Modulators of the Brain Stress System

Non CRF Targets

Preclinical data suggest that other neurotransmitter systems/neuromodulators in the extended amygdala may be dysregulated during the development of dependence and contribute to the “dark side” of addiction. Norepinephrine is dysregulated in alcohol, cocaine, and opioid dependence. Dynorphin is dysregulated in cocaine, opioid, and alcohol dependence. Vasopressin is dysregulated in opioid and alcohol dependence. Hypocretin and substance P are dysregulated in cocaine, opioid, and alcohol dependence. These are examples from animal models of components of the addiction cycle that are activated during the development of dependence. Norepinephrine/CRF interactions have been hypothesized to contribute to the brain stress activation associated with withdrawal from drugs of abuse, and some anti-addiction-like effects have been observed in animal models (for example, administration of the noradrenergic α1 receptor antagonist prazosin). Dynorphins are the presumed endogenous ligands for the κ opioid receptor. Dynorphin has long been hypothesized to mediate negative emotional states. κ Opioid receptor agonists produce conditioned place aversions, depression, and dysphoria in humans. Substantial evidence suggests that dynorphin peptide, dynorphin gene expression, and κ opioid receptors are activated in the striatum, ventral striatum (nucleus accumbens), and amygdala during acute and chronic administration of drugs in rats and humans. Activation of the dynorphin systems in the nucleus accumbens then decreases activity in dopamine systems. As a result, the activation of dynorphin systems could contribute to the dysphoric syndrome associated with cocaine dependence. κ Opioid receptor antagonists blunt compulsive-like cocaine self-administration in rats with extended access (for further reading, see Wee and Koob, 2010).

Other neuromodulatory systems may act in opposition to CRF in buffering stress and emotional behavior, which may become future targets for medications development for the treatment of addiction. These include neuropeptide Y, nociceptin, and endocannabinoid receptor agonists, all of which reduce excessive drinking associated with alcohol dependence.

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