Sex-based differences in drug addiction: stress and epigenetics -- Annie Bryant

Both of week’s papers examined how nature versus nurture can affect one’s vulnerability to cocaine addiction, with a focus on sex-specific differences. The latter part is important given that women tend to engage in cocaine usage younger and more extensively than males, and that maternal versus paternal cocaine exposure produce differential effect in male and female offspring. Holly et al. focused on “nurture” with stress as a key factor for females, while Vassoler et al. explored “nature” with epigenetic reprogramming of cocaine sensitivity in males.

Holly et al. cite findings that stress increases vulnerability to drug abuse, implementing an episodic social defeat stress paradigm in rats. This model was previously shown to increase male response to cocaine, with elevated behavioral and neural cross-sensitization. I was surprised that the male and female aggressor rats exhibited equal fight frequency and duration, and it’s cool that they had qualitatively distinct fight tactics. Overall, stressed females exhibited greater behavioral sensitization, neuronal (dopaminergic) sensitization, and cocaine self-administration than equivalently-stressed males. These differences emerged at different time points, suggesting different physiological mechanisms by which stress affects males and females. I wondered if male versus female rats would have responded differently to different doses of cocaine; perhaps females have a lower threshold for cocaine sensitivity.

Holly et al. also explored the role of estradiol, since other studies have highlighted its role in cocaine-induced locomotor and striatal dopamine sensitization in female rats in estrus. Indeed, in this study, stressed female rats in estrus did walk longer and more frequently after cocaine injection than did stressed males or stressed non-estrus females; however, stressed estrus females didn’t self-administer more cocaine or binge for longer than non-estrus females. While Holly et al. showed that stressed females as a whole exhibited greater and longer-lasting DA concentration in the NAc after cocaine delivery compared to all other groups, it’s unfortunate they didn’t have enough estrus vs non-estrus female rats in this experiment to have statistical power. This precluded them from directly comparing DA levels between these two groups, which (in my opinion) undermines their conclusion that there is a relationship between stress and estradiol in dopaminergic function in female rats. Moreover, they didn’t propose any mechanism by which estradiol might be exerting these effects. It would help to elucidate what molecules/pathways estradiol interacts with in this setting.

Nevertheless, I do think this paper supports the idea that stress exerts different effects on drug use proclivity in males versus females. I like their idea of investigating the causal relationship between estradiol, DA tone, and cocaine intake by treating ovariectomized female rats with estradiol and/or progesterone – the latter of which inhibits the effects of cocaine, as Vassoler et al. point out. Other groups have shown sex-related differences in dopamine receptor and transporter distribution, which could influence dopamine reuptake and concentration in the NAc. On that note, I was hoping for more justification as to why Holly et al. focused on the NAc in particular, beyond citing findings that cocaine upregulates dopamine expression there. Also, perhaps this is beyond the scope of this paper, but I would be interested to see the sex-specific effects of stress alone on locomotion and dopamine content without cocaine administration in the equation.

Switching gears to focus on nurture, Vassoler et al. developed a rat model to explore the influence of paternal cocaine intake on offspring gene expression, chromatin remodeling, and cocaine reinforcement. This model is advantageous because it eliminates confounding influences of in utero cocaine exposure and doesn’t influence maternal behavior toward offspring. I thought the sugar cube experiment was a great control to distinguish reduced acquisition/motivation from general learning deficits. Male offspring of cocaine-taking sires showed delayed acquisition of cocaine self-administration in the fixed ratio 1 schedule and reduced motivation for self-administration in the progressive ratio schedule. In the latter, the difference in breakpoint only emerged at the higher dose; the authors don’t address this (in fact, they don’t justify using two different doses at all), and I wonder if this has any relevance to human cocaine administration.

Vassoler et al. note that cocaine and BDNF have opposing effects in limbic nuclei: cocaine modulates BDNF expression in limbic nuclei, which in turn increases cocaine-seeking and intake behaviors. Conversely, BDNF (in the mPFC, specifically) curbs the effects of cocaine on behavior, mitigating the intrinsic reinforcing effectiveness of cocaine. They point out the (bizarre) fact that cocaine concentration in the testes after SC injection is second only to that in the brain. As such, Vassoler et al. hypothesized that the male offspring of cocaine-exposed sires inherited this drug-resistance phenotype via changes in the BDNF gene in the sires’ sperm. They found that cocaine-exposed sires had increased association between the Bdnf promoter and transcription-upregulating acetylation of histone H3 in their sperm. Accordingly, their offspring had increased BDNF mRNA transcripts and protein levels in the mPFC, with an increased association with acetylated H3. Furthermore, the BDNF receptor antagonist ANA-12 restored acquisition of cocaine self-administration in the male cocaine-sired rats, paralleling previous findings that RNAi-mediated BDNF knockdown in the mPFC increasing cocaine-seeking PR schedule breakpoint.

I think Vassoler et al. put forth a well-informed and evidence-supported hypothesis as to how cocaine exposure in male sires affects male offspring cocaine behavior via BDNF-related chromatin changes in sperm. However, I’m still unclear as to how these changes would only induce transcriptional changes and behavioral phenotypes in male offspring. The Bdnf gene is located on chromosome 11, so it’s not a sex-linked gene. I think it would be interesting to directly address BDNF levels by comparing controls with either BDNF knock-down or overexpression and measure resulting behavior from cocaine sires. I also wonder how much of their findings are specific to cocaine self-administration rather than the physiological effects of (involuntary) cocaine delivery? For example, how would offspring behavior compare from sires that were routinely injected with cocaine? Lastly, I wonder if this model could reproduce findings the authors cite wherein paternal cocaine intake produces working memory deficits in female offspring.