Environmental, genetic and epigenetic contributions to cocaine addiction

Abstract

Decades of research on cocaine has produced volumes of data that have answered many important questions about the nature of this highly addictive drug. Sadly, none of this information has translated into the development of effective therapies for the treatment of cocaine addiction. This review endeavors to assess the current state of cocaine research in an attempt to identify novel pathways for therapeutic development. For example, risk of cocaine addiction is highly heritable but genome-wide analyses comparing cocaine-dependent individuals to controls have not resulted in promising targets for drug development. Is this because the genetics of addiction is too complex or because the existing research methodologies are inadequate? Likewise, animal studies have revealed dozens of enduring changes in gene expression following prolonged exposure to cocaine, none of which have translated into therapeutics either because the resulting compounds were ineffective or produced intolerable side-effects. Recently, attention has focused on epigenetic modifications resulting from repeated cocaine intake, some of which appear to be heritable through changes in the germline. While epigenetic changes represent new vistas for therapeutic development, selective manipulation of epigenetic marks is currently challenging even in animals such that translational potential is a distant prospect. This review will reveal that despite the enormous progress made in understanding the molecular and physiological bases of cocaine addiction, there is much that remains a mystery. Continued advances in genetics and molecular biology hold potential for revealing multiple pathways toward the development of treatments for the continuing scourge of cocaine addiction.

Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

“…Genetic factors account for approximately 50% of the inter-individual differences in cocaine dependence (Ho et al, 2010). Despite the high heritability of cocaine dependence, very few genome-wide studies have investigated cocaine dependence (Pierce et al, 2018). A recent study identified a single nucleotide polymorphism in FAM53B significantly associated with cocaine dependence (Gelernter et al, 2014).…”

H3.3 Barcoding of Nucleus Accumbens Transcriptional Activity Identifies Novel Molecular Cascades Associated with Cocaine Self-administration in Mice

“…Posttranslational modifications to histones and chromatin remodeling are dynamic epigenetic processes that alter access of transcriptional machinery to promoter regions, thereby regulating patterns of gene expression (Strahl and Allis, 2000;Berger, 2007). A growing body of evidence indicates that chromatin remodeling, including stable enzymatic modifications of DNA and histone proteins, is associated with persistent changes in gene expression that may underlie drug addiction (Renthal and Nestler, 2008;Maze and Nestler, 2011;Pierce et al, 2018).…”

Behavioral Sensitization Induced by Methamphetamine Causes Differential Alterations in Gene Expression and Histone Acetylation of the Prefrontal Cortex in Rats

“…The enduring impact of these drugs, even after long periods of abstinence, has suggested persistent molecular events caused by transcriptional, epigenetic and translational effects [1] within addiction-related brain regions [2], such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus. Notably, a growing body of evidence has shown the important role of epigenetic regulation in the effects of psychostimulants [3] ( e.g., cocaine [4,5]) and found modifications of histones present in chromatin [6,7], DNA methylation [8,9], and DNA hydroxymethylation involved in the development of addiction. With respect to METH, however, only a few studies have investigated the epigenetic effects of these drugs, mainly focusing on the NAc and striatum [10][11][12][13][14].…”