esis paralleled the onset of depression-like behavior with both reversed by anti-depressant treatment (Stevenson et al. 2009). Similarly stress induced IL-1β reduces neurogenesis causing depression like behavior (Koo and Duman 2008). Thus, neurogenesis reflects mood, with reduced neurogenesis associated with innate immune gene induction, drug induced negative affect and depression-like behavior. Interestingly, recovery from alcoholism is associated with improved mood and cognition, human brain enlargement and increased neurogenesis (Crews and Nixon 2009). Overall findings suggest adult hippocampal stem cells and neurogenesis provide an index of mood and negative affect that allow molecular studies on regulation of mood, both negative and positive (Crews and Nixon 2003; Koo et al. 2011) (Fig.4). These findings are consistent with drug induced depression sharing common mechanisms with endogenous depression as well as the negative affect of substance use disorder, e. g. addiction.
The frontal cortex is involved in attention, rule setting, decisions and behavioral control. It connects to multiple brain regions through excitatory glutamatergic neurons. Reciprocal connections to thalamus and limbic regions involve focal excitation that is disrupted by innate immune gene induction. In astrocytes, activation of NF-κB increasing expression of proinflammatory innate immune genes (Zou and Crews 2006; Pascual et al. 2007; Zou and Crews 2010) and reduces astrocyte glutamate transport (Zou and Crews 2005) causing an increase in extracellular glutamate increasing neuron excitiation and excitotoxicity (Zou and Crews 2006). Innate immune induced hyperexcitability due to loss of cortical glutamate transporters inactivates the frontal lobes contributing to the neurobiology of addiction (Crews et al. 2006). Other studies have indicated genetic factors linked to a hyperglutamate state to alcoholism (Spinagel, 2005) and ethanol induced NF-κB activation to increased extracellular glutamate (Ward et al. 2009). Innate immune gene induction 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 p