⁹-THC and AM8936 that increased DA also elevated GABA to 219% and 157% of basal values, as well as Glu to 133% and 136% of basal values (respectively). In contrast, the low doses of AM11101 that increase DA have little effect on GABA and Glu. Δ⁹-THC produces no change in Glu or GABA at doses that decrease DA. However, high doses of AM11101 and AM8936 both decrease GABA to 54% and 58% basal values, as well as Glu to 70% and 73% basal values (respectively). Together, these data show a biphasic dose-response function on DA in the nAcc shell, but the effects on GABA and Glu are distinct among the three CB₁ drugs. Results from CPP studies demonstrate that Δ⁹-THC (0.1–0.32 mg/kg) and AM8936 (0.032 mg/kg) produce increases in preference score, whereas AM11101 (0.1–1.0 mg/kg) did not induced CPP. Correlation analysis of grouped data from all CB₁ drugs revealed a strong positive relationship between increases in DA, GABA, and Glu in the nAcc shell and rewarding properties of Δ⁹-THC, AM11101, and AM8936. Taken together, these findings point to a complex neurochemical dynamic where elevations in DA, GABA, and Glu may all contribute to the rewarding effects from CB₁ agonists.