Effects of Cannabinoid CB₁agonists on extracellular levels of dopamine in the nucleus accumbens shell of male mice

Abstract

The use of cannabis has led to a dramatic increase in cannabinoid (CB) abuse during the past decade, presenting a major public health challenge. Despite significant research there is a lack of full understanding on how cannabinoids that vary and efficacy and affinity at CB 1 receptors alter key neurotransmitters like dopamine (DA) in reward-related brain regions to impact behavior. Mounting evidence suggests that actions at CB 1 receptors modulate DA within the nucleus accumbens shell-a key brain region involved in the abuse-related neurobiological actions of most drugs of abuse. Here, we utilized in vivo microdialysis and liquid chromatography-mass spectrometry (LC-MS/MS) to quantify changes in DA within the nucleus accumbens shell of mice administered (i.p.) the synthetic full CB 1 agonist AM8936 (0.01-1.0 mg/kg), the synthetic partial CB 1 agonist AM11101 (0.1-3.2 mg/kg), or the phytocannabinoid partial CB 1 agonist D 9 -THC (0.1-3.2 mg/kg). At lower doses, AM8936, AM11101, and D 9 -THC administration increased extracellular levels of DA within the nucleus accumbens shell reaching a maximum of 134%, 140%, and 161% of baseline levels after 0.032, 0.32, and 0.32 mg/kg, respectively. AM11101 and D 9 -THC produced peak increases in DA at 20 minutes post-injection, which remained elevated for approximately 2 hours and then returned toward baseline levels. Conversely, the peak increases in DA after administration of 0.032 mg/kg AM8936 was observed at about 140 minutes post-injection, and DA remained elevated until the end of the experiment (5 hours post injection). At 10-fold higher doses, AM8936, AM11101, and D 9 -THC decreased DA to 62%, 72%, and 62% of baseline levels after 0.32, 3.2, and 3.2 mg/kg, respectively; for all drugs these decreases persisted until the end of the experiment. The calculated area under the curve for a 100-minute window centered around the peak DA increase for each agonist showed that low doses of AM8936 (0.01-0.032 mg/kg) AM11101 (0.1-0.32 mg/kg) and D 9 -THC (0.1-0.32 mg/kg) increased DA levels, whereas higher doses of AM8936 (0.1-1.0 mg/kg) AM11101 (1.0-3.2 mg/kg) and D 9 -THC (1.0-3.2 mg/kg) decreased extracellular levels of DA. Together, these results demonstrate that while AM11101 and D 9 -THC DA effects have quicker onset and shorter duration compared to AM8936, CB 1 partial and full agonists have similar, biphasic effects on DA within the nucleus accumbens shell.