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Volume 17, Number 20,
Issue of October 15, 1997
pp. 7890-7901
Copyright ©1997 Society for Neuroscience
CREB (cAMP Response Element-Binding Protein) in the Locus
Coeruleus: Biochemical, Physiological, and Behavioral Evidence for a
Role in Opiate Dependence
Received May 27, 1997; revised July 18, 1997; accepted July 25, 1997.
Sarah B. Lane-Ladd1,
Joseba Pineda1,
Virginia A. Boundy1,
T. Pfeuffer2,
John Krupinski3,
George K. Aghajanian1, and
Eric J. Nestler1
1 Laboratory of Molecular Psychiatry, Departments of
Psychiatry and Pharmacology, Yale University School of Medicine and
Connecticut Mental Health Center, New Haven, Connecticut 06508, 2 Institut fur Physiologische Chemie II, Dusseldorf
D-40225, Germany, and 3 Bristol-Myers Squibb Research
Institute, Princeton, New Jersey 08543
Chronic morphine administration increases levels of adenylyl
cyclase and cAMP-dependent protein kinase (PKA) activity in the locus
coeruleus (LC), which contributes to the severalfold activation of LC
neurons that occurs during opiate withdrawal. A role for the
transcription factor cAMP response element-binding protein (CREB) in
mediating the opiate-induced upregulation of the cAMP pathway has been
suggested, but direct evidence is lacking. In the present study, we
first demonstrated that the morphine-induced increases in adenylyl
cyclase and PKA activity in the LC are associated with selective
increases in levels of immunoreactivity of types I and VIII adenylyl
cyclase and of the catalytic and type II regulatory subunits of PKA. We
next used antisense oligonucleotides directed against CREB to study the
role of this transcription factor in mediating these effects. Infusion
(5 d) of CREB antisense oligonucleotide directly into the LC
significantly reduced levels of CREB immunoreactivity. This effect was
sequence-specific and not associated with detectable toxicity. CREB
antisense oligonucleotide infusions completely blocked the
morphine-induced upregulation of type VIII adenylyl cyclase but not of
PKA. The infusions also blocked the morphine-induced upregulation of
tyrosine hydroxylase but not of Gi , two other proteins induced in
the LC by chronic morphine treatment. Electrophysiological studies
revealed that intra-LC antisense oligonucleotide infusions completely
prevented the morphine-induced increase in spontaneous firing rates of
LC neurons in brain slices. This blockade was completely reversed by
addition of 8-bromo-cAMP (which activates PKA) but not by addition of
forskolin (which activates adenylyl cyclase). Intra-LC infusions of
CREB antisense oligonucleotide also reduced the development of physical
dependence to opiates, based on attenuation of opiate withdrawal.
Together, these findings provide the first direct evidence that CREB
mediates the morphine-induced upregulation of specific components of
the cAMP pathway in the LC that contribute to physical opiate
dependence.
Key words:
morphine;
opiate withdrawal;
gene expression;
cAMP;
adenylyl cyclase;
protein kinase A;
G-proteins;
tyrosine hydroxylase;
protein phosphorylation
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