The Role of Ciliary Melanin-Concentrating Hormone (MCH) Signaling in the Neurobehavioral Response to Cocaine

Abstract

Neuromodulatory peptides that modulate behavioral responses to psychostimulants are known to activate receptors enriched in neuronal primary cilia. Primary cilia are microtubule-based organelles that play a critical role in cellular signaling through their high density of G-protein-coupled receptors. One such receptor is the melanin-concentrating hormone receptor 1 (MCHR1). It is currently unclear how MCHR1 ciliary localization and MCH neuron activity modulate responses to psychostimulants. The objective of this project was to identify the role of primary cilia localized MCHR1 in modulating behavioral responses to cocaine. Male and female mice were subjected to conditioned place preference (CPP) to determine the rewarding effect of cocaine and locomotor activity tests. MCHR1 KO and MCHR1IFT88 KO strains exhibited increased acute locomotor responses and sensitization to cocaine compared to their control littermates. CPP testing showed that MCHR1 KO mice had a reduced preference to the cocaine-paired chamber compared to control littermates. In contrast, MCHR1Ift88 KO mice did not differ from control littermates in the development of CPP. Locomotor tests with MCHcre mice showed that activating MCH neurons 30min prior to cocaine administration resulted in decreased acute locomotor response and sensitization compared to mice that received saline and cocaine. These findings further support a role for MCH signaling in modulating response to psychostimulants and suggest that receptor loss and cilia loss impact responses differently.