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Neuroscience. 2014 Dec 5;281:241-50. doi: 10.1016/j.neuroscience.2014.07.017. Epub 2014 Jul 19.

Cocaine self-administration and extinction alter medullary noradrenergic and limbic forebrain cFos responses to acute, noncontingent cocaine injections in adult rats.

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  • 1Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, United States. Electronic address:
  • 2Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, United States.


Central noradrenergic (NA) signaling contributes critically to multiple behavioral effects of cocaine administration, particularly stress- and anxiety-related effects. The present study examined the ability of acute cocaine to induce the immediate early gene product, cFos, in NA neurons and stress-related neural circuits in rats that were cocaine-naïve, or had a history of cocaine self-administration with or without extinction. Rats implanted with jugular catheters were trained to self-administer cocaine (0.5-mg/kg/infusion), with a subset subsequently trained on extinction. Cocaine-naïve controls were handled daily. After a final day of self-administration, extinction, or handling, rats received an i.p. injection of either cocaine (20-mg/kg) or saline, and 90min later were anesthetized and perfused. Tissue sections were processed for immunoperoxidase labeling of nuclear cFos with either immunoperoxidase or immunofluorescent cytoplasmic labeling of dopamine beta hydroxylase or tyrosine hydroxylase. Acute cocaine increased the number of activated NA neurons within the caudal nucleus of the solitary tract (NTS; A2 cell group) in cocaine-naïve and extinguished rats, but not in rats that only self-administered. Extinction attenuated cocaine-induced cFos activation in NA neurons of the caudal ventrolateral medulla (A1/C1 cell groups), and attenuated cFos within the paraventricular nucleus of the hypothalamus, the apex of the central neuroendocrine stress axis. Cocaine consistently increased cFos in the bed nucleus of the stria terminalis, regardless of history. NA neurons of the locus coeruleus (A6 cell group) were not activated after cocaine administration in any experimental group. Thus, the ability of cocaine to activate central stress circuitry is altered after cocaine self-administration. Our results suggest a unique role for the NTS in cocaine-induced reinstatement, as extinction training enhanced the ability of cocaine to activate NA neurons within this region. These findings suggest central NA systems originating in the caudal brainstem as potential targets for the treatment of cocaine addiction.


bed nucleus of the stria terminalis; cocaine; locus coeruleus; nucleus of the solitary tract; paraventricular nucleus of the hypothalamus; ventrolateral medulla

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