Increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. Here we have tested whether cocaine reinstatement in rats depends on interactions between accumbal dopamine and glutamate systems that are mediated by Ca(2+)/calmodulin-mediated kinase II (CaMKII). We show that stimulation of D1-like dopamine receptors in the nucleus accumbens shell reinstates cocaine seeking by activating L-type Ca(2+) channels and CaMKII. Cocaine reinstatement is associated with D1-like dopamine receptor-dependent increases in accumbens shell CaMKII phosphorylated on Thr286 and glutamate receptor 1 (GluR1) phosphorylated on Ser831 (a known CaMKII phosphorylation site), in addition to increases in cell-surface expression of GluR1-containing AMPA receptors in the shell. Consistent with these findings, cocaine reinstatement is attenuated by intra-shell administration of AAV10-GluR1-C99, a vector that impairs the transport of GluR1-containing AMPA receptors. Thus, CaMKII may be an essential link between accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine craving and relapse.

A heritable phenotype resulting from the self-administration of cocaine in rats was delineated. We observed delayed acquisition and reduced maintenance of cocaine self-administration in male, but not female, offspring of sires that self-administered cocaine. Brain-derived neurotrophic factor (BDNF) mRNA and protein were increased in the medial prefrontal cortex (mPFC) and there was an increased association of acetylated histone H3 with BDNF promoters only in the male offspring of cocaine-experienced sires. Administration of a BDNF receptor antagonist (the TrkB receptor antagonist ANA-12) reversed the diminished cocaine self-administration in male cocaine-sired rats. In addition, the association of acetylated histone H3 with BDNF promoters was increased in the sperm of sires that self-administered cocaine. Collectively, these findings indicate that voluntary paternal ingestion of cocaine results in epigenetic reprograming of the germline resulting in profound effects on mPFC gene expression and resistance to cocaine reinforcement in male offspring.

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.polyglutamine | neurodegeneration H untington disease (HD), a neurodegenerative disease (1, 2) characterized by cognitive dysfunction, psychiatric symptoms, and choreic movements (2), exhibits brain region-specific neuronal degeneration in the striatum and cortex. Currently, no disease-modifying treatment is available. The genetic basis of HD is the expansion of an in-frame CAG repeat sequence encoding polyglutamine. Progressive transcriptional dysregulation in both cortex and striatum and atrophy of the cortex are characteristic features (3). Transcriptional repression of key neuronal transcripts, including neurotransmitters, growth factors, and their cognate receptors, is consistently observed and implicated in disease pathogenesis. Among the critical genes whose expression is repressed in HD mouse models and human brain tissue are the dopamine receptor 2 (Drd2), preproenkephalin (Penk1), the cannabinoid receptor (Cb2), and brain-derived neurotrophic factor (Bdnf) (4, 5).We hypothesized that a central event in the pathological program underlying transcriptional dysregulation includes alterations in chromatin structure in the regulatory regions of genes down-regulated in HD. To evaluate this hypothesis, we focused on H3K4 trimethylation (H3K4me3), a mark of transcription start sites (TSSs) and active chromatin (6-8). Growing evidence suggests that this mark is plastic and modulated in conditions of chronic stress, developmental disorders, psychiatric disorders (9-11) as well as during long-term memory consolidation from contextual fear conditioning (12), suggesting a critical function in brain.We first investigated H3K4me3 in the R6/2 mouse model of HD, which shows patterns of transcriptional dysregulation similar to postmortem HD brain (13,14). Using chromatin immunoprecipitation (ChIP), we examined H3K4me3 levels for Bdnf, which is expressed in the cortex, provides trophic support for GABAergic medium spiny neurons, and is expressed at lower levels in HD (5, 15). The potential significance of Bdnf in HD is reflected by transcriptional profiling (16) and therapeutic preclinical studies (17,18). Because H3K4me3 levels were lowered at Bdnf and other promoters in R6/2 mice and key neuronal genes in human HD brain cortex and striata, we expanded our approach to investigate the genome-wide relationship between H3K4me3 an...