Chapp Andrew D, McMullan Hannah M, Phan Chau-Mi H, Jagtap Pramit P, Mermelstein Paul G
bioRxiv. 2025 Jun 23:2025.06.18.660420. doi: 10.1101/2025.06.18.660420.
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 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.
There are sex-and estrous-cycle dependent changes to D1R-MSNs in the NAcC that are sensitive to cocaine exposure. In males, cocaine has no effect on D1R-or D2R-MSNs excitability. During the estrous cycle, D1R-MSNs exhibit increased excitability during estrus. This fluctuation is halted by cocaine, such that D1R-MSNs recorded in diestrus show increased excitability following cocaine exposure whereas female D1R-MSNs recorded in estrus have decreased excitability.
The nucleus accumbens core (NAcC) is a brain region associated with regulating motivated behavior. The primary neuronal populations of the NAcC are dopamine D1 receptor expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor expressing medium spiny neurons (D2R-MSNs). No studies exist which examine sex differences and estrous cycle effects in the NAcC following cocaine administration. Using electrophysiology, we found inherent sex-and estrous-cycle differences in cocaine-induced changes in MSN neuroplasticity. D1R-MSN excitability was unaffected in males, increased in females recorded during the diestrus phase, and decreased in females recorded during estrus following cocaine exposure. This ran counter to estrous cycle effects under drug-naive conditions where D1R-MSN excitability was higher in estrus versus diestrus. The estrous cycle effects on D1R-MSNs were eliminated following cocaine administration. For both sexes, D2R-MSN excitability was not impacted following cocaine. These results highlight fundamental sex differences that might underpin differences in substance abuse.
先前的研究表明，可卡因引起的伏隔核壳（NAcSh）中多棘神经元（MSNs）的变化因多巴胺受体亚型表达、动物性别以及雌性动物的发情周期阶段而异。这些发现凸显了在研究药物介导的神经生理学改变时考虑性别和发情周期的必要性。本研究调查了伏隔核核心（NAcC）中发挥不同成瘾作用的MSNs在给予可卡因后是否会表现出类似的性别和发情周期效应。
通过每日给予可卡因（15mg/kg，皮下注射）对小鼠进行为期5天的运动致敏范式，随后是1至4天的无药戒断期。我们通过对从处于发情期或间情期的雄性小鼠或雌性小鼠中获得的差异标记的多巴胺D1受体表达MSNs（D1R-MSNs）和多巴胺D2受体表达MSNs（D2R-MSNs）进行全细胞记录，来检测NAcC MSN的兴奋性。
在这种小鼠遗传背景下，雄性和雌性小鼠对可卡因的致敏方式相似。在雄性小鼠中，可卡因未引起D1R-MSN或D2R-MSN兴奋性的变化，其中D2R-MSNs表现出更高的兴奋性。在生理盐水处理的雌性小鼠中，D1R-MSN兴奋性在发情周期中波动，发情期兴奋性增加。给予可卡因后，发情周期依赖性的D1R-MSN兴奋性被阻断，与生理盐水对照组相比，固定在发情期和间情期之间的中间值。D2R-MSNs在发情周期或给予可卡因后均未发生变化。比较MSN亚型时，在间情期，生理盐水条件下D2R-MSNs更易兴奋，但给予可卡因后与D1R-MSNs无差异。相反，在发情期，生理盐水处理的动物中D1R-和D2R-MSN兴奋性相似，但给予可卡因后，D2R-MSNs表现出更高的兴奋性。
可卡因引起的NAcC中D1R-MSNs兴奋性变化存在基本的性别差异。可卡因暴露后，处于间情期的雌性小鼠MSN兴奋性出现显著的主效应变化，这与之前在NAcSh中所证明的情况相反，在NAcSh中未观察到可卡因引起的变化。这些数据表明，可卡因对雄性和雌性的神经药理学作用存在明显差异，且具有壳和核心特异性。
NAcC中D1R-MSNs存在性别和发情周期依赖性变化，对可卡因暴露敏感。在雄性小鼠中，可卡因对D1R-或D2R-MSNs兴奋性无影响。在发情周期中，D1R-MSNs在发情期表现出兴奋性增加。这种波动被可卡因阻断，使得在间情期记录的D1R-MSNs在可卡因暴露后兴奋性增加，而在发情期记录的雌性D1R-MSNs兴奋性降低。
伏隔核核心（NAcC）是一个与调节动机行为相关的脑区。NAcC的主要神经元群体是多巴胺D1受体表达的多棘神经元（D1R-MSNs）和多巴胺D2受体表达的多棘神经元（D2R-MSNs）。目前尚无研究考察给予可卡因后NAcC中的性别差异和发情周期效应。通过电生理学方法，我们发现可卡因引起的MSN神经可塑性变化存在内在的性别和发情周期差异。D1R-MSN兴奋性在雄性小鼠中未受影响，在间情期记录的雌性小鼠中增加，在发情期记录的雌性小鼠中给予可卡因后降低。这与未接触药物条件下的发情周期效应相反，在未接触药物条件下，发情期D1R-MSN兴奋性高于间情期。给予可卡因后，发情周期对D1R-MSNs的影响被消除。对于两性而言，给予可卡因后D2R-MSN兴奋性均未受到影响。这些结果凸显了可能构成药物滥用差异基础的基本性别差异。
