title: Chronic Intracerebroventricular Infusion of Monocyte Chemoattractant Protein-1 Leads to a Persistent Increase in Sweetened Ethanol Consumption During Operant Self-Administration But Does Not Influence Sucrose Consumption in Long-Evans Rats.
abstract: BACKGROUND
  Among the evidence implicating neuroimmune signaling in alcohol use disorders are increased levels of the chemokine monocyte chemoattractant protein-1 (MCP-1) in the brains of human alcoholics and animal models of alcohol abuse. However, it is not known whether neuroimmune signaling can directly increase ethanol (EtOH) consumption, and whether MCP-1 is involved in that mechanism. We designed experiments to determine whether MCP-1 signaling itself is sufficient to accelerate or increase EtOH consumption. Our hypothesis was that increasing MCP-1 signaling by directly infusing it into the brain would increase operant EtOH self-administration.
  
  
  METHODS
  We implanted osmotic minipumps to chronically infuse either one of several doses of MCP-1 or vehicle into the cerebral ventricles (intracerebroventricular) of Long-Evans rats and then tested them in the operant self-administration of a sweetened EtOH solution for 8 weeks.
  
  
  RESULTS
  There was a significant interaction between dose of MCP-1 and sweetened EtOH consumed across the first 4 weeks (while pumps were flowing) and across the 8-week experiment. Animals receiving the highest dose of MCP-1 (2 μg/d) were the highest consumers of EtOH during weeks 3 through 8. MCP-1 did not influence the acquisition of self-administration (measured across the first 5 days), the motivation to consume EtOH (time to lever press or progressive ratio), withdrawal-induced anxiety, or the consumption of sucrose alone.
  
  
  CONCLUSIONS
  We provide novel evidence that neuroimmune signaling can directly increase chronic operant EtOH self-administration, and that this increase persists beyond the administration of the cytokine. These data suggest that EtOH-induced increases in MCP-1, or increases in MCP-1 due to various other neuroimmune mechanisms, may further promote EtOH consumption. Continued research into this mechanism, particularly using models of alcohol dependence, will help determine whether targeting MCP-1 signaling has therapeutic potential in the treatment of alcohol use disorders.
authors.affiliation: Division of Pharmacology/Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
authors.forename: John P
authors.initials: JP
authors.lastname: Valenta
authors.affiliation: Division of Pharmacology/Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
authors.forename: Rueben A
authors.initials: RA
authors.lastname: Gonzales
mesh_terms: D000437:Alcoholism / Q000276:immunology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D018932:Chemokine CCL2 / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage*; D057967:Infusions, Intraventricular; D008297:Male; D009042:Motivation; D051381:Rats; D020318:Rats, Long-Evans; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage*; D013549:Sweetening Agents / Q000008:administration & dosage*
chemical_list: D002492:Central Nervous System Depressants; D018932:Chemokine CCL2; D013549:Sweetening Agents; D000431:Ethanol; D013395:Sucrose
keywords: Dopamine Neurons; Dose-Response; NF-κB; Neuroinflammation; Neuromodulation