Sex differences in cocaine self-administration - Dana Walker


These two articles, published in the same year, take slightly different approaches to studying sex differences in behaviors resulting from cocaine in mice. Holly and colleagues built on research on social defeat and cocaine use in male mice, as well as established gender differences in cocaine sensitivity, and adds circulating ovarian hormones as a factor. They proposed that females, especially those in estrus/proestrus, would show a greater effect of behavioral and dopaminergic cross-sensitization to cocaine. Males and females underwent social defeat stress or control handling, and estrous cycle was measured. They were then divided into one of three experiments (behavioral sensitization, in vivo microdialysis, and cocaine self-administration.)
For experiment 1, both stressed and non-stressed females in estrus walked for longer than other stressed or non-stressed groups. Stressed females showed increased walk duration 25-30 min after injection, while males had returned to baseline by this point. For experiment 2, both males and females, stressed or unstressed, showed elevated DA concentration. However, females showed effects that began faster and lasted longer. There was only a significant effect of sex for stressed animals, not unstressed animals. There was also no effect of estrous cycle. For experiment 3, stressed groups of both sexes showed increased number and duration of administrations. Stressed females also binged longer than stressed males. Overall, it was concluded that behavioral and neurochemical changes resulting from episodic social defeat can occur to a larger degree in females than males. Estrous cycle only influenced behavioral sensitization.
Vassoler et al. studied paternal cocaine self-administration and how it affects gene expression in the following generation of mice, based on past research on both phenotype transmission and the effects of drug abuse. Male rats self-administered cocaine before mating with naïve females. Their offspring were tested in a fixed-ratio schedule of reinforcement for cocaine. Males showed delayed acquisition and reduced maintenance when sired from cocaine rats, while there were no differences in females. When switched to a progressive ratio schedule, only male cocaine-sired rats didn’t work as hard as controls to receive cocaine. These effects were not due to impaired learning, as these mice showed normal intake of sucrose. The authors hypothesized that effects of cocaine on gene transcription and hormones contributed in part to the different behavioral phenotypes in males and females. Furthermore, increased levels of BDNF were found in the mPFC of male cocaine-sired rats. There was also an increased association of AcH3 with Bdnf exon IV in these rats. Administering ANA-12 reestablished self-administration behaviors, suggesting that BDNF played a role in its decrease.
Holly et al. were able to measure social defeat stress in female mice, something our class has discussed in the past. While the resident-intruder paradigm consists of pairing males with a larger male, females were paired with a lactating dam. I have been wondering if there was a good social defeat paradigm for females, since they don’t have the same aggressive instincts as males. If this paradigm is capable of accurately creating the same type of stress for both males and females, it would be useful for other studies, including those we have already read this semester. Furthermore, the mice were kept with the member of the same sex until defeated (10 bites and/or 6 sec in a supine position). This is different from a timed social defeat trial, where the mice are paired for a set amount of time, and those with excessive injuries are removed from the study. It’s not clear which paradigm is better, as the current study ensures that mice receive the same amount of physical damage. However, the physical injuries or variation in time spent with the enemy could skew the results.

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