Description:

Jones G. Parker, PhD
Assistant Professor of Physiology and Pharmacology
Northwestern University Feinberg School of Medicine

Abstract: Excess dopamine transmission in psychosis is predicted unbalance striatal output via D1- and D2-dopamine receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by attenuating striatal D2-receptor signaling. Here we imaged D1- and D2-SPN Ca2+ dynamics in vivo to determine whether they can predict antipsychotic effect. Initially we compared effective (clozapine and haloperidol) to ineffective (MP-10) antipsychotic treatments. Clozapine and haloperidol normalized hyperdopaminergic D1-SPN ensemble dynamics, while MP-10 only normalized D2-SPN activity. Clozapine, haloperidol and chemogenetic manipulations of D1- but not D2-SPNs also normalized sensorimotor gating. Given the link between D1-SPN modulation and antipsychotic effect, next we evaluated compounds selectively targeted to D1-SPNs. D1R partial agonism, antagonism, or positive modulation of M4 cholinergic receptors all normalized the levels of D1-SPN activity, locomotion, and sensorimotor gating. Our results suggest that D1-SPNs are a more relevant therapeutic target than D2-SPNs in psychotic disorders and adjudicate basic strategies for doing so