Week 8 Papers

          Both the Holly et al and Vassoler et al paper had clear hypotheses that were backed up by a decade of previous research. Both groups went into their studies knowing the specific question they were asking and expecting a very specific answer. That made these papers informative but not exciting at all. The entire groundwork of these papers was laid in the introduction and the results were just a retelling of everything that had been hypothesized and backed up with research in the introduction. I thought that Holly et al had the more interesting of the two papers even though their experimental manipulations seemed brief. The fact that the group found a specific sex x stress x time interaction when looking at basal DA levels was interesting. There were no cross interactions besides this three way interaction and I found that curious that it took all of these conditions in order to see the interplay and effect. Overall the results that females had a heightened predisposition to cocaine and its effects was sort of already known as they mentioned and the estrous cycle affecting these crossover sensitizations had been hinted at before.

            The Vassoler paper was interesting due to its excessive drug paradigm. A 60d self administration where the dosage was essentially controlled by the animal must have caused a lot of effects in the F₀ generation rodent. This drug riddled rodent paradigm allowed for the sperm to become altered by cocaine’s affects and that was the key. The idea that a drug addicted father could cause a less drug sensitive male offspring was an interesting finding. The fact that previous research had been done into the mechanism and they were able to find the proteins and transcriptional processes behind this desensitization was impressive as well. I do fail to see the translatability of these findings however and even in the paper they mention that it cannot translate to the human condition. Without the information gained from the experiment being able to help in the understanding of a problem in the human condition then was the experiment really worth completing?

Week 8

The concept of the Vassolar et al. paper was a little interesting to me due to the focus on how a mal parent’s actions can affect the offspring. I think, generally speaking, when it comes to parents and drugs, the mothers are always the topic of discussion. You really only hear of people making sure mothers are cautious not to drink alcohol while pregnant. There’s always discussion of mother’s who did drugs while pregnant and how that affects the offspring but no one really talks about the fathers. Initially, the lack of discussion about the fathers in this sense, made sense because they aren’t housing the offspring in their bodies. Therefore, this paper was a bit of a surprise to me as to the fact that people do this research as well as that there are actually translated effects of the paternal parent’s actions. Aside from that, I didn’t find the paper all that cool.

The Holly et al. paper was pretty boring and tough to pay attention to. Well they both were really. I like how the papers brought to light some sex differences but I just didn’t really take away much from this. Not sure how, but I expected reading about cocaine and its effects to be exciting but that was not the case. The findings of both papers seemed valid and applicable though, so I can’t really fault them for that.

Week 8

While both papers seemed well structured in their hypothesis and experimental design, I felt as though I didn't have much to say on either. The Holly et al. paper seemed to confirm what has long been considered in regards to stress and sex interactions on cocaine use. While not entirely unsurprising, given my own experience with stress and the desire to have a glass of wine, it was great to see how clean the data was in regards to the interaction between stress and behavioral sensitization. However, I did find it alarming that it appears as though females are more susceptible to stress induced behavioral sensitization. One interesting thing about the results were that it seemed as though, on the whole, females were more susceptible to cocaine and a stress X cocaine interaction, however males had a higher baseline DAergic tone in comparison to females. Especially when coupled with the data suggesting that stressed males have a higher DAergic tone than non stressed, but do not necessarily show the same stress X cocaine interaction as females, it seems as though perhaps a higher DAergic tone at baseline "protects" stressed males from an augmented reaction to cocaine. I did have one significant question about the methods of this paper: why would they have the rats on a reverse light-dark cycle? I thought that perhaps it was to counteract some of the effects of a circadian rhythm, but the more I think about that the more I'm convinced that there must be another reason. One thing I did not like about this paper was the "binge" results based on estrous cycle. While their explanation of finding no significance made sense, it seemed as though this was an inherent flaw in the experimental design that could have been easily rectified using their suggestion of  OVX females + estradiol replacement. This would have added to their results and helped fill a missing gap that was present solely based on the short estrous cycles of rats (4 days I believe). 

While females may be more inherently susceptible to an augmented reaction to cocaine (especially under stressed conditions), it seems from the Vassoler et al. paper that males are more susceptible to a dampened "desire", indicated by self-administration studies, for cocaine if sired from a cocaine addicted male. One thing I loved about this study was the inclusion of the sucrose FR1 and PR self-administration tests. While I had not thought about a general operant learning deficit until I read that part of the paper, especially in relating the results to humans, it seemed important to include based on the belief that offspring of drug-addicted parents are inherently "cognitively deficient". 

