Dnmt3a2 in the Nucleus Accumbens Shell Is Required for Reinstatement of Cocaine Seeking

Abstract

Epigenetic mechanisms have gained increasing attention as regulators of synaptic plasticity and responsiveness to drugs of abuse. In particular, it has been shown that the activity of the DNA methyltransferase 3a (Dnmt3a) mediates certain long-lasting effects of cocaine. Here we examined the role of the Dnmt isoforms, and, within the nucleus accumbens (NAc) on transcriptional activity of immediate early genes (IEGs) and acute and long-lasting responsiveness to cocaine and cocaine conditioned cues. Using primary striatal cultures, we show that transcription of , but not that of, is activated by dopamine D1 receptor signaling and that knockdown of using viral vector-mediated expression of Dnmt3a2-specific shRNAs impairs induction of the IEGs,, , and Acute cocaine administration increases expression of but not that of in the NAc shell. In contrast, in the NAc core, expression of and was unaffected by cocaine administration. shRNA-mediated knockdown of impairs the induction of IEGs, including and indicating that Dnmt3a2 regulates cocaine-dependent expression of plasticity genes in the rat NAc shell. Cocaine self-administration experiments in rats revealed that Dnmt3a2 regulates drug cue memories that drive reinstatement of cocaine seeking as well as incubation of this phenomenon within the NAc shell. Dnmt3a2 does not influence the primary reinforcing effects of cocaine. Thus, Dnmt3a2 mediates long-lasting cocaine cue memories within the NAc shell. Targeting expression or function may interfere with cocaine craving and relapse. In humans, drug craving can occur in response to conditioned cues, even after extended periods of abstinence. In rats, cue-induced cocaine seeking has been shown to increase progressively during the first 2 months of abstinence from drug self-administration. This phenomenon, referred to as incubation of cocaine seeking, is consistent with the hypothesis that in humans craving increases over time and remains high following prolonged abstinence. Those long-lasting behavioral changes are likely to be mediated by epigenetic effects and neuroplastic changes within the mesolimbic brain reward system. Here we show that a specific isoform of DNA-methyltransferases in the NAc shell regulates drug cue memories that drive reinstatement of cocaine seeking after both early abstinence and incubation of cocaine craving.

DNMT3a in the hippocampal CA1 is crucial in the acquisition of morphine self‐administration in rats

“…Recent studies showed that expression of DNMT3a2 but not that of DNMT3a1 is regulated by neuronal activity in the hippocampus and that DNMT3a2 is required for the formation and extinction of fear memory . On the other side, DNMT3a2 but not DNMT3a1 in the NAc shell is required for cue‐induced reinstatement and incubation of cocaine seeking . Based on these studies, we propose that DNMT3a2 but not DNMT3a1 may be required in the acquisition of morphine SA.…”

“…Based on these findings, in the present study, we focused only on the NAc shell but not the NAc core. One recent study also shows that DNMT3a2 expression in the NAc shell but not in the NAc core is involved in conditioned reinstatement and incubation of cocaine SA . Another interesting finding is that immediately after SA training, neither morphine SA nor saccharin SA affected the DNMT3a expression in the NAc shell.…”

“…Exposure to many drugs (cocaine, morphine, and methamphetamine) leads to DNA methylation, which is associated with transcriptional silencing . Moreover, DNA methylation in the NAc is implicated in the regulation of cocaine‐induced behavioral sensitization, incubation of craving, and reinstatement/incubation of cocaine SA . DNA methylation in the sperm has an impact on the heritable cocaine‐seeking motivation .…”

Neuronal ensemble-specific DNA methylation strengthens engram stability

“…Taken together, these studies indicated that particularly the function of Dnmt3a is important for hippocampal memory formation. We showed that the Dnmt3a isoform, Dnmt3a2 is required for different forms of long-lasting neuronal adaptions, including long-term memory formation, and that the expression of Dnmt3a2, but not Dnmt3a1, is induced by neuronal activity and learning [12][13][14][15] . Therefore in the current study, we employed activity-dependent tools to overexpress and reinforce the function of the activity- Our results demonstrate that restricting the overexpression of Dnmt3a2 to the majority of the DG neuronal population (~75%) activated by CFC was sufficient to positively modulate the memory engram, and to specifically strengthen the memory encoding for the aversive context.…”

“…Recently developed technologies 10,11 allowed us to manipulate the levels of a DNA methyltransferase (Dnmt) specifically within hippocampal neuronal ensembles formed after contextual fear learning and to investigate the consequences of this manipulation for the strength of fear memory and stability of the engram. In particular, we elevated the levels of the de novo DNA methyltransferase (Dnmt3a2) in the dentate gyrus (DG) of the mouse hippocampus, as Dnmt3a2 expression is regulated by neuronal activity 12 and has established functions in long-lasting neuronal adaptations [13][14][15] . We showed that reinforcing DNA methylation-related mechanisms through Dnmt3a2 overexpression within memory-encoding neuronal ensembles specifically during consolidation was sufficient to strengthen contextual fear memory and the stability of the engram.…”