CHOLINERGIC MUSCARINIC MODULATION OF DOPAMINE RELEASE DYNAMICS IN DRUG-SENSITIZED MICE

Substance use disorder is a growing global issue affecting roughly 2,2% of the population. Despite that, current treatment options are insufficient. Except for alcohol use disorder and opioid use disorder, there is yet no approved medical treatment and the relapse rate is alarmingly high with 50-80% during the first year of abstinence. These statistics showcases the complexity of the disorder and underscores the urgent need for new treatment options. Previous preclinical research has shown that the administration of muscarinic 4 receptor agonist reduces drug-seeking behavior in rodents. Further, the muscarinic compound, Cobenfy, was recently approved by FDA as treatment for schizophrenia, highlighting the therapeutic potential of cholinergic modulation. Therefore, the present study investigates how positive allosteric modulation of muscarinic 4 receptor (M4 PAM) affects dopamine release in the striatum. Dopamine signaling is measured in real time in drug-sentisized mice using fiber photometry and a genetically encoded dopamine sensor. Preliminary results show that there is no effect of M4 PAM on overall dopamine release; however M4 PAM might be opposing dopamine transient frequency post amphetamine injection. Consistently, activation of the M4 receptor reduces calcium transient frequency in both D1- and D2-medium spiny neurons without affecting amplitude, indicating that cholinergic modulation alters dopamine dynamics. Ongoing experiments assess whether long-term M4 modulation, alone or in combination with a muscarinic 1 agonist (to simulate the pharmacological profile of Cobenfy), produces sustained changes in dopamine signaling in amphetamine-sensitized mice.