title: CRF-amplified neuronal TLR4/MCP-1 signaling regulates alcohol self-administration.
abstract: Alcohol dependence is a complex disorder that initiates with episodes of excessive alcohol drinking known as binge drinking. It has a 50-60% risk contribution from inherited susceptibility genes; however, their exact identity and function are still poorly understood. We report that alcohol-preferring P rats have innately elevated levels of Toll-like receptor 4 (TLR4) and monocyte chemotactic protein-1 (MCP-1) that colocalize in neurons from the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA). To examine the potential role of a TLR4/MCP-1 signal, we used Herpes Simplex Virus (HSV) vectors (amplicons) that retain in vivo neurotropism. Infusion of amplicons for TLR4 or MCP-1 siRNA into the CeA or VTA from the P rats inhibited target gene expression and blunted binge drinking. A similarly delivered amplicon for scrambled siRNA did not inhibit TLR4 or MCP-1 expression nor reduce binge drinking, identifying a neuronal TLR4/MCP-1 signal that regulates the initiation of voluntary alcohol self-administration. The signal was sustained during alcohol drinking by increased expression of corticotropin-releasing factor and its feedback regulation of TLR4 expression, likely contributing to the transition to alcohol dependence.
authors.affiliation: Neuropsychopharmacology Laboratory, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Neuropsychopharmacology Laboratory, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Kaitlin T
authors.initials: KT
authors.lastname: Warnock
authors.affiliation: Neuropsychopharmacology Laboratory, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bell
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Balan
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bollino
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Puche
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Aurelian
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D063425:Binge Drinking / Q000378:metabolism; D002460:Cell Line; D066274:Central Amygdaloid Nucleus / Q000187:drug effects / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D012646:Self Administration; D018139:Simplexvirus / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: C491766:Ccl2 protein, rat; D002492:Central Nervous System Depressants; D018932:Chemokine CCL2; D034741:RNA, Small Interfering; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000431:Ethanol; D003346:Corticotropin-Releasing Hormone