title: Regional and cellular mapping of cAMP response element-mediated transcription during naltrexone-precipitated morphine withdrawal.
abstract: 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 beta-galactosidase (beta-gal) expression during naltrexone-precipitated withdrawal. Consistent with our model of opiate dependence, beta-gal expression increased in the LC, but decreased in the lateral ventral tegmental area (VTA) and dorsal raphe nucleus (DRN). In addition, withdrawal increased beta-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, beta-gal was found in cells both with and without mu opioid receptors as well as in corticotropin-releasing factor-expressing cells. In nucleus accumbens, beta-gal was expressed in several major subpopulations of neurons. In LC, beta-gal expression was induced predominantly in tyrosine hydroxylase-expressing cells, whereas in the VTA and DRN the majority of cells expressing beta-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.
authors.affiliation: Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
authors.forename: Tamara Z
authors.initials: TZ
authors.lastname: Shaw-Lutchman
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
authors.forename: Tanya
authors.initials: T
authors.lastname: Wallace
authors.forename: Lauren
authors.initials: L
authors.lastname: Gilden
authors.forename: Venetia
authors.initials: V
authors.lastname: Zachariou
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
authors.forename: Daniel
authors.initials: D
authors.lastname: Storm
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000679:Amygdala / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000009:adverse effects*; D009271:Naltrexone / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000096:biosynthesis; D020218:Response Elements / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D015854:Up-Regulation; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D009020:Morphine; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase; D001616:beta-Galactosidase