This is going to be a harsh assessment and I completely understand if people don’t agree with me on this, but I am finding to difficult to articulate the value of the Holly et al paper. First, I want to fully acknowledge that the quantifications in the paper do show me convincing evidence that there is an interaction between sex and stress on cross-sensitization to cocaine. Figure 2 shows that the effects of stress on females is greater than in males (a and b), Figure 4 shows there is a greater effect of stress on DA concentration in females, and Figure 5 shows there is more infusions and longer “binge” durations in stressed females. Importantly, these do not seem to be just additive effects of stress on top of already existing sex differences because in all three experiments they show/state that the data for the non-stressed males and females is not significantly different. However, I still take issue with the paper because it does not seem to add anything to the existing body of knowledge that they themselves cite in the introduction. They establish from the beginning that people have already shown “females are more sensitive to the reinforcing effects of cocaine,” that “females subjected to social defeat stress self-administer significantly more cocaine than similarly stressed males,” and “ovariectomized females outperform males in every phase of self administration...and all these effects are potentiated with estradiol treatment.” In light of these previous studies, the experiments in these papers seem to be something you would find in the supplements of these cited works, if not simply redundant, but this would have been forgivable if they had explored the effects of the estrous cycle on these sex differences, as they proposed. Unfortunately, they try but fail to do so. Figure 2 shows that there is a difference in female response to endogenous changes in cycling hormones, (even though this should be the case based on the ovariectomy and estradiol replacement paper they already reference), but this branch of investigation ceases from here on because their sample size in the microdialysis experiments was too low to do statistical comparison (see discussion). The authors already state that their cocaine “binge” data is “expected” based on the existing studies, so perhaps Figure 4 could be the novel part of the paper as it potentially provides a biochemical basis for the enhanced reinforcing effects of cocaine in females (cited in the introduction), but this feels like such a minor advance since I would expect this to constitute one panel in one figure or a supplemental figure in another major journal.
I was surprised to see that the results of the Vassoler et al paper showed the opposite trend of epigenetic inheritance seen in humans--cocaine exposure in male sired rats resulted in a drug-resistance phenotype in the offspring. The results seem very clean in my opinion and, as the authors state, leaves the open question as to how to consolidate these results with the data from human studies. The use of paternal exposure, rather than the usual maternal exposure, was an interesting choice that I had not considered, but it is useful in that it isolated the effects of exposure to epigenetic influences, as opposed to in utero condition etc. that could have been encountered in a maternal exposure model. On a somewhat tangential note, I think it is increasingly valuable to have studies like this that look at male epigenetic contributions to offspring because the majority of papers I have seen disproportionately focus on female influences. Without getting too deep into the social debates, I think that this imbalance has implications regarding the social perception of motherhood and childbearing responsibilities, particularly the social consequences for having children later in life, lifestyle choices (i.e. diet, physical activity, breastfeeding), overall health (obesity, etc.)--basically anything you can think of--and how that adds risk for autism, schizophrenia, and a thousand other disorders despite the fact that there also studies that show paternal contributions to these same risk factors, though these studies are considerably fewer in number. To give a rough sense of how disproportionately maternal contributions are covered, a quick search for the keywords “paternal” and “epigenetic” yield a little less that 50,000 results, whereas “maternal” and “epigenetic” produce around 124,000 results. Add “contributions” and you get around 24,000 hits regarding paternal epigenetic influences and around 54,000 for maternal epigenetic influences.