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The Journal of Neuroscience, May 1, 2002, 22(9):3663-3672

Regional and Cellular Mapping of cAMP Response Element-Mediated Transcription during Naltrexone-Precipitated Morphine Withdrawal

Tamara Z. Shaw-Lutchman^{1, 2}, Michel Barrot¹, Tanya Wallace², Lauren Gilden², Venetia Zachariou^{1, 4}, Soren Impey³, Ronald S. Duman², Daniel Storm³, and Eric J. Nestler¹

¹ Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, ² Interdepartmental Neuroscience Program and Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, ³ Department of Pharmacology, University of Washington, Seattle, Washington 98195, and ⁴ Department of Pharmacy, University of Patras School of Health, Patras, Greece 26500

Chronic opiate exposure is associated with upregulation of the cAMP signaling pathway and the transcription factor cAMP response element-binding protein in the locus ceruleus (LC) and certain other brain areas. To determine whether these adaptations ultimately affect transcription mediated by the cAMP response element (CRE), we induced morphine dependence in CRE-LacZ transgenic mice and performed a regional and cellular mapping of -galactosidase (-gal) expression during naltrexone-precipitated withdrawal. Consistent with our model of opiate dependence, -gal expression increased in the LC, but decreased in the lateral ventral tegmental area (VTA) and dorsal raphe nucleus (DRN). In addition, withdrawal increased -gal expression in the continuum of the extended amygdala and nucleus accumbens, macrostructures associated with the coupling of emotional stimuli to motor and autonomic responses. At the cellular level, in the central nucleus of the amygdala, -gal was found in cells both with and without µ opioid receptors as well as in corticotropin-releasing factor-expressing cells. In nucleus accumbens, -gal was expressed in several major subpopulations of neurons. In LC, -gal expression was induced predominantly in tyrosine hydroxylase-expressing cells, whereas in the VTA and DRN the majority of cells expressing -gal were nonmonoaminergic. These results show that molecular adaptations to chronic morphine alter CRE-mediated transcription during opiate withdrawal in physiologically salient regions involved in arousal, reward, mood, and affective responses. We propose that CRE-mediated transcription serves as a functional marker for neuronal plasticity during withdrawal. CRE-mediated transcription may itself contribute to re-establishing homeostasis in the organism through target gene regulation in these regions.

Key words: CREB; cAMP; locus ceruleus; nucleus accumbens; amygdala; ventral tegmental area; dorsal raphe; gene expression

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2293663-10$05.00/0

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