Differential effects of acute versus repeated chemogenetic activation of the mesocorticolimbic dopamine pathway on cocaine choice in male and female TH:Cre rats

Mesocorticolimbic dopamine neurotransmission is hypothesized to play a central role in both cocaine reinforcement and amphetamine maintenance-induced decreases in cocaine self-administration. One method to selectively modulate dopamine neurotransmission is by using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Therefore, the study goal was to selectively activate ventral tegmental area (VTA) dopaminergic neurons using DREADDs and determine the effects of acute and repeated activation of these neurons on cocaine self-administration using a cocaine-vs-food choice procedure in female and male rats. Two main experiments were conducted in tyrosine hydroxylase (TH):Cre female and male rats trained to respond under a concurrent “choice” schedule of IV cocaine and liquid food availability during daily behavioral sessions. Experiment 1 determined acute deschloroclozapine (DCZ) effects before and after VTA Gq-DREADD expression. Experiment 2 determined repeated DCZ effects via osmotic pump both pre and post Gq-DREADD expression. Cocaine maintained a dose-dependent increase in cocaine choice pre- and post-VTA DREADD expression. Acute and continuous DCZ in the absence of DREADD expression did not alter cocaine choice. Acute DCZ significantly increased cocaine choice in rats expressing Gq-DREADDs similar to acute amphetamine. Continuous DCZ treatment via osmotic pump post Gq-DREADD expression failed to significantly alter cocaine choice. These results suggest acute activation of mesocorticolimbic VTA neurons is sufficient to enhance cocaine’s relative reinforcing effectiveness. The lack of effect following continuous DCZ suggests potential tolerance to DCZ effects complicating the utility of these tools in rigorous behavioral neuroscience research.