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Blog 7: Holly et al. (2012) and Vassoler et al. (2013)

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Holly et al. (2012) and Vassoler et al. (2013) were both fairly straightforward reads and discussed two aspects of sex differences in the development of cocaine addiction in rodents. The former focused on the effects of social defeat stress while the latter was concerned with paternal epigenetic inheritance of a cocaine-resistance phenotype. 

One question I had for both articles concerned their use of ketamine as an anesthetic drug. It caught my attention in the methods as it was recently discussed in another course of mine for its role as an antidepressant. Briefly, we know ketamine is an NMDA receptor antagonist which preferentially binds to receptors on GABA neurons. It is also known that clinical depression and addiction are highly co-morbid and have circuitry involving many overlapping regions, such as the nucleus accumbens and prefrontal cortex as studied here. Unsurprisingly, GABA inhibition via ketamine could increase glutamate release from excitatory neurons and theoretically impact levels of related neurotransmitters. Therefore, is it possible that the administered ketamine could impact the measured levels of dopamine from baseline? In Holly et al., ketamine was notably dosed 10x higher than the acute cocaine. Although there was no measured difference in average dopamine concentration, can it be assumed that the measurements were collected after the ketamine anesthetic was given? This may be an easily dismissible concern, but seemed relevant enough to me given the related circuitry. 

The same experiment in Holly et al. raised another question regarding the sex differences in the temporal distribution of dopaminergic sensitization after cocaine administration. Stressed females had an earlier increase of extracellular dopamine which remained elevated for a longer period of time compared to the males and the non-stressed females. The authors offer that it is most likely due to episodic stress modifying the re-uptake mechanisms for dopamine - but why does this affect females so strikingly? I think estradiol might play a role and it would have been interesting to see a side-by-side comparison between estradiol levels in all animals at the different timepoints after cocaine was given.

Overall, I appreciated both articles for furthering addiction research (an important disorder to me on a personal level) and especially for their consideration of both sexes in doing so. Of course, given that sex is particularly influential in developing risk for drug abuse in humans, it will be fascinating to see this type of research continue and hopefully expand into clinical applications.  

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