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.

Keywords: Dopamine Neurons; Dose-Response; NF-κB; Neuroinflammation; Neuromodulation.