This week's article by Holly et al. focused on the effects of stress and sex in behavioral and dopaminergic cross-sensitization to cocaine in addition to cocaine self-administration (or "binge" behavior as they called it). The researchers conducted 3 main experiments to explore this topic. First, in order to study behavioral sensitization, they tested the locomotion of both stressed and non-stressed rats (both male and female) after administering a low dose of cocaine. They also took the estrous cycle of the females into account (as they did with each of the other experiments as well). They found that the stressed group overall walked more after cocaine, that the females walked more than the males, and that the estrus group walked more than the non-estrus group. I found this to be a beautiful example proving the importance of sex differences in these studies, and even the estrous cycle differences within females. While I can understand why research has typically only been done on males, this is just one example of how males may be affected less or not at all to something that affects females much more, demonstrating the importance of sex differences in research.
I did have a few questions regarding the methods for this experiment though. When stressing the animals, a same sex rodent was used as the "resident" (stressor) rat. I was curious as to why this was, and what would happen if the opposite sex was used as a stressor. I also noticed that the resident rats were housed in opposite sex pairs. Will opposite sex rats not attack each other? I was just curious about the reasoning behind this. In addition, this was specifically a social defeat stress model - I wonder if other types of stress would have similar effects. Perhaps those are areas for further research.
In the next experiment, Holly et al. used in vivo microdialysis to look at DA levels in the NAc shell after cocaine administration, again comparing the stressed and non-stressed groups. I liked how they compared each animal to its own baseline level rather than just comparing levels between groups - I thought this was effective. However, the figure (Figure 4) had quite a lot of important data and is a little difficult to summarize. Overall, it seems that stressed rats in general were more greatly affected, and that stressed females specifically had a much larger and longer-lasting increase in dopamine levels than the other groups.
While experiment 2 yielded interesting results, there is quite a lot that we have yet to learn regarding the dopamine mechanisms to account for these effects. I appreciated the way this paper clearly laid out steps for future research and I'm interested to see what comes of it. While this is a good start on the differences in males and females, getting the specific mechanism of the pathway causing these effects will have greater implications for translation to humans.
Finally, Holly et al. examined binge behavior in the different groups. I found it interesting that there were no effects of estrous cycle, although they stated that this could be due to the fact that binges could last longer than one stage of the cycle. I wonder if they would see clearer effects from the methods they proposed of controlling estradiol and progesterone levels.
Another question I had in general about the study was the effects of interactions between different factors. This was mentioned a few times - some experiments had significant effects and others did not. I'm not sure I quite understand the importance of these interactions and what they mean in terms of application.
Overall, I enjoyed reading this paper and am happy to see research that determines such specific groups in terms of sex and estrous cycle. This has shed light on differences between males in females for cocaine addiction, vulnerability, and cross-sensitization, and has built a strong foundation for future research. I would like to see more studies on the actual dopamine pathways and mechanisms that could be accounting for these differences, and I would also be interested to see studies of other drugs and the effects of sex and stress. I think there is a lot of potential in this field and could have a lot of human application looking ahead.
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