Commentary

Will a cocaine epidemic follow the opioid crisis?


 

Ongoing efforts to understand the impact of cocaine on the brain and on behavior have gained considerable momentum over the past few decades. It was only 30 years ago when cocaine was widely considered both safe and nonaddicting – “the champagne” of drugs.1 Progress has been steady since the cocaine-dopamine depletion theory was proposed, and ultimately supported by functional and PET imaging.2,3

Additional discoveries promise further insights into the neuroscience of addiction, pleasure, and mood. While cocaine use, abuse, and dependence might seem relatively quiescent, compared with the scourge of opiate-related deaths and addiction, it remains a public health concern – and now is the second-leading cause of drug deaths. Cocaine cultivation, smuggling, use, and the number of first-time users are all escalating.4

These developments suggest that cocaine problems might get much worse and beg an important question: Will new research give us insight into better solutions?

What the neuroscience shows

As discussed, we already know quite a bit about the neuroscience behind cocaine addiction. The positron emission tomography studies conducted by Nora D. Volkow, MD, and her associates have shown long-lasting changes in abstinent cocaine addicts. Specifically, their findings clearly demonstrated that cocaine changes the brain and depletes dopamine-rich areas. Furthermore, dopamine recovery is negligible after months of abstinence.5

However, large gaps in our understanding remain. The realm of epigenetic study and protein expression behind abuse will be key in bridging our understanding of phenotype to genotype. A recent article by Eric J. Nestler, MD, PhD, and his research team, published in the Journal of Biological Psychiatry and titled “Cocaine self-administration alters transcriptome-wide responses in the brain’s reward circuitry,” offers exciting new insights (Biol Psychiatry. 2018 Apr. doi: 10.1016/jbiopsych.2018.04.009).

The study, led by Deena M. Walker, PhD, offers perhaps the most complete illumination to date of the genetic and epigenetic changes seen in the brain after cocaine self-administration and application.

Dr. Walker and her associates used a mouse model and sorted them into one of several groups. One group examined self-administered acute cocaine exposure only, with the mice immediately harvested thereafter. Two longer-term groups included one that had cocaine exposure with prolonged (30-day) withdrawal followed by context re-exposure (context re-exposure defined as being placed back in the special chamber and lighting they first received cocaine in) and another that had a cocaine exposure with prolonged withdrawal followed by both context and cocaine re-exposure.

The researchers also ran a parallel set of control groups substituting saline for cocaine with otherwise identical durations of observation and context re-exposure. Reward-related brain regions were harvested from each subject and examined with RNA-sequencing analysis to investigate the full genomic/transcriptomic profile of each. Pairwise comparison of the various experimental groups against the control groups (for example, the theoretical baseline of genetic expression in a non–cocaine-exposed brain) uncovered telling patterns, which the investigators aptly described as a comprehensive picture of transcriptome-wide change cocaine causes within the reward circuit.

The novel and creative approach used by Dr. Walker and her associates allowed them to uncover a wealth of clinically significant findings. Much could be said about their spotlighting of specific gene/protein targets for potential future pharmacological therapies toward cocaine treatment – an area that is indeed in sore need of invention. While we have highly efficacious medications for overdose and chronic treatment of opiate abuse, the landscape of treatment options for cocaine is far bleaker and shrouded in theory. With that in mind, perhaps the most salient take-home point is the evidence that cocaine, even after one exposure/withdrawal event, causes a dramatic rewiring in the very way genes are expressed across the reward circuit. The researchers found large shifts in the patterns of genetic transcription, unique and specific to discrete regions of the examined brain tissue, such as the ventral tegmental area, ventral hippocampus, and basolateral amygdala.

More interestingly, similar patterns of these genetic alternations were observed based on the exact history of the cocaine exposure. Dr. Walker and her associates concluded that the withdrawal phase and context re-exposure appear to be crucial components in the re-sculpting of the transcriptomic profile of the reward circuity.

The brain is unprepared by evolution for the reinforcing and reorganizing effects of cocaine. Clinicians, too, have learned that cocaine is addicting and can quickly replace drives such as food, water, sex, and survival. These new data from Dr. Nestler’s team reinforce the importance of prevention. In addition, they are reminders to physicians that cocaine causes changes in brain and behavior that are persistent and not necessarily reversible. Patterns of transcriptomic change are alarming enough and have only recent begun to be fleshed out, but patterns of global substance use trends suggest that we need to begin cocaine prevention activities.

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