A Functional Interaction Between LMO4 And Kappa Opioid Receptors In The Basolateral Amygdala Regulates Alcohol Consumption and Reward

Abstract

Repeated alcohol exposure leads to changes in gene expression that are thought to underlie the transition from moderate to excessive alcohol drinking. However, the mechanisms by which these gene expression changes are mobilized to a maladaptive response are not well understood. One mechanism could involve the recruitment of transcriptional co-regulators that bind and modulate the activity of several transcription factors. Our results indicate that the transcription cofactor LMO4 is one such candidate regulator. Previous results demonstrate that knock down of LMO4 in the basolateral amygdala (BLA) decreased alcohol consumption and preference as well as reduced conditioned place preference to alcohol. To identify transcriptional targets of LMO4 in the BLA we carried out unbiased transcriptome profiling of the BLA in WT and Lmo4gt/+ mice, in which LMO4 expression is reduced by approximately 50%. Our analysis revealed a number of genes whose expression was significantly up or downregulated in the BLA of Lmo4gt/+ mice compared to WT. We took a systems approach to identify gene networks that were responsive to LMO4 downregulation in the BLA. Weighted gene co-expression network analysis revealed genes related to the extracellular matrix and the kappa opioid receptor (KOR) as putative transcriptional targets of LMO4 in the BLA. Chromatin immunoprecipitation studies indicated that LMO4 bound to the KOR promoter elements in the amygdala and that infusion of Nor-BNI, a selective KOR antagonist into the BLA reduced alcohol consumption. Further, knockdown of LMO4 in the BLA attenuated the ability of U50,488, a KOR agonist to enhance alcohol consumption. Studies are currently underway to determine if restricting LMO4 knockdown to KOR cells in the BLA using intersectional strategies will reduce alcohol consumption and reward. In summary, our results reveal a functional interaction between LMO4 and KOR in the BLA in regulating alcohol consumption.