SIGMA-1 RECEPTOR SIGNALING IN D1 NEURONS SHAPES COCAINE-INDUCED PLASTICITY OF INTRINSIC EXCITABILITY AND COCAINE-SEEKING BEHAVIOR

Persistent reductions in intrinsic excitability of nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs) is a key cellular adaptation to cocaine exposure and contribute to addiction-related processes. Our ongoing work in mice shows that firing rate depression is more persistent after intravenous cocaine self-administration than non-contingent exposure, lasting up to 90 days in an incubation-of-craving protocol. These adaptations are restricted to dopamine D1 receptor–expressing (D1R) MSNs and are prevented by pharmacological blockade of the sigma-1 receptor (S1R), an endoplasmic reticulum chaperone protein, without altering natural reward seeking. While these findings identify S1R as a key regulator of cocaine-induced neuronal hypoactivity in NAcSh D1R-MSNs, its cell-type–specific role and behavioral relevance remain unclear. To address this, we selectively deleted S1R from D1-MSNs using a conditional knockout mouse model. Preliminary whole-cell patch-clamp recordings indicate that S1R deletion alters synaptic transmission and intrinsic excitability in a sex-dependent manner. Consistently, male D1-S1R cKO mice exhibit enhanced cocaine reward in a conditioned place preference task and altered cocaine self-administration, particularly during extinction. Together, these results demonstrate that S1R within D1-MSNs acts as a sex-dependent modulator of neuronal excitability and cocaine-related behaviors. Ultimately, our objective is to determine whether S1R’s differential ability to control neuronal activity is a contributor of sex differences in drug addiction.