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Sex Differences in Cocaine Addiction in Rats

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Addiction is a very interesting topic to me and I believe there is so much progress to be made in this field, making it very exciting in terms of research. I have done some clinical research in addiction during one of my co-ops at MGH in the pediatric psychopharmacology department. The clinical study was based on the comorbidity of mood disorders and substance use disorders in young adults and the effects of treating this mood disorder on the subject's substance use. While this correlation of improved substance use post-treatment of an underlying mood disorder seemed obvious to me, it is not a very well studied area. I was excited to dive into the Holly paper and learn about the effects of stress on addiction and drug response. The Holly et al. paper published in 2012 investigates the effects of episodic social defeat stress on cross-sensitization to cocaine. The central theme within this investigation were the sex differences among these effects and how the estrous cycle further changes the responses in female rats. After several introductions to the social defeat paradigm I was excited to read a study which implemented this model in both male and female mice, using a dominate male mouse and a lactating dam as the aggressors. Based on my knowledge of human addiction statistics and some of the information reported in the introduction, the results were somewhat of a surprise to me. In the introduction, it is stated that in 2010 35.9% of cocaine users in the USA were female (SAMSHA 2010). Based on the results of this paper, females seem more susceptible to cocaine addiction, despite making up less of the using population. However, this is where stress comes in as a factor. Sex became a more differentiation factor amount stressed populations than in the male and female unstressed groups. The combination of stress and sex made females have a higher sensitization to cocaine measured with increased locomotion, increased levels of dopamine, and have a higher number of infusions with a longer "binge" than any other cohort, with even more dramatic results in females in estrous. Stressed males also showed increased sensitization and use compared to the non-stress group, however the results were more robust in female rats, alluding to a significant finding for addiction medicine. With addiction being generally more prevalent in males, this study led me to contemplate the effects of why addiction occurs in people. While males may make up a greater percent of users, females have a greater likelihood of becoming binge users and a higher predisposition to relapse. I am curious about the data on stress in these females users and the motivation to begin using.
The Vasselor et al. paper published also in 2012, took a different approach to sex differences in cocaine addiction, studying the potential for epigenetic to facilitate the inheritance of a cocaine-resistance phenotype. While in humans we have narrowed down a predisposition to addiction (or other risk taking behaviors) to a gene loci, I have never learned about epigenetic factors of such a complex and multifaceted behavior. Based on the results of this paper, Vesselor and their team was able to show an increase in cocaine-resistance in male rates who's paternal predecessor was exposed to cocaine. The cocaine resistance was observed both in quantity and duration of self-administered cocaine. I appreciated the amount of "rule-out" experiments preformed by this group in order to more closely observe the effects of cocaine exposure in a parent as opposed to co-founding variables. They were able to show more certainly that there effects were due to changes in BDNF protein concentration in there brain rather than paternal involvement with the mother, generalized learning deficits in the pups, or decreased sucrose preference. With information pointing to the possibility of epigenetic playing a role in addiction we can look more closely at the cause of substance use disorders at a clinical level. In addition, the information provided in this paper showing changes in protein levels affecting resistance and maintenance of drug addiction, provides forward progress to treatment options for those with substance use disorders.












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