on causes hyperexcitability in the spinal cord related to neuropathic pain (Graeber 2010) and in the hippocampus related to seizures (Maroso et al. 2010). Hyperexcitability in the frontal cortex results in loss of cognitive flexibility creating addiction-like behavior (Gruber 2010). Kalivas' laboratory in elegant studies have established that cocaine and stimulant addiction are related to hyperglutamate states due to alterations in the cortical glutamate transporters, (Reissner and Kalivas 2010). These studies and others have suggested that anti-oxidants and other drugs that block innate immune gene cascades may provide new therapies for addiction.
Frontal cortical dysfunction is often investigated using reversal learning tasks. In reversal learning, expected outcomes are wrong requiring flexible behavior in response to outcomes that do not match those predicted by the preceding cues (Stalnaker et al. 2009). Reversal learning tasks in behavioral studies mimic the inability of drug addicted individuals to learn new healthy behaviors, when alcohol and other drugs have established strong associations. A frontal cortical signal is needed to indicate the value of decisions and is needed when new learning and/or behavior is necessary. We found that models of binge drinking induce persistent deficits in reversal learning in rats (Obernier et al. 2002) and in adult mice following a model of adolescent binge drinking (Coleman 2010). Other studies have found rats with previous experience either with self-administration of cocaine or with passive cocaine injections, are abnormally slow to learn reversals, even though they learn initial contingencies at a normal rate (Schoenbaum et al. 2004; Calu et al. 2007). Lesions of the frontal cortex cause reversal learning deficits in tasks similar to chronic drug abuse induced deficits (Schoenbaum et al. 2006). Studies of both human cocaine and alcohol addicts have found dysfunctional decision making in tasks involving delaying reward for more value and reversal learning tasks that probe 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 involv