Xpression PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/20978850 of the dopamine transporter, so their mechanisms of action are likely to become complex114. Ultimately, arginine exporter protein ARGO2 — which can be critical in microRNA-mediated gene silencing — as well as various specific microRNAs have recently been implicated in cocaine regulation of gene expression selectively in the D2 subclass of striatal MSNs115. Other drugs of abuse have been linked to microRNAs also. Opioid receptor activation downregulates miR-190 in cultured rat hippocampal neurons within a beta-arrestin2-dependent manner116, along with the let-7 family members of microRNA precursors is upregulated by chronic morphine exposure in mice117. Interestingly, the opioid receptor is itself a direct target for let-7, plus the resulting repression of the receptor has been suggested as a novel mechanism for opiate tolerance117. In zebrafish and in cultured immature rat neurons, morphine decreases miR-133b expression, and this could possibly influence dopamine neuron differentiation114. Additionally, both acute and chronic alcohol exposure upregulates miR-9 in cultured striatal neurons, and this might contribute to alcohol tolerance by way of regulation of large-conductance Ca2+ activated K+ (BK) channels118. miR-9 seems to preferentially downregulate BK channel isoforms which might be sensitive to alcohol potentiation, possibly shifting BK channel expression toward much more tolerant subytpes119. miR-9 also targets the D2 dopamine receptor119, and so almost certainly influences alcohol reward. Within the future, next-generation sequencing of microRNAs in several brain regions soon after exposure to drugs of abuse will be vital to uncover regulation of precise microRNAs and ultimately the genes they regulate. Certainly, this process has already begun, as such screens are revealing several mcicroRNAs regulated in the NAc soon after chronic cocaine115,120. For instance, cocaine regulation in the miR-8 loved ones suggests novel mechanisms for drug-induced alterations within the neuronal cytoskeletal and synaptic structure120. Exploring this mechanism in drug-induced regulation of NAc dendritic morphology is definitely an vital line of future investigation.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptFuture DirectionsThis Evaluation has summarized the growing array of findings that assistance a function for regulation of the transcriptional prospective of myriad genes within the brain’s maladaptations to drugs of abuse. The mechanisms of transcriptional and epigenetic regulation are themselves varied and very complex, and future studies are ISA-2011B site necessary to catalogue the vast variety of regulatory events that take place also as to understand the precise underlying mechanismsNat Rev Neurosci. Author manuscript; accessible in PMC 2012 May 1.Robison and NestlerPageinvolved. Important inquiries include: What controls the recruitment or expulsion of individual transcriptional regulatory proteins to a specific target gene? Our hypothesis is that the underlying epigenetic state of that gene is a essential determining factor, but then what controls the formation and maintenance of distinct epigenetic states at certain genes? Also, what are the intracellular signaling cascades that transduce the initial drug action in the neurotransmitter-receptor level towards the neuronal nucleus to regulate the epigenetic state of particular subsets of genes? The existing literature on transcriptional and epigenetic mechanisms of addiction is limited in a number of key methods. Most research to date have employed conditioned place preference an.