The role of monocyte chemoattractant protein-1 on operant ethanol self-administration in Long-Evans rats

The neuroimmune system can exert a powerful influence over behavior, and evidence is mounting that the neuroimmune system can influence the intake of drugs of abuse. Insight into the interaction between drugs of abuse and the neuroimmune system will teach us more about the inner workings of the brain and can lead to new treatment options for addiction. Previous research has demonstrated that alcoholics have elevated levels of immune signaling molecules. My dissertation project demonstrated that elevating immune signaling molecules in the brain can directly increase ethanol consumption. A variety of cytokines are elevated in human alcoholics and animal models of ethanol dependence. However, recent research has suggested that monocyte chemoattractant protein -1 (MCP-1) is particularly important. Researchers have found elevated levels of MCP-1 in the brains of human alcoholics, in animal brains after chronic exposure to ethanol, and in brain slices exposed to ethanol. Also, MCP-1 or MCP-1 receptor (CCR2) knockout mice had a significant reduction in ethanol consumption and a reduced preference for ethanol. My goal was to clarify if MCP-1 signaling could increase ethanol intake. Generally speaking, I accomplished this by increasing the amount of MCP-1 signaling in the brain and then measuring ethanol drinking behavior. I infused MCP-1 into the cerebral ventricles of rodents for 4 weeks and measured their ethanol intake for those 4 weeks as well as 4 additional weeks. There was a significant interaction between dose of MCP-1 and ethanol 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/day) were the highest consumers of ethanol during weeks 3 through 8. My second goal was to determine how the modulation of brain MCP-1 signaling could influence drinking behavior in ethanol-dependent rodents. I made progress toward this goal by reliably reaching target BAC’s in rodents through the use of ethanol vapor inhalation chambers, but I did not reach the point of inducing dependence or modulating MCP-1. The neuroimmune system seems to be paramount in the progressive loss of control over drug intake seen in drug addiction and presents a potential route for the treatment of addiction. The results of my experiments support this hypothesis by providing evidence that neuroimmune signaling can increase ethanol consumption, show that MCP-1 signaling is critical in this phenomenon, and identify MCP-1 signaling as a strong candidate for investigating the therapeutic potential of neuroimmune signaling for alcohol use disorders.