D3 dopamine receptors implicate a subtype of medium spiny neuron in the aversive effects of antipsychotic medications

Second generation antipsychotics (SGAs) are widely used clinical tools, yet they often cause negative side effects and take weeks to become effective, leading to poor patient compliance. The effect/side effect profile of individual SGAs is highly variable, and the mechanisms that underlie this variability are not well understood. We found that SGA activity at D3 dopamine receptors (D3R) in the Nucleus Accumbens (NAc) mediates the aversive effects of SGAs. Using single-nucleus RNA sequencing, we found that D3R is expressed in a subpopulation of D1R neurons and defines its own distinct NAc cell type. We demonstrate that while multiple SGAs (clozapine and quetiapine) cause acute conditioned place aversion in mice, only chronic treatment with quetiapine, an arrestin-biased agonist at D3R, causes aversion to abate. We further show at both the cell and population level that quetiapine inhibits D3R-neurons in the lateral shell (LatSh) of the NAc. Selective optogenetic inhibition of D3R-neurons in the LatSh produces real time place aversion in mice, implicating this cell type in the aversive effects of SGAs. Our findings suggest a cellular and systems-level mechanism underlying aversion to SGAs and highlight the pathway to selective tolerance to this aversion, providing a framework for future therapeutic strategies in SGA development.