Behavioral Phenotyping from deleted CB1 receptors on cholinergic neuron terminals

Abstract

Marijuana is the most widely used illicit drug in the Western Hemisphere and affects physiological processes and cognition. Clear deficits are observed in working memory (WM) that involve the temporary storage and online manipulation of information to solve complex tasks. Marijuana-induced WM deficits have been ascribed to the primary psychoactive compound in marijuana, {Delta}9-tetrahydrocannabinol, which acts at CB1 cannabinoid receptors (CB1r). Recent work emphasized the role of CB1r and cholinergic interaction across this cognitive domain without formal anatomical demonstration. We generated mice with a conditional deletion of CB1r on cholinergic neuron terminals, and WM was evaluated in operant chambers. Control of physiological variables (temperature, nociception, neuromuscular function) was also performed, and additional motor, motivation, time estimation behavior, and effort-based decision-making. Discrete WM enhancement measured in a novel Delay-Non-Matching-To-Position task was evidenced that incorporates early acquisition during randomized delays (mixed procedure), and remarkably, improved performance when these (2s, 8s, 16s, 20s) were kept constant (same procedure) across a testing block of trials. We reported higher motivation in an exponential progressive ratio schedule whilst locomotor activity did not differ between genotypes in the rotarod and open field. However, timing behavior was modified as indicated by higher discriminated motor responses for the shortest interval in conditional deleted mice in the Fixed-Interval time task (10s, 30s). We reported no effect on effort-based decision-making. Our work outlines presynaptic CB1r-cholinergic neuron function(s), and the hippocampus, neocortex, and amygdala brain regions as critical loci through known basal forebrain efferent projections possibly involved in WM and motivation in marijuana intoxication.