Distinct Roles of Adenylyl Cyclases 1 and 8 in Opiate Dependence

Behavioral, Electrophysiological, and Molecular Studies

Venetia Zachariou, Rongjian Liu, Quincey LaPlant, Guanghua Xiao, William Renthal, Guy C. Chan, Daniel R. Storm, George Aghajanian, Eric J. Nestler

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background: Opiate dependence is a result of adaptive changes in signal transduction networks in several brain regions. Noradrenergic neurons of the locus coeruleus (LC) have provided a useful model system in which to understand the molecular basis of these adaptive changes. One of most robust signaling adaptations to repeated morphine exposure in this brain region is upregulation of adenylyl cyclase (AC) activity. Earlier work revealed the selective induction of two calmodulin-dependent AC isoforms, AC1 and AC8, after chronic morphine, but their role in opiate dependence has remained unknown. Methods: Whole cell recordings from LC slices, behavioral paradigms for dependence, and gene array technology have been used to dissect the role of AC1 and AC8 in chronic morphine responses. Results: Both AC1 and AC8 knockout mice exhibit reduced opiate dependence on the basis of attenuated withdrawal; however, partially distinct withdrawal symptoms were affected in the two lines. Loss of AC1 or AC8 also attenuated the electrophysiological effects of morphine on LC neurons: knockout of either cyclase attenuated the chronic morphine-induced enhancement of baseline firing rates as well as of regulation of neuronal firing by forskolin (an activator of ACs). The DNA microarray analysis revealed that both AC1 and AC8 affect gene regulation in the LC by chronic morphine and, in addition to common genes, each cyclase influences the expression of a distinct subset of genes. Conclusions: Together, these findings provide fundamentally new insight into the molecular and cellular basis of opiate dependence.

Original languageEnglish (US)
Pages (from-to)1013-1021
Number of pages9
JournalBiological Psychiatry
Volume63
Issue number11
DOIs
StatePublished - Jun 1 2008

Fingerprint

Opioid-Related Disorders
Morphine
Locus Coeruleus
Adenylyl Cyclases
Genes
Adrenergic Neurons
Substance Withdrawal Syndrome
Brain
Patch-Clamp Techniques
Colforsin
Calmodulin
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Knockout Mice
adenylyl cyclase 8
adenylyl cyclase 1
Signal Transduction
Protein Isoforms
Up-Regulation
Technology

Keywords

  • DNA microarray
  • drug abuse
  • forskolin
  • knockout mice
  • locus coeruleus
  • opiate withdrawal

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Distinct Roles of Adenylyl Cyclases 1 and 8 in Opiate Dependence : Behavioral, Electrophysiological, and Molecular Studies. / Zachariou, Venetia; Liu, Rongjian; LaPlant, Quincey; Xiao, Guanghua; Renthal, William; Chan, Guy C.; Storm, Daniel R.; Aghajanian, George; Nestler, Eric J.

In: Biological Psychiatry, Vol. 63, No. 11, 01.06.2008, p. 1013-1021.

Research output: Contribution to journalArticle

Zachariou, V, Liu, R, LaPlant, Q, Xiao, G, Renthal, W, Chan, GC, Storm, DR, Aghajanian, G & Nestler, EJ 2008, 'Distinct Roles of Adenylyl Cyclases 1 and 8 in Opiate Dependence: Behavioral, Electrophysiological, and Molecular Studies', Biological Psychiatry, vol. 63, no. 11, pp. 1013-1021. https://doi.org/10.1016/j.biopsych.2007.11.021
Zachariou, Venetia ; Liu, Rongjian ; LaPlant, Quincey ; Xiao, Guanghua ; Renthal, William ; Chan, Guy C. ; Storm, Daniel R. ; Aghajanian, George ; Nestler, Eric J. / Distinct Roles of Adenylyl Cyclases 1 and 8 in Opiate Dependence : Behavioral, Electrophysiological, and Molecular Studies. In: Biological Psychiatry. 2008 ; Vol. 63, No. 11. pp. 1013-1021.
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