CRF-Amplified Neuronal TLR4/MCP-1 Signaling Regulates Alcohol Self-Administration

• DOI: 10.1038/npp.2015.4
• Publication Date: 2015-01-08T11:54:42Z
• Authors: Harry L June; Juan Liu; Kaitlin T Warnock; Kimberly A Bell; Irina Balan; Dominique Bollino; Adam Puche; Laure Aurelian
• Keywords: Neurons; 0301 basic medicine; Alcohol Drinking; Ethanol; Corticotropin-Releasing Hormone; Central Amygdaloid Nucleus; Genetic Vectors; Ventral Tegmental Area; Central Nervous System Depressants; Self Administration; Binge Drinking; Cell Line; Rats; 3. Good health; Toll-Like Receptor 4; Mice; 03 medical and health sciences; Animals; Simplexvirus; Genetic Predisposition to Disease; RNA, Small Interfering; Chemokine CCL2

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.