Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA.
Neuropharmacology. 2011 Jul-Aug;61(1-2):217-27. doi: 10.1016/j.neuropharm.2011.04.002. Epub 2011 Apr 13.
Human and animal studies indicate that drugs of abuse affect males and females differently, but the mechanism(s) underlying sex differences are unknown. The nucleus accumbens (NAc) is central in the neural circuitry of addiction and medium spiny neurons (MSNs) in the NAc show drug-induced changes in morphology and physiology including increased dendritic spine density. We previously showed in drug-naïve rats that MSN dendritic spine density is higher in females than males. In this study, we investigated sex differences in the effects of cocaine on locomotor activity as well as MSN dendritic spine density and excitatory synaptic physiology in rats treated for 5 weeks followed by 17-21 days of abstinence. Females showed a greater locomotor response to cocaine and more robust behavioral sensitization than males. Spine density was also higher in females and, particularly in the core of the NAc, the magnitude of the cocaine-induced increase in spine density was greater in females. Interestingly, in cocaine-treated females but not males, cocaine-induced behavioral activation during treatment was correlated with spine density measured after treatment. Miniature EPSC (mEPSC) frequency in core MSNs also was higher in females, and increased with cocaine in both the core and shell of females more than males. We found no differences in mEPSC amplitude or paired-pulse ratio of evoked EPSCs, suggesting that sex differences and cocaine effects on mEPSC frequency reflect differences in excitatory synapse number per neuron rather than presynaptic release probability. These studies are the first to demonstrate structural and electrophysiological differences between males and females that may drive sex differences in addictive behavior.
人类和动物研究表明，滥用药物会对男性和女性产生不同的影响，但导致性别差异的机制尚不清楚。伏隔核（NAc）是成瘾神经回路的核心，NAc 中的中脑腹侧被盖区神经元（MSNs）在形态和生理学上表现出药物诱导的变化，包括树突棘密度增加。我们之前在未经药物处理的大鼠中表明，MSN 的树突棘密度在雌性中高于雄性。在这项研究中，我们研究了可卡因对运动活动以及接受 5 周治疗后 17-21 天戒断的大鼠 MSN 树突棘密度和兴奋性突触生理学的影响中的性别差异。雌性对可卡因的运动反应更大，比雄性表现出更强的行为敏化。在雌性中，树突棘密度也更高，特别是在 NAc 的核心区域，可卡因引起的树突棘密度增加幅度在雌性中更大。有趣的是，在接受可卡因治疗的雌性中，但不是雄性中，可卡因在治疗期间引起的行为激活与治疗后测量的树突棘密度相关。核心 MSNs 中的微小兴奋性突触后电流 (mEPSC) 频率在雌性中也更高，并且在雌性的核心和壳体内，可卡因引起的 mEPSC 频率增加大于雄性。我们没有发现 mEPSC 幅度或诱发 EPSC 的成对脉冲比的差异，这表明性别差异和可卡因对 mEPSC 频率的影响反映了每个神经元的兴奋性突触数量的差异，而不是突触前释放概率的差异。这些研究首次证明了男性和女性之间的结构和电生理差异，这些差异可能导致成瘾行为中的性别差异。
