Indirect and direct cannabinoid agonists differentially affect mesolimbic dopamine release and related behaviors.

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase inhibition while also inhibiting transient receptor potential vanilloid Type 1 channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor Type 1 agonist arachidonoyl-2'-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with seven daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA decreased rearing and decreased phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference, then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a conditioned place preference or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct cannabinoid receptor Type 1 agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Age-dependent effects of social isolation on mesolimbic dopamine release.

In humans, social isolation is a known risk factor for disorders such as substance use disorder and depression. In rodents, social isolation is a commonly used environmental manipulation that increases the occurrence of behaviors related to these disorders. Age is thought to influence the effects of social isolation, but this predictive relationship is not well-understood. The present study aimed to determine the effects of social isolation on mesolimbic dopamine release at different developmental age points in mice. The experimental ages and their corresponding comparison to human age stages are as follows: 1 month = adolescence, 4 months = mature adulthood, 12 months = middle adulthood, and 18 months = older adult. Mice were socially isolated for 6 weeks during these developmental stages, then in vivo fixed potential amperometry with recording electrodes in the nucleus accumbens was used to measure stimulation-evoked dopamine release, the synaptic half-life of dopamine, dopamine autoreceptor functioning, and the dopaminergic response to cocaine. Isolation altered dopamine functioning in an age-dependent manner. Specifically, isolation increased dopamine release in the adult ages, but not adolescence, potentially due to increased inhibitory effects of dopamine autoreceptors following adolescent social isolation. Regarding the cocaine challenge, isolation increased dopaminergic responses to cocaine in adolescent mice, but not the adult mice. These findings have implications for clinical and experimental settings. Elucidating the relationship between age, social isolation, and neurochemical changes associated with substance use disorder and depression may lead to improvements in preventing and treating these disorders.