 |
 Previous Article | Next Article 
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
This article has been cited by other articles:
|
|
|
|
 
A. R. Gintzler and S. Chakrabarti
The Ambiguities of Opioid Tolerance Mechanisms: Barriers to Pain Therapeutics or New Pain Therapeutic Possibilities
J. Pharmacol. Exp. Ther.,
June 1, 2008;
325(3):
709 - 713.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. G. Cruz, F. Berton, M. Sollini, C. Blanchet, M. Pravetoni, K. Wickman, and C. Luscher
Absence and Rescue of Morphine Withdrawal in GIRK/Kir3 Knock-out Mice
J. Neurosci.,
April 9, 2008;
28(15):
4069 - 4077.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Li and A. N. van den Pol
{micro}-Opioid Receptor-Mediated Depression of the Hypothalamic Hypocretin/Orexin Arousal System
J. Neurosci.,
March 12, 2008;
28(11):
2814 - 2819.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Chester and V. J. Watts
Adenylyl Cyclase 5: A New Clue in the Search for the "Fountain of Youth"?
Sci. Signal.,
November 20, 2007;
2007(413):
pe64 - pe64.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-H. Huang, H.-Q. Wang, W. R. Roeske, Y. Birnbaum, Y. Wu, N.-P. Yang, Y. Lin, Y. Ye, D. J. McAdoo, M. G. Hughes, et al.
Mediating {delta}-opioid-initiated heart protection via the beta2-adrenergic receptor: role of the intrinsic cardiac adrenergic cell
Am J Physiol Heart Circ Physiol,
July 1, 2007;
293(1):
H376 - H384.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. J. Watts
Adenylyl Cyclase Isoforms as Novel Therapeutic Targets: An Exciting Example of Excitotoxicity Neuroprotection
Mol. Interv.,
April 1, 2007;
7(2):
70 - 73.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Li, M. L. Lee, M. R. Bruchas, G. C. Chan, D. R. Storm, and C. Chavkin
Calmodulin-Stimulated Adenylyl Cyclase Gene Deletion Affects Morphine Responses
Mol. Pharmacol.,
November 1, 2006;
70(5):
1742 - 1749.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-H. Han, C. A. Bolanos, T. A. Green, V. G. Olson, R. L. Neve, R.-J. Liu, G. K. Aghajanian, and E. J. Nestler
Role of cAMP response element-binding protein in the rat locus ceruleus: regulation of neuronal activity and opiate withdrawal behaviors.
J. Neurosci.,
April 26, 2006;
26(17):
4624 - 4629.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-S. Kim, K.-W. Lee, K.-W. Lee, J.-Y. Im, J. Y. Yoo, S.-W. Kim, J.-K. Lee, E. J. Nestler, and P.-L. Han
Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action.
PNAS,
March 7, 2006;
103(10):
3908 - 3913.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. McClung, E. J. Nestler, and V. Zachariou
Regulation of Gene Expression by Chronic Morphine and Morphine Withdrawal in the Locus Ceruleus and Ventral Tegmental Area
J. Neurosci.,
June 22, 2005;
25(25):
6005 - 6015.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. G. Olson, C. P. Zabetian, C. A. Bolanos, S. Edwards, M. Barrot, A. J. Eisch, T. Hughes, D. W. Self, R. L. Neve, and E. J. Nestler
Regulation of Drug Reward by cAMP Response Element-Binding Protein: Evidence for Two Functionally Distinct Subregions of the Ventral Tegmental Area
J. Neurosci.,
June 8, 2005;
25(23):
5553 - 5562.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-P. Xu, E. Van Bockstaele, B. Reyes, T. Bethea, and R. J. Valentino
Chronic Morphine Sensitizes the Brain Norepinephrine System to Corticotropin-Releasing Factor and Stress
J. Neurosci.,
September 22, 2004;
24(38):
8193 - 8197.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. E. Culm and R. P. Hammer Jr.
Recovery of Sensorimotor Gating without G Protein Adaptation after Repeated D2-Like Dopamine Receptor Agonist Treatment in Rats
J. Pharmacol. Exp. Ther.,
February 1, 2004;
308(2):
487 - 494.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chakrabarti, N.-J. Liu, and A. R. Gintzler
Reciprocal modulation of phospholipase C{beta} isoforms: Adaptation to chronic morphine
PNAS,
November 11, 2003;
100(23):
13686 - 13691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. C. Alonzo and B. M. Bayer
Antagonism of N-Methyl-D-aspartate Receptors Reduces the Vulnerability of the Immune System to Stress after Chronic Morphine
J. Pharmacol. Exp. Ther.,
November 1, 2003;
307(2):
793 - 800.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. C. Holm, F. J. Rodriguez, A. Kresse, J. M. Canals, I. Silos-Santiago, and E. Arenas
Crucial role of TrkB ligands in the survival and phenotypic differentiation of developing locus coeruleus noradrenergic neurons
Development,
August 1, 2003;
130(15):
3535 - 3545.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Suzuki, T. Yamakuni, M. Hagiwara, and H. Ichinose
Identification of ATF-2 as a Transcriptional Regulator for the Tyrosine Hydroxylase Gene
J. Biol. Chem.,
October 18, 2002;
277(43):
40768 - 40774.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-W. Lee, J.-H. Hong, I. Y. Choi, Y. Che, J.-K. Lee, S.-D. Yang, C.-W. Song, H. S. Kang, J.-H. Lee, J. S. Noh, et al.
