Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward

Abstract

Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. Primary cilia are microtubule-based organelles that project from the surface of nearly all mammalian cells, including neurons. They function as signaling hubs and are enriched with a diverse array of GPCRs, including several known to be associated with motivation and drug-related behaviors; however, our understanding of how cilia regulate neuronal function and behavior is still limited. The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in male and female mice. Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons exhibited greater locomotor sensitization to cocaine compared to wild-type littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 & 30mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to wild-type littermates. Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell-and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.