d and bad actions (or better and best), override and suppress unacceptable social responses, and determine similarities and differences between things or events. The frontal lobes also play an important part in retaining long term emotional memories and adjusting emotions to fit socially acceptable norms important for individual integration into society. Frontal behavioral control mechanisms block impulsive mistakes and predict future rewards (Schoenbaum and Shaham 2008). Loss of these functions is a key element of the neurobiology of addiction and substance dependence (Fig. 1).
The limbic system supports a variety of functions particularly emotion, fear or elation, needs and urgency, long term memory, and olfaction. Addiction induced negative affect, mood and fear are associated with amygdale and hippocampus human temporal lobe structures (Fig. 1). Limbic urgency helps drive impulsive behaviors (Crews and Boettiger 2009). Across drugs of addition, the progression from abuse to addiction involves increasing drug wanting, negative emotional urgency and decreasing behavioral control (Jentsch and Taylor 1999; Robinson and Berridge 2003). Thus, the neurobiology of addiction involves dysfunctional frontal cortex behavioral control as well as exaggerated limbic urgency (Fig. 1). This review will present the hypothesis that innate immune gene induction in frontal cortex blunts behavioral control, whereas it amplifies limbic negative affect and bad feelings.
Neuroimmune signaling contributes to enteric, sensory, endocrine hypothalamic-adrenal (HPA) responses to external and internal environmental factors. Monocytes and brain microglia, are sensitive key cells involved in innate immune signaling. Neuroimmune signaling through microglia and other monocyte-like cells integrates sensory and endocrine enteric responses with brain. Microglia are unique monocyte-macrophage-like cells that share multiple stages of activation reflected morphologically and in gene expression (Hingson et al. 2009; Graeber 2010). Microglia are formed embryonically and migrate to fetal brain early in development creating a unique self-renewing monocyte-like cell that is maintained by self-renewal. Microglia and vascular monocyte-macrophages are the primary innate immune cells in brain (Ransohoff and Cardona 2010). Healthy brain contains ramified “resting” microglia known to survey brain and regulate synapses (Graeber 2010). Microglia have a low threshold of activation with initial states secreting signaling molecules, increasing expression of Major Histocompatibility Complex (MHC) proteins and Toll-like receptor proteins (TLR), key proteins involved in innate immune amplification. Morphological activation states show cellular enlargement, increased cell matrix and adhesion protein expression and progressive induction of other specific genes. Efforts to establish subtypes of microglia have designated M1 and M2 states as proinflammatory and trophic respectively, although additional subtypes continually emerge (Colton and Wilcock 2010). Activated enlarged morphology is often associated with secretion of chemokines regulating cellular movement, particularly to sites of tissue damage, that progress to proinflammatory-oxidative activation that includes protease secretion. Highly activated microglia progress to mitosis, proliferation and phagocyte oxidative bursts that oxidize and engulf waste (Graeber 2010). “Amoeboid” phagocytic rounded macrophage-like cell morphology is common in neurodegenerative diseases and senescence (Colton and Wilcock 2010). Microglia can also initiate trophic and other signals needed for healing (Crews et al. 2006). Microglia are important components of brain that regulate brain function in complex ways not fully understood. Emerging studies suggest brain suppress microglial activation promoting a trophic “resting” state (Liu et al.). Stress, ethanol, other addictive drugs as well as sensory and hormonal signals activate monocytes and microglia. Cycles of stimuli lead to microglial adaptive conditioning (Shpargel et al. 2008). Interesting