robe cognitive flexibility and frontal lobe function (Bechara et al. 2002). The persistence of addiction, a chronic relapsing disorder, compares with the persistence in innate immune gene induction (Qin et al. 2007; Qin et al. 2008) and loss of behavioral flexibility.
Adolescence is an important developmental period when drug experimentation increases and behavioral control mechanisms mature. The frontal cortex develops during adolescence in parallel with the development of behavioral control (Ernst et al. 2009). The adolescent frontal cortex is uniquely sensitive to binge drinking neurotoxicity (Crews et al. 2000) and adolescent hippocampus uniquely sensitive to alcohol inhibition hippocampal of neurogenesis (Crews et al. 2006). Loss of frontal cortical function causes perseveration and repetition of previously learned behaviors due to failure to associate new information, e.g. negative consequences, into decision making. Models of adolescent binge drinking result in persistent reversal learning deficits (Coleman 2010) and persistent increases in proinflammatory innate immune gene expression and markers of neurodegeneration (Pascual et al. 2007). Anti-infammatory drugs protect against adolescent binge drinking brain damage models (Pascual et al. 2007) Initiation of drug experimentation during adolescence when frontal cortical behavioral control circuitry is developing increases vulnerability for life-long addiction (Crews et al. 2007). These studies suggest anti-inflammatory therapies may have value in reducing drug induced changes in neurobiology that contribute to addiction.
The neurobiology of addiction develops over a course of repeated drug abuse and/or stress. Changes in neurobiology underline altered mood and cognition related to increased limbic negative affect and loss of frontal cortical behavioral control. Drug abuse, stress and other factors increase NF-κB transcription of multiple proinflammatory genes that spread across brain cell types further amplifying of NF-κB transcription through loops involving cytokines, chemokines, oxidases and proteases. Evidence supports the spread and persistence of brain innate immune gene induction as creating the neurobiology of addiction. Human studies of genetic risk for alcoholism and post-mortem brain support the role of innate immune genes in addiction. Animal behavior studies indicate increasing drug consumption and mounting negative affect and depression-like behavior are due to innate immune gene induction. Further, frontal cortical hyperexcitability, behavioral flexibility and loss of behavioral control can all be linked to innate immune genes. Together these finding suggest the neurobiology of addiction is due to innate immune gene altered signaling inducing the behaviors that define addiction. Therapies that blunt brain innate immune gene induction may represent new and novel approaches to preventing and/or reversing addiction.
The Authors wish to acknowledge Diana Lotito for help with the preparation of the manuscript as well as support from the Bowles Center for Alcohol Studies, School of Medicine University of North Carolina and the National Institutes of Health, National Institute on Alcoholism and Alcohol Abuse, AA020023, AA020024, AA020022, AA019767, AA11605.
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