Fundamental Sex Differences in Cocaine-Induced Plasticity of D1R- and D2R-MSNs in the Mouse Nucleus Accumbens Core

Previous studies have shown that cocaine-induced changes in nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs) differ based on dopamine receptor subtype expression, the sex of the animal, and for females, phase of the estrous cycle. These findings highlight the need to account for both sex and estrous cycle when studying drug-mediated alterations in neurophysiology. Whether MSNs of the nucleus accumbens core (NAcC), which serve different aspects of addiction, will exhibit similar sex and estrous cycle effects with cocaine administration was investigated.

Mice underwent a 5-day locomotor sensitization paradigm via daily cocaine administration (15 mg/kg, s.c.) followed by a 1- to 4-day drug-free abstinence period. We examined NAcC MSN excitability by obtaining ex vivo whole-cell recordings from differentially labeled dopamine D1-receptor expressing MSNs (D1R-MSNs) and dopamine D2-receptor expressing MSNs (D2R-MSNs) obtained from male mice or female mice that were either in estrus or diestrus.

In this genetic background of mice, both male and female mice sensitized to cocaine in a similar manner. In males, there were no cocaine-induced changes in D1R-MSN or D2R-MSN excitability, with D2R-MSNs exhibiting greater excitability. In saline-treated females, D1R-MSN excitability fluctuated across the estrous cycle with increased excitability during estrus. Following cocaine, estrous cycle-dependent D1R-MSN excitability was arrested, fixed at an intermediate value between estrus and diestrus when compared to saline controls. D2R-MSNs did not change either across the estrous cycle or following cocaine. When comparing MSN subtypes, in diestrus, D2R-MSNs were more excitable under saline conditions, but indistinguishable from D1R-MSNs following cocaine. In contrast, during estrus, D1R- and D2R-MSN excitability was similar in saline treated animals, but with cocaine, D2R-MSNs displayed heightened excitability.

There are fundamental sex differences in cocaine-induced changes to the excitability of D1R-MSNs in the NAcC. After cocaine exposure, female mice in diestrus exhibited a significant main effect change in MSN excitability, an inversion of what had previously been demonstrated in the NAcSh where no cocaine-induced changes were observed. These data suggest that there are distinct differences in the neuropharmacological effect of cocaine in males versus females that are shell and core specific.