**12. Concluding remarks**

**Figure 5.** Epigenetic inheritance. For pregnant F0 females (top left panel), drug exposure directly affects (red-outlined symbols) both the F0 female and the fetus, including the brain and germ cells of the upcoming F1 generation. Howev‐ er, the F2 generation also receives direct effects of drug exposure from the F0 generation via the germ cells of the F1 generation. For males (top right panel), drug exposure directly affects both the F0 generation and the germ cells that lead to the F1 generation. Therefore, the F3 and F2 generation of the pregnant female and male, respectively, can re‐ ceive transgenerational epigenetic inheritance from the F0 generation without having been in direct contact with drugs

The idea that addiction-like phenotypes can be passed down across generations based on experiences of the parents is compelling in terms of uncovering potential biomarkers that could be used to predict one's risk of developing drug addiction. Only a few studies have investi‐ gated this possibility in the context of drug abuse models. Vassoler and colleagues [75] found that male adult rats with a history of cocaine self-administration passed an addiction-*resist‐ ant* phenotype onto male, but not female, offspring. One potential mediator of these effects is mPFC BDNF expression, where both the male F0 generation's sperm and the mPFC of the male, but not female, offspring exhibited increased H3 acetylation at the BDNF promoter, as well as increased BDNF expression in the mPFC of the male offspring. Consistent with this idea, mPFC BDNF is associated with resilience to drug effects [47, 49, 50]. These data are

of abuse (orange-outlined symbols).

**11.1. Drug abuse-related traits passed across generations**

36 Recent Advances in Drug Addiction Research and Clinical Applications

The studies reviewed provide compelling evidence for a link between drug-induced epigenetic regulation of gene expression and drug abuse-related behavior in animals. The epigenetic changes in gene expression occur in brain regions involved in reward learning and motivation. This leads to plasticity-related changes within the neurocircuitries that mediate these processes and is associated with aberrant behaviors that resemble hallmark symptoms of human drug addiction, such as escalation of drug intake [42, 44, 80, 81] and increased willingness to exert effort to obtain drug [46, 82]. Given that epigenetic mechanisms can produce long-lasting changes in gene expression, they are likely candidate explanations for the persistent nature of drug addiction in humans.

Current understanding of experience-dependent epigenetic changes is in its infancy. One notable limitation in this field is the dearth of research on drugs of abuse other than psychos‐ timulants and alcohol. This is a particularly important gap to fill given that regulatory changes in addiction-related genes can have opposite effects on abuse-related behaviors depending on drug class [25, 83, 84]. The field also faces many challenges in discerning the involvement of epigenetic mechanisms in drug addiction given the vast number of molecular regulatory events that are altered by stress and drug experience, the complex interactions that can occur among these regulatory events, and their drug-, region-, and time-specificity. Indeed, high comorbidity exists between drug addiction and stress-related emotional disorders (e.g., PTSD and depression) [85, 86]; therefore, additional work is needed to test whether epigenetic factors underlie the co-occurrence or are specific for one disorder over the other. It will be vital to test the generalizability versus specificity of epigenetic modifications in drug abuse-related behavior.

Despite the challenges that lie ahead, growing knowledge in this field will provide opportu‐ nities for novel preventions and interventions of drug abuse and dependence. New technol‐ ogies for identifying and specifically targeting epigenetic processes hold promise not only for understanding the complex interactions between drug exposure, life experiences, and gene expression, but also as treatment strategies designed to counter epigenetic dysregulation. For instance, the use of synthetic transcription factors may allow drug-induced or inherited epigenetic marks to be erased in order to increase resilience when one is exposed to addictive drugs [69]. Future epigenetics research may also identify biomarkers of vulnerability that may aid prevention strategies. Collectively, these new avenues of drug abuse research are exciting given the urgent need for better treatments of this devastating disorder.
