Rabbit Anti-Mouse OPRK1 (Phospho-Ser369) polyclonal antibody

Repeated alcohol exposure leads to changes in gene expression that are thought to underlie the transition from moderate to excessive drinking. However, the mechanisms by which these changes are integrated into a maladaptive response that leads to alcohol dependence are not well understood. One mechanism could involve the recruitment of transcriptional co-regulators that bind and modulate the activity of transcription factors. Our results indicate that the transcriptional regulator LMO4 is one such candidate regulator. Lmo4-deficient mice (Lmo4gt/+) consumed significantly more and showed enhanced preference for alcohol in a 24 h intermittent access drinking procedure. shRNA-mediated knockdown of Lmo4 in the nucleus accumbens enhanced alcohol consumption, whereas knockdown in the basolateral amygdala (BLA) decreased alcohol consumption and reduced conditioned place preference for alcohol. To ascertain the molecular mechanisms that underlie these contrasting phenotypes, we carried out unbiased transcriptome profiling of these two brain regions in wild type and Lmo4gt/+ mice. Our results revealed that the transcriptional targets of LMO4 are vastly different between the two brain regions, which may explain the divergent phenotypes observed upon Lmo4 knockdown. Bioinformatic analyses revealed that Oprk1 and genes related to the extracellular matrix (ECM) are important transcriptional targets of LMO4 in the BLA. Chromatin immunoprecipitation revealed that LMO4 bound Oprk1 promoter elements. Consistent with these results, disruption of the ECM or infusion of norbinaltorphimine, a selective kappa opioid receptor antagonist, in the BLA reduced alcohol consumption. Hence our results indicate that an LMO4-regulated transcriptional network regulates alcohol consumption in the BLA.

Heroin and drug dependence are major contributors to global health burden worldwide, but their underlying mechanisms remain elusive and may vary from population to population. Reward-and memory-related candidate genes dopamine D2 receptor (DRD2) and brain-derived neurotrophic factor (BDNF), as well as the opioid receptor genes (OPRM1, OPRD1, and OPRK1), have been implicated in drug dependence, but relatively little is known on their contributions to heroin dependence in populations worldwide. Hence, we evaluated the contributions of the above five candidate genes in heroin dependence and several important related endophenotypes (the onset age of heroin use and subjective response to first heroin use), at single single-nucleotide polymorphism as well as haplotype levels, in a Han Chinese population sample. We genotyped 546 unrelated and heroindependent subjects for the candidate genes noted, and 228 sex-and age-matched unrelated controls. The G allele of rs4654327 (OPRD1), DRD2 haplotype block CCGCCGTT (rs6277-rs1076560-rs2283265-rs2734833-rs 2075652-rs1079596-rs4436578-rs11214607), and OPRD1 haplotypes TACG (rs6669447-rs2236857-rs508448rs4654327), CG (rs508448-rs4654327), and TG (rs6669447-rs4654327) were significantly associated with heroin dependence phenotype. Homozygotes AA at rs6265 (BDNF), TT at rs16917234 (BDNF), and CC at rs508448 (OPRD1) also appeared as risk factors for the endophenotype earlier age of onset for heroin use. Two OPRM1 haplotypes, AG (rs1799971-rs1381376) and AT (rs1799971-rs3778151), were observed as potential protective factors. These emerging findings contribute to the literature on genetic biomarkers of drug dependence and related endophenotypes, and call for replication in independent population.