things that hurt themselves and others. The continued and often escalating horrific, unpleasant, awful events associated with increasing drug use resulting in addiction are well known. Medical emergencies due to accidents, drug overdoses, violent desperate, impulsive illegal behavior, physical injuries criminal justice problems (Li 2008; Gilson 2010) and other negative consequences associate with drug addiction (Hingson et al. 2009; Mendelson et al. 1986). Alcohol or opiate dependence was first defined by neurological and physiological withdrawal symptoms including hyperexcitability, fever, anxiety and feelings of sickness. However, modern medicine focuses psychological dependence that causes loss of behavioral control (Kalivas and O'Brien 2008; Koob and Volkow 2010). Addiction can be defined as a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include impaired control over drug use, compulsive use, continued use despite harm, and craving (Ries et al. 2009; Volkow et al. 2011). Substance Dependence, a Psychiatric diagnosis is defined as “repeated use of alcohol or other drugs despite problems related to use of the substance (O'Brien 2008). Critical to these medical diagnoses of severe addiction is the continued use of drugs despite the harm to the individual, family and community due to the loss of ability to alter behavior in spite of problems. This review will describe changes in the neurobiology of the brain related to severe addiction.
The loss of behavioral control that underlies addiction has at least 2 components, decreased frontal cortical regulation of attention and cognitive flexibility and increased limbic fear-negative feelings (Fig. 1). The frontal lobes of brain are involved in decision making and other executive functions such as motivation, planning, goal setting and inhibition of impulses. Frontal lobe functions also predict future consequences, choose between good 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 forme