Holly & Vassoler

First of all, I find it absolutely mind-boggling that the scientific standard up until recent decades has been to completely neglect sex differences in research. Nearly every sex difference-inclusive study I have ever read has yielded fascinating results about the modulatory role of circulating ovarian hormones, and as exemplified by the Holly paper, sometimes important findings arise such as the identification of estradiol as a facilitator of dopaminergic sensitization. The potential avenues of largely untapped research are boundless, and our understanding of the brain is lacking this dynamic.

I admired the experimental design in the Holly paper and thought the researchers did a good job highlighting the cross-sensitization/comorbidity effects in the female rats. Tangentially, I found it interesting that in one of the papers they cited, a group of male rats were treated with estradiol and their DA tone was observed – neither intact nor castrated males were affected by the circulating estradiol, but estradiol administration significantly affects DA tone in females. For some reason, I can’t wrap my head around why – females likely express more receptors for estrogen-like ligands in the brain, but since estradiol/estrogen can act as a transcription factor, I would expect it to at least have some effect in the male brain as well. I hope for more research on neurobiological questions such as these in the future.

The Vassoler paper is a promising model of heritable drug addiction risk factors, and the paper was wonderfully clear. The research lays out major groundwork for future studies on epigenetics (and sex differences!) in addiction and their discovery of the actual pathway for increased expression of BDNF in male CocSired mice is important, and honestly an impressive testament to the scientific method.

week 8

Before I go into the papers, I just wanted to briefly comment on the general lack of research conducted on female animals. I have heard about these discrepancies in my classes, so I did a quick Google search and found a study published in 2010 examining the sex biases in biomedical research. To my surprise, the field of study that was most biased to using male-only studies was neuroscience, with male studies outnumbering female studies 5.5 to 1. With known sexual dimorphisms and different morbidities for diseases, I believe it is of the utmost importance that the scientific community lobbies to include more female animals in their research designs. The majority of current research is still done solely on male animals, with only 15% of studies examining both males and females. Women comprise 51% of the population, and if we want our research to eventually lead to therapeutics, we should use animal models that represent that half of the population as well. Amazingly, the NIH did not mandate the enrollment of women in human clinical trials until 1993, and there is no current mandate for research to include female animals. If anyone wants to see the article, here is the url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008499/

The Holly et al paper perfectly exemplifies the importance of sex-specific analysis. I had actually never heard of the differences in behavior in female mice going through different phases of the estrus cycle (which probably points to the lack of research on females), so I thought it was really beneficial to read about that. It was also interesting to see that they housed male mice close to the female mice in order to ensure regular estrous cycles, I wondered if that had to do with the male hormones influencing the estrous cycle (I should probably learn more about this before conducting my own research…). I thought this paper’s methods were valid, and the result that stressed females were the most vulnerable to cocaine addiction was interesting, but otherwise I didn’t find the paper that captivating. I had trouble understanding the significance of increased locomotion in response to cocaine and how this would relate to increased susceptibility to relapse or addition. I also wished the authors had gone into more detail about the dopaminergic changes they found, and what kind of implications those could have on the addiction/reward pathway. This neural circuitry is also involved in OCD and anxiety, which are also more common in females. Perhaps changes due to stress induced anxiety could be mediating changes in this pathway that is then hijacked by cocaine.

The Vassoler et al paper was interesting because it shows the role that the father can have in downstream genetic effects on the offspring. The fact that the father can pass on epigenetic changes has so many implications for multiple diseases. While I was reading this, I wondered why the authors didn’t examine the acetylation of the male and female offspring sired by cocaine-experienced rats. I would have liked to see whether both male and female offspring had the epigenetic changes in their genome, to get a clearer idea of why females didn’t express the cocaine-resistant phenotype. If both sexes inherit the increased acetylation, then I could get on board with the author’s hypothesis that the differences in hormone and testosterone expression is what dictates expression of the protective phenotype. This paper has some great research with wide implications, but will be hard to translate into human experience. Like the authors mention, addiction has so many environmental factors as well, and currently it is thought that children from addict fathers have a higher risk of addiction. Maybe studies using children with absentee fathers could evaluate risk of addiction, accounting in socioeconomic conditions and behavior of the mother too of course. Addiction is such a variable disease, but it definitely helps to solve small pieces of the puzzle, and find the genetic and neural pathways that contribute to increased or decreased risk.