Hyper-brain connectivity in binge drinking college students: a diffusion tensor imaging study.

The current study used diffusion tensor imaging to examine patterns/degree of brain connectivity in 12 college-aged binge drinking (BD) and 12 moderate drinking individuals. Voxel-level and region-of-interest analyses revealed increased connectivity of the BD brain in the right corona radiata, right external capsule, and both the right and left cingulum. Also, fractional anisotropy and axial diffusivity values of these regions correlated with a number of drinking behaviors of the BD as well as both groups combined.

Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice.

Background: Alcohol use disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually (New Engl J Med, 2003, 348, 1786). Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies.

Effective Reduction in High Ethanol Drinking by Semisynthetic Tetracycline Derivatives.

Background: New pharmacotherapies to treat alcohol use disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol (EtOH) drinking in mice.

Up-regulation of steroid biosynthesis by retinoid signaling: Implications for aging.

Retinoids (vitamin A and its derivatives) are critical for a spectrum of developmental and physiological processes, in which steroid hormones also play indispensable roles. The StAR protein predominantly regulates steroid biosynthesis in steroidogenic tissues. We have reported that regulation of retinoid, especially atRA and 9-cis RA, responsive StAR transcription is largely mediated by an LXR-RXR/RAR heterodimeric motif in the mouse StAR promoter.

Bioinformatics analyses reveal age-specific neuroimmune modulation as a target for treatment of high ethanol drinking.

Background: Use of in silico bioinformatics analyses has led to important leads in the complex nature of alcoholism at the genomic, epigenomic, and proteomic level, but has not previously been successfully translated to the development of effective pharmacotherapies. In this study, a bioinformatics approach led to the discovery of neuroimmune pathways as an age-specific druggable target. Minocycline, a neuroimmune modulator, reduced high ethanol (EtOH) drinking in adult, but not adolescent, mice as predicted a priori.

The Oct DNA motif participates in the alcohol inhibition of the inducible nitric oxide synthase gene promoter in rat C6 glioma cells.

Induction of nitric oxide synthase-2 (iNOS) by cytokines and bacterial products is associated with protein binding at the proximal promoter and in an upstream enhancer region of the Nos2 gene. To clarify how ethanol suppresses rat iNOS activity, we constructed several deletion mutants of the Nos2 promoter fused to the luciferase gene and transfected the constructs into C6 glial cells. Acute ethanol exposure of stably transfected cells for 24 h inhibits induced activity of Nos2 promoter constructs containing deletions in the 5' flanking region, including a 94 bp promoter that lacks any known NF-kappaB site but which carries a C/EBPbeta and overlapping gamma-IRE, GAS and Oct motifs.

Interactions of alcohol and nitric-oxide synthase in the brain.

Nitric oxide (NO) is an important molecule associated with both physiological and pathological brain events. Three separate genes encode for nitric-oxide synthase (NOS), the rate-limiting enzyme in NO production, all of which are expressed within brain tissue. Effects of ethanol on NO production may be important to ethanol modification of brain function.

Effects of mechanistically distinct NF-kappaB inhibitors on glial inducible nitric-oxide synthase expression.

Nuclear factor (NF)-kappaB is an important regulator of inflammatory gene expression. Transcriptional regulation of Nos2, the inducible nitric-oxide synthase (iNOS) gene, is complex and not fully understood, but appears to be regulated in part by NF-kappaB. To further understand the role of NF-kappaB in Nos2 expression, we compared three functionally distinct NF-kappaB inhibitors on NF-kappaB transactivation and iNOS induction by rat C6 glial cells.

Ethanol increases nuclear factor-kappa B activity in human astroglial cells.

Alcohol abuse adversely affects essentially all the organs of the body, either directly or indirectly. Ethanol may contribute to brain damage via inflammation. Ethanol may also alter CNS immunocompetence and further the progression of certain CNS infections.

Acute ethanol exposure modulates expression of inducible nitric-oxide synthase in human astroglia: evidence for a transcriptional mechanism.

Astroglia are important in immunocompetence and response to injury within the CNS. Activated astroglia respond, in part, by expressing inducible nitric-oxide synthase (iNOS) and subsequent catalytic production of nitric oxide. Results from a previous study in our laboratory, in the human A172 astroglial cell line, revealed that induction of iNOS activity by tumor necrosis factor-alpha + interferon-gamma + interleukin-1 beta was inhibited by 24-h exposure to a high ethanol concentration (200 mM), but enhanced by 50 mM ethanol.

