Investigating Sex-Specific Effects of Cocaine Exposure on NAc Glutamate Transmission

Abstract

Substance use disorder (SUD) is a health problem, with relatively few effective treatments particularly in the case of psychostimulant drugs like cocaine. Preclinical intravenous drug self-administration models have been useful for understanding the neural and behavioral pathophysiology of SUD. However, very little is known about sex differences in addiction. Additionally, current self-administration models need to be improved, especially in regard to modeling human patterns of drug use. Within the reward system, the nucleus accumbens (NAc) mediates reward and motivational processes, and changes in NAc function contribute to addiction. Specifically, enhancements in glutamate transmission in the NAc have been established to mediate some addiction-like behaviors in rodents. Although, in humans there are sex differences in the development and persistence of addiction there have been very few preclinical studies investigating sex differences in glutamate plasticity following different regiments of cocaine exposure. Chapter 2 examines the effects of sex on behavioral sensitization and glutamatergic transmission. We found that females showed a stronger acute locomotor response to cocaine than males. Furthermore, locomotor sensitization was seen in both male and female rats that had repeated cocaine exposure. However the magnitude of sensitization (i.e., the change in cocaine-induced locomotor activity on day 1 vs day 8) displayed no significant sex differences. Interestingly, despite robust sensitization in both sexes, only males showed enhancements in glutamate transmission, specifically an enhancement in spontaneous excitatory post synaptic current frequency, but no changes in amplitude or pair pulse ratio. Finally, regardless of sex, calcium permeable AMPAR (CP-AMPAR) mediated transmission was similar to drug naïve animals. In Chapter 3, we directly compare the effects of long access (LgA) vs intermittent access (IntA) self-administration on the incubation of cocaine craving and NAc core CP-AMPAR transmission in male and female rats. We found that both LgA and IntA experience result in clear escalation of cocaine intake. However, LgA males increased cocaine infusions to a greater magnitude than LgA females, whereas there were no sex differences in escalation within IntA. Furthermore, both male and female animals show similar magnitude of incubation of craving in both LgA and IntA groups. Lastly, we see an upregulation of CP-AMPAR transmission following LgA and IntA compared to drug naïve rats. Potential sex differences and cell-type specificity are discussed further in this chapter. Given that there is overlap in neural and behavioral alterations induced by food and cocaine, Chapter 4 examines the effects of junk-food and junk-food deprivation on MSN intrinsic excitability and glutamate transmission in females. Rats were given free access to junk-food and followed by a short junk-food deprivation period (1-2 days) and then NAc function was assessed. We found increases in NAc glutamate transmission, and reductions in neuronal excitability. This effect required a junk-food deprivation period. However, these effects were transient as they did not persist after 14-16 days of junk-food deprivation. Together these studies examine how the factors of sex and pattern of drug exposure affect plasticity in the NAc. They also begin to address potential cell-type specificity and how effects of essential reinforcers like food may or may not differ from drugs of abuse like cocaine.