Cocaine use, paternal epigenetic influence, and sex differences- Sierra Smith

This week's two papers both addressed understudied issues surrounding cocaine addition in a rat model, with the Holly group examining the influence of sex differences, including different stages of the estrous cycle for female rate and the Vassoler group unpacking sex-specific paternal epigenetic influence on F1 acquired cocaine addiction.

I was disappointed while reading the Holly paper to discover that the only significant effects of estrous cycle in female rats was related to increased locomotion (walk duration) and not on actual dopamine levels in the nucleus accumbans or measures of a cocaine binge. Essentially, it seems that estrous cycle does not actually significantly impact the severity of a cocaine addiction on a neural system or behavioral level, but only heightens the response to the same dose of cocaine. The effect of stress, however, on both males and females but particularly on female cocaine addiction is quite shocking, but not surprising. Drug abuse is more frequent in human populations under stressful conditions, so it's amazing to be able to see clear evidence of this effect in rats as well. Stressed male and female mice have significantly increased locomotion at least 5 minutes after cocaine administration, if not also at 25 minutes in many of the groups. The dopamine effect in the nucleus accumbans is also profoundly effected by stress in both sexes, but especially in female rats. Finally, stressed male and female rats both administered more cocaine and for longer duration, with the female effect being significant even at p = 0.01 at all conditions, if not more. It's amazing to be able to see such clear evidence even in a rat model for sexually differential effects of cocaine on tendency to become addicted, and how much stress can elevate cocaine addiction symptoms across sexes. I am a bit skeptical of the small group sizes in this paper, and would like to see particularly the nucleus accumbans dopamine level analysis repeated with experimental groups greater than n = 6 to see if any estrous cycle effects become more evident, since we do see the heightened locomotory response in these groups.

The Vassoler paper was fascinating to me, as it was previously poorly understood how paternal cocaine experience may impact the germline and the F1 generation's tendency to become addicted to cocaine after being allowed to self-administer. Unlike the sex differences in the Holly paper of which there is much human evidence to back up the results, paternal cocaine experience leading to a cocaine resistance phenotype in male offspring was surprising. I would have expected paternal cocaine experience to predispose offspring to developing cocaine addiction themselves, but the fact that the results in this paper showed the opposite actually makes sense in the context of other epigenetic studies I have read. In several neuroscience classes, I have read about the increased likelihood of obesity in descendants of famine victims due to similar histone acetylations/methylations in the germline. If the AcH3 associations with BDNF promoters in cocaine experienced sperm occur under tonic cocaine use in paternal rats, these changes would be passed onto the male F1 generation. This would make the male F1 epigenetic patterns more resemble an experienced cocaine user, and could explain the resistance observed in this paper in terms of total infusions per day, breakpoint, and BDNF levels. It was also quite amazing that the Vassoler group identified TrkB, the specific BDNF receptor where these behavioral changes are likely occurring, through a receptor antagonist study using ANA-12. This inhibitor completely reversed the cocaine resistance phenotype observed in the male F1 offspring of cocaine experienced sires, really pinpointing the elevated BDNF levels as being responsible for this entire mechanism and the inherited epigenetic alternations.

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