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Addiction occurs through repeated abuse of drugs that progressively reduce behavioral control and cognitive flexibility while increasing limbic negative emotion. Recent discoveries indicate neuroimmune signaling underlies addiction and co-morbid depression. Low threshold microglia undergo progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress, and/or cell damage signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and innate immune target gene expression. Human post-mortem alcoholic brain has increased NF-κB and NF-κB target gene message, increased microglial markers and chemokine-MCP1. Polymorphisms of human NF-κB1 and other innate immune genes contribute to genetic risk for alcoholism. Animal transgenic and genetic studies link NF-κB innate immune gene expression to alcohol drinking. Human drug addicts show deficits in behavioral flexibility modeled pre-clinically using reversal learning. Binge alcohol, chronic cocaine, and lesions link addiction neurobiology to frontal cortex, neuroimmune signaling and loss of behavioral flexibility. Addiction also involves increasing limbic negative emotion and depression-like behavior that is reflected in hippocampal neurogenesis. Innate immune activation parallels loss of neurogenesis and increased depression-like behavior. Protection against loss of neurogenesis and negative affect by anti-oxidant, anti-inflammatory, anti-depressant, opiate antagonist and abstinence from ethanol dependence link limbic affect to changes in innate immune signaling. The hypothesis that innate immune gene induction underlies addiction and affective disorders creates new targets for therapy.
Chronic use of alcohol stimulants and/or opiates lead to progressive changes in the brain and behavior, often leading good, smart and sane people to do bad, stupid and crazy 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 goo