Muscarinic Receptor Mediation of Cocaine-Dependent Reward Signals: Impact of Pharmacological Modulation

Project Summary Stimulant use disorder (SUD), defined as the patterned use/abuse of psychostimulants such as cocaine, methamphetamine, or prescribed amphetamines, is an epidemic that directly affects around 2.5 million people in the United States. Currently, there are no FDA-approved pharmacotherapies for SUD. Signaling through the neurotransmitter dopamine (DA) in the mesolimbic circuit brain regions, the nucleus accumbens (NAc) and ventral tegmental area (VTA), is necessary for the maintenance of SUD. Muscarinic acetylcholine receptors (mAChRs) in the NAc have been shown to modulate the dopaminergic tone in the region and decrease cocaine preference in rats. Of the five subtypes of mAChR, the M1 and M4 receptors show promise as pharmacological targets for the treatment of SUD. These two receptors are located on the dendritic spines of medium spiny neurons (MSNs) within the NAc and are fed by inputs from cholinergic interneurons (CINs). MSNs are projection neurons containing either D1 or D2 DA receptors, which mediate the direct (reward) and indirect (aversion) reward pathways, respectively. Previously, the modulation of mAChR activity has been shown to reduce cocaine choice in rodents. The M1-preferring agonist xanomeline, for example, has been shown to lower preference for cocaine in rodents. However, not only does this produce undesirable peripheral side effects, the highly conserved orthosteric binding site makes subtype-selectivity difficult. Allosteric modulators of mAChRs effectively solve both problems and could prove valuable for the treatment of SUD through attenuation of cocaine-dependent increases in DA signaling in the NAc. Two mAChR PAMS, the M4- selective VU0152100 and VU0364572, have both been shown to reduce cocaine preference in a drug versus non-drug reinforcer assay and to reduce DA in the NAc using microdialysis. Here the following hypothesis is proposed: Administration of mAChR-selective compounds will reduce cocaine-dependent increases in reward signaling by modulating M1 and M4 mAChRs located on MSNs in the NAc. Aim 1 will determine the ability of these two compounds to reduce the cocaine-dependent alterations in DA levels and dynamics in the NAc using fiber photometry with the GRABDA fluorescent label for DA activity. Aim 2 will explore the differential role that mAChR modulation may have on Ca2+ signaling D1- and D2-containing MSNs using fiber photometry on D1- and D2-Cre rats.