Brain Structures and Functions Relevant to the Three Stages of the Addiction Cycle

Neuroadaptational Summary

Drug addiction involves a three-stage cycle - binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation - that worsens over time and involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process (see What is Adiction).

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 the brain reward and stress systems within the ventral striatum, extended amygdala, and frontal cortex. Specific neurochemical elements in these structures include decreases in reward system function (within-system opponent processes), recruitment of the classic stress axis mediated by CRF in the frontal cortex and extended amygdala, and recruitment of aversive dynorphin-κ opioid systems in the frontal cortex, ventral striatum, and extended amygdala (both between-system opponent processes). Acute withdrawal from all major drugs of abuse increases reward thresholds, decreases mesocorticolimbic dopamine activity, increases anxiety-like responses, increases extracellular levels of CRF in the central nucleus of the amygdala, and increases dynorphin in the ventral striatum. CRF receptor antagonists block anxiety-like responses associated with withdrawal. They also block increases in reward thresholds produced by withdrawal from drugs of abuse and blunt compulsive-like drug taking during extended access.

Excessive activation of dopamine receptors in the nucleus accumbens via the release of mesocorticolimbic dopamine or opioid peptide activation of opioid receptors also activates the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block the dysphoric-like effects associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress system that contributes to compulsive drug seeking. Thus, the brain reward systems become compromised, and the brain stress systems become activated by acute excessive drug intake. These changes become sensitized during repeated withdrawal, continue into protracted abstinence, and contribute to the development and persistence of addiction. The loss of reward function and recruitment of brain stress systems provide a powerful neurochemical basis for the negative emotional states that are responsible for the negative reinforcement that drives the compulsivity of addiction. Excessive drug taking also activates CRF in the medial prefrontal cortex, paralleled by deficits in executive function that may facilitate the transition to compulsive-like responding. Dysregulation of the prefrontal cortex can impair executive function and drive impulsivity and help perpetuate disinhibition of the brain stress systems. The combination of the facilitation of incentive salience for drugs, reward dysfunction, stress sensitization, and impaired executive function captures most of the addiction phenotype.

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