title: TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation.
abstract: Alcohol dependence is a complex disorder that initiates with episodes of excessive alcohol drinking known as binge drinking, and has a 50-60% risk contribution from inherited susceptibility genes. Cognitive impulsivity is a heritable trait that may set the stage for transition to alcohol dependence but its role in the ethanol-seeking behavior and the involved genes are still poorly understood. We have previously shown that alcohol-preferring P rats have innately elevated levels of a neuronal Toll-like receptor 4 (TLR4) signal in the ventral tegmental area (VTA) that controls the initiation of excessive alcohol drinking. Here we report that TLR4 is localized in dopaminergic (TH+) neurons and it upregulates the expression of tyrosine hydroxylase (TH) through a cAMP-dependent protein kinase (PKA)/cyclic AMP response element binding protein (CREB) signal. P rats have higher impulsivity than wild-type (WT) rats and VTA infusion of a non-replicating Herpes simplex virus (HSV) vector for TLR4-specific small interfering RNA (siRNA; pHSVsiTLR4) inhibits both impulsivity and TLR4/TH expression. A scrambled siRNA vector does not affect gene expression or impulsivity. The data suggest that TLR4 signaling in VTA dopaminergic neurons controls impulsivity related to the regulation of TH expression, likely contributing to the initiation of alcohol drinking and its transition to alcohol dependence.
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Aurelian
authors.affiliation: Neuropsychopharmacology Laboratory, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Warnock
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: I
authors.initials: I
authors.lastname: Balan
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Puche
authors.affiliation: Neuropsychopharmacology Laboratory, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA.
authors.forename: H
authors.initials: H
authors.lastname: June
mesh_terms: D000437:Alcoholism / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D007175:Impulsive Behavior; D008297:Male; D034741:RNA, Small Interfering; D051381:Rats; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D034741:RNA, Small Interfering; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases