Cross-talk between the epigenome and neural circuits in drug addiction

Abstract

Drug addiction is a behavioral disorder characterized by dysregulated learning about drugs and associated cues that result in compulsive drug seeking and relapse. Learning about drug rewards and predictive cues is a complex process controlled by a computational network of neural connections interacting with transcriptional and molecular mechanisms within each cell to precisely guide behavior. The interplay between rapid, temporally specific neuronal activation, and longer-term changes in transcription is of critical importance in the expression of appropriate, or in the case of drug addiction, inappropriate behaviors. Thus, these factors and their interactions must be considered together, especially in the context of treatment. Understanding the complex interplay between epigenetic gene regulation and circuit connectivity will allow us to formulate novel therapies to normalize maladaptive reward behaviors, with a goal of modulating addictive behaviors, while leaving natural reward-associated behavior unaffected.

Epigenetic Priming in Drug Addiction

“…Epigenetic processes are known to play key roles in the synaptic plasticity that mediates learning and memory formation, involving a multitude of chromatin-modifying enzymes and regulatory proteins that control activitydependent transcription (Gräff and Tsai 2013;) (see Box 1: Epigenetics and Chromatin). Similarly, chromatin-based mechanisms establish and adapt neuronal ensembles, or "engrams," across many brain regions to encode drug-associated information and promote continued drug use (Mews and Calipari 2017;Whitaker and Hope 2018). Notably, repeated drug exposure remodels neuronal cells in a way that changes their response to future stimuli, involving altered patterns of gene regulation that persist even when the original drug-induced stimulus has long faded (Walker et al 2015).…”

GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine

“…Methamphetamine self-administration is considered the gold standard animal model of MUD (Panlilio and Goldberg, 2007;Mews and Calipari, 2017). GZ-11608 dose dependently decreased methamphetamine self-administration.…”

From Circuits to Chromatin: The Emerging Role of Epigenetics in Mental Health

“…To make genes involved in neural plasticity accessible to RNA polymerase, the compact chromatin structure must be temporarily "opened." This process involves the recruitment of chromatin-modifying enzymes to immediate-early genes (e.g., Fos, FosB, and Junb), which become rapidly induced and subsequently regulate numerous other genes that encode membrane receptors and neuronal signaling proteins, which, in turn, modify the excitability and connectivity of neural circuits (Mews and Calipari, 2017). Notably, while it is well established that transient changes in chromatin mediate acute transcription in response to neuronal activity, evidence has been accumulating that certain epigenetic marks have long-lasting effects on gene expression that outlive the initial transient signal of neural stimulation (Robison and Nestler, 2011;Fischer, 2014).…”

“…Despite their very different chemical structures and initial protein targets, drugs of abuse ultimately converge by producing long-lasting changes in gene regulation in a central brain region of reward, the nucleus accumbens (NAc) (Robison and Nestler, 2011;Mews and Calipari, 2017). In the NAc, drugs of abuse elevate dopamine levels and consequently alter transcriptional programs that are believed to promote long-lasting synaptic and behavioral adaptations (Day et al, 2007).…”

“…Both transient and long-lasting changes in neuronal chromatin structure are emerging with essential roles for memory and the expression of complex behaviors; and it is evident that dysregulation in these processes is central to vulnerability, manifestation, and trajectory of mental health disorders (Bastle and Maze, 2019). One such example is substance use disorder, where chromatin-based processes have been linked to persistent changes in neural circuit activity and behavior (Mews and Calipari, 2017;Nestler and Lüscher, 2019). However, although years of research have shown that epigenetic mechanisms are critical to learning and behavioral control, the fundamental question of how epigenetic processes within neural circuits help transform experiences into long-term memory remains to be fully understood.…”