Induction of innate immune genes in brain create the neurobiology of addiction

Abstract

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.

CC-Chemokine Ligand 2 Facilitates Conditioned Place Preference to Methamphetamine Through the Activation of Dopamine Systems

“…CCL2 is upregulated in the postmortem brain of alcoholic patients, and chronic exposure to alcohol increases CCL2 levels in the brain of the mouse (14,26). These findings may suggest a common mechanism underlying the development of psychic dependence on different addictive drugs.…”

“…Thus, it has been considered that this machinery contributes to Parkinson's disease (12,13). There are several reports suggesting that CCL2-mediated neuroinflammation also underlies the pathogenesis of drug abuse (14). Moreover, upregulation of CC-chemokine receptor 2 (CCR2), a dominant receptor for CCL2, mediates behavioral sensitization to methamphetamine, which reflects a psychosis (15).…”

Ethane-β-Sultam Modifies the Activation of the Innate Immune System Induced by Intermittent Ethanol Administration in Female Adolescent Rats

“…NFkappaB, [11] which is referred to as neuro-adaptation. Over the period of chronic alcohol abuse, >10 years, there will be progressive loss of behavioural control, caused by decreased frontal cortical regulation of attention and cognitive flexibility, combined with increased limbic negative feelings [12]. In addition the hippocampus will be adversely affected by chronic ethanol abuse, and shows decreased hippocampal volume as well as deficits in hippocampal-dependent learning and memory [13].…”

Impact of Drug Addiction on Mental Health

“…Addiction is an interminable state in which a man expends sedates over and over which prompts steady changes in his behavior, feelings, and thinking in which the individual loses his/her control and damages him/her or others [5]. Drug addiction alludes to physiological compulsion and psychological dependency.…”