Chronic ethanol inhibits CXC chemokine ligand 10 production in human A172 astroglia and astroglial-mediated leukocyte chemotaxis.

Astroglia are the most prevalent cell type in the human central nervous system (CNS) and perform important roles in normal tissue homeostasis, during pathological events and following trauma. Astroglial-derived chemokines have important neurotrophic effects and are important to CNS immunocompetence and response to injury, in part, due to their direct role in leukocyte and microglial cell recruitment. However, while ethanol is known to induce CNS pathologies and to be peripherally immunosuppressive, ethanol effects on chemokine expression in human astroglia are essentially unknown.

Identification of cis-regulatory regions necessary for robust Nos2 promoter activity in glial cells: indirect role for NF-kappaB.

Previous reports suggest the nitric-oxide synthase 2 (Nos2) promoter contains negative and positive cis-regulatory regions. This study identified such regions using rat C6 glial cells. Activity of the serially deleted rat Nos2 promoter fused to a luciferase reporter gene was found to vary with construct size independent of stimuli, decreasing markedly from 160 to 130 bp then increasing significantly from 110 to 94 bp.

Regulation of steroid hormone biosynthesis in R2C and MA-10 Leydig tumor cells: role of the cholesterol transfer proteins StAR and PBR.

The MA-10 mouse Leydig tumor cell line produces large amounts of steroids only in response to hormonal stimulation while the R2C rat Leydig tumor cell line is constitutively steroidogenic in nature. In an effort to uncover the potential reasons for constitutive steroidogenesis in R2C cells, we have recently shown that compared to MA-10 cells, R2C cells express much higher levels of the Scavenger Receptor Class B type 1 which results in a higher capacity for cholesteryl ester uptake through the selective uptake pathway. We also found an enhanced expression of Hormone Sensitive Lipase and the Steroidogenic Acute Regulatory protein in these cells and reasoned that they may further facilitate the conversion of cholesteryl esters to free cholesterol and its mobilization to the inner mitochondrial membrane, thus rendering them constitutively steroidogenic.

An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain.

Recent data implicate locally produced steroids, termed neurosteroids, as regulators of neuronal function. Adrenal and gonadal steroidogenesis is controlled by changes in the steroidogenic acute regulatory protein (StAR); however, little is known about the regulation of neurosteroid production. We now demonstrate unequivocally that StAR mRNA and protein are expressed within glia and neurons in discrete regions of the mouse brain, and that glial StAR expression is inducible.

Ethanol-induced modulation of inducible nitric-oxide synthase activity in human A172 astrocytoma cells.

Background: Glial cells are critical in the functioning of the central nervous system (CNS), including responsiveness to injury and immunocompetence. The immune and inflammatory response involves the inducible form of nitric-oxide synthase (iNOS), and subsequent nitric oxide (NO) production. Previously, we have demonstrated that ethanol inhibits cytokine-induced iNOS expression and activity in rat glial cells.

Dual mechanisms for ethanol-induced inhibition of monocyte chemotactic protein-3 mRNA expression in activated glial cells.

The differential display of mRNA technique was used to screen the expressed genes in control and 50 mM chronic ethanol-treated rat C6 glial cells, with and without activation by lipopolysaccharide (LPS) combined with phorbol 12-myristate 13-acetate (PMA). One differentially expressed transcript was identified as that corresponding to the chemokine monocyte chemotactic protein (MCP)-3. MCP-3 is a broadly active chemokine that functions in chemoattraction and activation of monocytes, T lymphocytes, eosinophils, basophils, natural killer cells, and dendritic cells.

Hypoglycemia-induced suppression of luteinizing hormone (LH) secretion in intact female rhesus macaques: role of vasopressin and endogenous opioids.

The first objective of this study was to determine whether insulin-induced hypoglycemia (IIH) inhibits LH secretion in unrestrained female macaques during the follicular phase of the menstrual cycle. There was a consistent inhibitory effect of hypoglycemia on LH secretion within 3 h in these females. This inhibition was likely an indirect effect since low glucose levels did not inhibit GnRH secretion from GT1-1 neurones in vitro.