Sex differences and effects of cocaine on excitatory synapses in the nucleus accumbens

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.