Review
Neurobiological substrates for the dark side of compulsivity in addiction

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Abstract

Drug addiction can be defined by a compulsion to seek and take drug, loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug is prevented. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in reward and stress within the basal forebrain structures involving the ventral striatum and extended amygdala. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreases in dopamine and opioid peptide function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, increases in anxiety-like responses, and increases in extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of addiction. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include norepinephrine, dynorphin, and neuropeptide Y. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement driving, at least in part, the compulsivity of addiction.

Section snippets

Definitions and conceptual framework for compulsivity in addiction

Drug addiction is a chronically relapsing disorder characterized by (i) compulsion to seek and take the drug, (ii) loss of control in limiting intake, and (iii) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented (defined here as dependence) (Koob and Le Moal, 1997). Addiction is assumed to be identical to the syndrome of substance dependence (as currently defined by the Diagnostic

Within-system neuroadaptations that contribute to the negative emotional state component of compulsivity

Within-system neuroadaptations to chronic drug exposure include decreases in function of the same neurotransmitter systems in the same neurocircuits implicated in the acute reinforcing effects of drugs of abuse. One prominent hypothesis is that dopamine systems are compromised in crucial phases of the addiction cycle, such as withdrawal and leads to decreased motivation for non-drug-related stimuli and increased sensitivity to the abused drug (Melis et al., 2005). Activation of the mesolimbic

Within-system neuroadaptations

In a series of studies, dopamine partial agonists have not only been shown to reverse psychostimulant withdrawal but also to block the increase in psychostimulant self-administration associated with extended access. Dopamine partial agonists decrease the reinforcing effects of psychostimulant drugs in non-dependent limited access paradigms (Izzo et al., 2001, Pulvirenti et al., 1998). However, animals with extended access show an increased sensitivity to a dopamine partial agonist (Wee et al.,

Compulsivity in addiction: an allostatic view

Compulsivity in addiction can derive from multiple sources, including enhanced incentive salience, engagement of habit function, and impairment in executive function. However, underlying each of these sources is a negative emotional state that may strongly impact on compulsivity. The development of the negative emotional state that drives the negative reinforcement of addiction has been defined as the “dark side” of addiction (Koob and Le Moal, 2005, Koob and Le Moal, 2008) and is hypothesized

Acknowledgments

The author would like to thank Michael Arends and Mellany Santos for their outstanding assistance with the preparation of this manuscript. Research was supported by National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA10072, DA04043, and DA04398 from the National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research also was supported by the Pearson Center for

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