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
