Elsevier

Brain Research

Volume 1293, 1 October 2009, Pages 61-75
Brain Research

Review
Brain stress systems in the amygdala and addiction

https://doi.org/10.1016/j.brainres.2009.03.038Get rights and content

Abstract

Dysregulation of the brain emotional systems that mediate arousal and stress is a key component of the pathophysiology of drug addiction. Drug addiction is a chronically relapsing disorder characterized by a compulsion to seek and take drugs and the development of dependence and manifestation of a negative emotional state when the drug is removed. Activation of brain stress systems is hypothesized to be a key element of the negative emotional state produced by dependence that drives drug-seeking through negative reinforcement mechanisms. The focus of the present review is on the role of two key brain arousal/stress systems in the development of dependence. Emphasis is placed on the neuropharmacological actions of corticotropin-releasing factor (CRF) and norepinephrine in extrahypothalamic systems in the extended amygdala, including the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition area in the shell of the nucleus accumbens. Compelling evidence argues that these brain stress systems, a heretofore largely neglected component of dependence and addiction, play a key role in engaging the transition to dependence and maintaining dependence once it is initiated. Understanding the role of the brain stress and anti-stress systems in addiction not only provides insight into the neurobiology of the “dark side” of addiction but also provides insight into the organization and function of basic brain emotional circuitry that guides motivated behavior.

Section snippets

Conceptual framework: addiction, stress, motivational withdrawal, and negative reinforcement

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take the drug and loss of control in limiting intake. A third key element included by some and particularly relevant to the present review is the emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented (defined here as dependence) (Koob and Le Moal, 1997, Koob and Le Moal, 2008). Addiction is used interchangeably in the present treatise with

Hormonal stress systems: hypothalamic-pituitary-adrenal axis

The HPA axis is composed of three major structures: the paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland (for review, see Smith and Vale, 2006). Neurosecretory neurons in the medial parvocellular subdivision of the paraventricular nucleus synthesize and release CRF into the portal blood vessels that enter the anterior pituitary gland. Binding of CRF to the CRF1 receptor on pituitary corticotropes induces the release of ACTH into the

Brain stress systems: corticotropin-releasing factor and norepinephrine

Corticotropin-releasing factor is a 41 amino acid polypeptide that controls hormonal, sympathetic, and behavioral responses to stressors. The discovery of other peptides with structural homology, notably the urocortin family (urocortins 1, 2, and 3), suggested broad neurotransmitter roles for the CRF systems in behavioral and autonomic responses to stress (Bale and Vale, 2004, Hauger et al., 2003). Substantial CRF-like immunoreactivity is present in the neocortex, extended amygdala, medial

Extended amygdala: interface of stress and addiction

Recent neuroanatomical data and new functional observations have provided support for the hypothesis that the neuroanatomical substrates for many of the motivational effects of drug addiction may involve a common neural circuitry that forms a separate entity within the basal forebrain, termed the “extended amygdala” (Alheid and Heimer, 1988). The extended amygdala represents a macrostructure composed of several basal forebrain structures: the bed nucleus of the stria terminalis, central medial

Pharmacological evidence for a role of CRF and norepinephrine in negative emotional states associated with drug withdrawal

A common response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like or aversive-like responses. Animal models have revealed anxiety-like responses to all major drugs of abuse during acute withdrawal (Fig. 2). The dependent variable is often a passive response to a novel and/or aversive stimulus, such as the open field or elevated plus maze, or an active response to an aversive stimulus, such as defensive burying of an electrified

Neurochemical evidence for a role of CRF and norepinephrine in motivational effects of acute drug withdrawal

Chronic administration of drugs of abuse either via self-administration or passive administration increases extracellular CRF from the extended amygdala measured by in vivo microdialysis (Fig. 3). Continuous access to intravenous self-administration of cocaine for 12 h increased extracellular CRF in dialysates of the central nucleus of the amygdala (Richter and Weiss, 1999). Opioid withdrawal induced after chronic morphine pellet implantation in rats increased extracellular CRF in the central

Pharmacological evidence of a role for CRF and norepinephrine in increased motivation for drug-seeking in withdrawal

The ability of neuropharmacological agents to block the anxiogenic-like and aversive-like motivational effects of drug withdrawal would predict motivational effects of these agents in animal models of extended access to drugs. Animal models of extended access involve exposure of the animals to extended sessions of intravenous self-administration of drugs (cocaine, 6 h; heroin, 12 h; nicotine, 23 h) and passive vapor exposure (14 h on/12 h off) for ethanol. Animals are then tested for

Cellular basis in the central nucleus of the amygdala for motivational effects of CRF and norepinephrine interactions in dependence

Cellular studies using electrophysiological techniques have shown that γ-aminobutyric acid (GABA) activity within interneurons of the extended amygdala may reflect the negative emotional state of motivational significance for drug-seeking in dependence (Koob, 2008). CRF itself enhances GABAA inhibitory postsynaptic potentials (IPSCs) in whole-cell recordings of the central nucleus of the amygdala and bed nucleus of the stria terminalis in brain slice preparations, and this effect is blocked by

Brain stress systems and addiction

Drug addiction, similar to other chronic physiological and psychological disorders such as high blood pressure, worsens over time, is subject to significant environmental influences (e.g., external stressors), and leaves a residual neural trace that allows rapid “re-addiction” even months and years after detoxification and abstinence. These characteristics of drug addiction have led to a reconsideration of drug addiction as more than simply a homeostatic dysregulation of emotional function, but

Summary and conclusions

Acute withdrawal from all major drugs of abuse increases reward thresholds, anxiety-like responses, and CRF in the amygdala, each of which have motivational significance. Compulsive drug use associated with dependence is mediated by not only loss of function of reward systems but also recruitment of brain stress systems such as CRF and norepinephrine in the extended amygdala. Brain arousal/stress systems in the extended amygdala may be key components of the negative emotional states that drive

Acknowledgments

This is publication number 19930 from The Scripps Research Institute. Research was supported by the Pearson Center for Alcoholism and Addiction Research and National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA04043 and DA04398 from the National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. The author would like to thank Mike Arends for his help with manuscript

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