Sunday, November 20, 2016

cocaine - joe

Holly et al vs Vassoler et al
Seminar in BioPsych
Fall 2016
Professor Shansky

I thought it was interesting that the intro of Holly et al alluded to a 1995 paper by Haney et al regarding sex differences in cocaine self administration, and the paper ended up following up on it by using different measures to assess sex and stress differences to cocaine administration. Effectively, they asked, “what is happening to the dopamine system to lead to these changes in cocaine use and what about the female biological system leads to higher cocaine administration?” I think that they’re really interesting questions and probe the infrastructure of addiction; however, the finding was modest and did not answer fully any fundamental questions. I thought it was super interesting that DA levels remained strikingly high for so much longer in stressed females. This says that there is something happening to the dopaminergic system in response to stress; however, this response only occurs in females. Isn’t it crazy the differences in phenotype that can occur from one chromosomal change? Even more bizarre is the fact that these differences are highly neglected in research. It was also interesting to see that despite the higher levels of dopamine in stressed females, those animals were also less satiated (as indicated by their long binges of cocaine infusion). Quick note: did the stressed females have a higher number of total infusions because they binged for longer? Or is that adjusted for binge time? Would it more correctly be titled infusion rate then?
Anyway, where is this dopamine going if so much more is needed for them? And is there desensitization occurring more quickly on the post synapse of DA neurons? Is there a broken negative feedback in these stressed mice? Is cocaine not being biotransformed as well in them? I’ve been told many times that good science addresses a question and is able to prompt a bunch of new questions that can be addressed because of that finding. For example, this paper took differences in cocaine administration in stressed vs non stressed and male vs female mice and asked if there might be some dopaminergic differences between them, and whether that precipitates the behavioral changes. One can follow up on this by addressing any of the above questions regarding cocaine drug action or DA modulation.
Regarding the second paper, I think epigenetics is the coolest thing since sliced ham; it adds a very interesting level of complexity to what the genetic code means. I thought it was interesting that they addressed the transgenerational effects of cocaine administration in sires only because of potential confounds of in utero and maternal behavior effects — I think these should both be addressed. I think this especially because they had to account for maternal behavior with their experimental design anyway (because of the differential allocation hypothesis)!

I appreciated that they took into account the potential confound of learning deficits in the offspring with a sucrose learning task. But I also think that it was lucky that the differential male offspring effect that they found was well coupled with the BDNF exon IV transcript expression patterns. But then it was really cool that stopping BDNF signaling in the offspring was sufficient to abolish this tolerance, and furthermore that BDNF increase was accompanied by AcH3 level increases in the sperm of the sires.

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