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Central nervous system corticotropin releasing factor (CRF) systems contribute to increased anxiety-like behavior during opioid withdrawal : an analysis of neuroanatomical substrates


Increased release of the stress neurotransmitter corticotropin-releasing factor (CRF) in the extended amygdala mediates ethanol withdrawal signs such as anxiety -like behaviors. The present study determined whether anxiety-like consequences of naloxone-precipitated withdrawal from morphine dependence also involves CRF hyperactivity in the extended amygdala, by selectively infusing antalarmin, an antagonist that selectively blocks CRF 1 receptors, into the nucleus accumbens shell (NAC) or the central amygdala (CeA). Anxiety-like behavior was assessed as a reduction in willingness to explore the open arms of an elevated plus maze. Male Wistar rats were implanted with bilateral cannulae in the NAC shell or the CeA. Dependence was induced by daily injections of 10 mg/ kg of morphine over a period of 4 days (non-dependent controls received vehicle in place of morphine). Eight hours after morphine injection on the fourth day, withdrawal was precipitated by naloxone (0.33 mg/kg; controls received vehicle in place of naloxone. Bilateral infusion of the CRF-1 receptor antagonist antalarmin (1.0, 3.3, or 10.0nmol) or vehicle preceded naloxone by 10 min. Naloxone administered after morphine but not vehicle reduced the relative time spent in, and number of entries into, the open vs. closed arms of the maze. Antalarmin dose-dependently attenuated these morphine withdrawal anxiety-like signs when infused in the NAC shell but not CeA. The same dose of intra-NAC antalarmin that attenuated anxiety-like signs antalarmin reduced activity (number of closed arm entries), suggesting that blunting CRF's arousing effects in the NAC may result in a reduction of morphine withdrawal anxiety

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