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Venniro, 2018 & de Guglielmo, 2019 - Drug Addiction

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April 6 Papers (Venniro et. al, de Guglielmo et. al)

The Venniro et. al paper explores the influence volitional social interaction has on drug addiction in rats. The study gave rats a choice between social interaction and self-administration of either methamphetamines or heroin, and the results showed that they vastly preferred social interaction even after long periods of forced abstinence from drugs. The effect was still present but decreased when social interaction was delayed or punished. These results held true regardless of sex, drug class or dose, abstinence duration, housing conditions, or level of addiction. Additionally, abstinence due to social interaction also protected against methamphetamine cravings, and this was linked to increased activation of protein kinase C-δ  (PKCδ )-expressing inhibitory neurons in the central amygdala (CeA) and inhibition of activity in the anterior ventral insular (AIV) cortex.

What I appreciated the most about this paper is that it highlights the importance of keeping in mind the differences between rats (or mice) and humans when running animal studies, and of trying to imitate the human experience as closely as possible in these animal models if we want the research to be applicable for the development of clinical treatments for humans. Clearly, the human experience is always going to be more complex and include far more variables than can be replicated in research with animals, but we should strive to close the gap between the two as much as we can. In line with this, I found particularly relevant the comments in the Discussion section about how cultural frames of reference and long-term expectations affect the choices humans make regarding drug use, and how this might explain why the drug-seeking behaviors seen in rats in this study differed from what has been observed in humans. 

The paper also did a good job at controlling for numerous variables including sex, housing conditions, drug class, drug dose, duration of abstinence, addiction score, etc. However, it was surprising that there were no significant differences between male and female rats, especially given the fact that other papers we have read pointed out important differences in how the sexes respond to drug addiction both behaviorally and on a biological level. Furthermore, since many of the papers we have read about drug addiction thus far have dealt with cocaine, it would be interesting to see whether the results of this study would hold true if the rats were given access to cocaine instead of methamphetamine or heroin. Even though this experiment controlled for drug class, and despite the fact methamphetamine and cocaine are both stimulants, the drugs act through different mechanisms and can have varying effects in those who take them. Lastly, I was curious as to what the “innovative social-media approaches” alluded to at the end of the paper entail and what they would look like in the treatment of drug addiction or other psychiatric disorders. 

On the other hand, the de Guglielmo et. al paper revealed how optogenetic inactivation of corticotropin-releasing factor (CRF) neurons in the CeA prevented recruitment of the CeA neuronal ensemble that is recruited during alcohol withdrawal, which led to decreased drinking and ameliorated the symptoms of alcohol withdrawal in dependent rats. The results also showed that inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) reduced behaviors associated with addiction, and that inhibition of this CRF CeA-BNST pathway was mediated by inhibition of the CRF-CRF system and cell firing in the BNST.  

Both papers highlighted the role of the CeA in generating the cravings and withdrawals associated with addiction, yet focused on different components within the CeA. The Venniro paper was concerned with PKCδ -expressing inhibitory neurons, while the de Guglielmo paper looked at CRF+ neurons. Similarly, while both papers studied CeA projections to and from other brain regions they focused on different areas, with the Venniro paper examining projections from the AIV to the lateral CeA subdivision (CeL) and the de Guglielmo paper focusing on projections from the CeA to the BNST. This suggests that while the CeA is certainly associated with addiction cravings and withdrawals, the details of exactly how are still unclear, and it is likely that several different pathways and neuronal components are involved in the process. As such, we can think of these papers as complementing each other to show different angles of the mechanisms by which the CeA influences withdrawal experiences. 

Lastly, the de Guglielmo paper only studied male rats, so further research is needed, as noted at the end of the paper, to determine whether their findings are applicable to females. 

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