Impaired D2 Dopamine Receptor Function in Mice Lacking Type 5 Adenylyl Cyclase
J. Neurosci.,
September 15, 2002;
22(18):
7931 - 7940.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. J. Watts
Molecular Mechanisms for Heterologous Sensitization of Adenylate Cyclase
J. Pharmacol. Exp. Ther.,
July 1, 2002;
302(1):
1 - 7.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. K. Sunahara and R. Taussig
Isoforms of Mammalian Adenylyl Cyclase: Multiplicities of Signaling
Mol. Interv.,
June 1, 2002;
2(3):
168 - 184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Torrecilla, C. L. Marker, S. C. Cintora, M. Stoffel, J. T. Williams, and K. Wickman
G-Protein-Gated Potassium Channels Containing Kir3.2 and Kir3.3 Subunits Mediate the Acute Inhibitory Effects of Opioids on Locus Ceruleus Neurons
J. Neurosci.,
June 1, 2002;
22(11):
4328 - 4334.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Sakai, J. Thome, S. S. Newton, J. Chen, M. B. Kelz, C. Steffen, E. J. Nestler, and R. S. Duman
Inducible and Brain Region-Specific CREB Transgenic Mice
Mol. Pharmacol.,
June 1, 2002;
61(6):
1453 - 1464.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Akbarian, M. Rios, R.-J. Liu, S. J. Gold, H.-F. Fong, S. Zeiler, V. Coppola, L. Tessarollo, K. R. Jones, E. J. Nestler, et al.
Brain-Derived Neurotrophic Factor Is Essential for Opiate-Induced Plasticity of Noradrenergic Neurons
J. Neurosci.,
May 15, 2002;
22(10):
4153 - 4162.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Z. Shaw-Lutchman, M. Barrot, T. Wallace, L. Gilden, V. Zachariou, S. Impey, R. S. Duman, D. Storm, and E. J. Nestler
Regional and Cellular Mapping of cAMP Response Element-Mediated Transcription during Naltrexone-Precipitated Morphine Withdrawal
J. Neurosci.,
May 1, 2002;
22(9):
3663 - 3672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Pandey, A. Roy, and N. Mittal
Effects of Chronic Ethanol Intake and Its Withdrawal on the Expression and Phosphorylation of the CREB Gene Transcription Factor in Rat Cortex
J. Pharmacol. Exp. Ther.,
March 1, 2001;
296(3):
857 - 868.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. H. Tso and Y. H. Wong
Gz Can Mediate the Acute Actions of {micro}- and kappa -Opioids but Is Not Involved in Opioid-Induced Adenylyl Cyclase Supersensitization
J. Pharmacol. Exp. Ther.,
October 1, 2000;
295(1):
168 - 176.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
N. Defer, M. Best-Belpomme, and J. Hanoune
Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase
Am J Physiol Renal Physiol,
September 1, 2000;
279(3):
F400 - F416.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Martin, S. H. Ahmed, T. Blank, J. Spiess, G. F. Koob, and G. R. Siggins
Chronic Morphine Treatment Alters NMDA Receptor-Mediated Synaptic Transmission in the Nucleus Accumbens
J. Neurosci.,
October 15, 1999;
19(20):
9081 - 9089.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Quock, T. H. Burkey, E. Varga, Y. Hosohata, K. Hosohata, S. M. Cowell, C. A. Slate, F. J. Ehlert, W. R. Roeske, and H. I. Yamamura
The delta -Opioid Receptor: Molecular Pharmacology, Signal Transduction, and the Determination of Drug Efficacy
Pharmacol. Rev.,
September 1, 1999;
51(3):
503 - 532.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-H. Fan, L.-Z. Wang, H.-C. Qiu, L. Ma, and G. Pei
Inhibition of Calcium/Calmodulin-Dependent Protein Kinase II in Rat Hippocampus Attenuates Morphine Tolerance and Dependence
Mol. Pharmacol.,
July 1, 1999;
56(1):
39 - 45.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
L. M. Muglia, M. L. Schaefer, S. K. Vogt, G. Gurtner, A. Imamura, and L. J. Muglia
The 5'-Flanking Region of the Mouse Adenylyl Cyclase Type VIII Gene Imparts Tissue-Specific Expression in Transgenic Mice
J. Neurosci.,
March 15, 1999;
19(6):
2051 - 2058.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. A. Boundy, S. J. Gold, C. J. Messer, J. Chen, J. H. Son, T. H. Joh, and E. J. Nestler
Regulation of Tyrosine Hydroxylase Promoter Activity by Chronic Morphine in TH9.0-LacZ Transgenic Mice
J. Neurosci.,
December 1, 1998;
18(23):
9989 - 9995.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chakrabarti, L. Wang, W.-J. Tang, and A. R. Gintzler
Chronic Morphine Augments Adenylyl Cyclase Phosphorylation: Relevance to Altered Signaling during Tolerance/Dependence
Mol. Pharmacol.,
December 1, 1998;
54(6):
949 - 953.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Chakrabarti, M. Rivera, S.-Z. Yan, W.-J. Tang, and A. R. Gintzler
Chronic Morphine Augments Gbeta gamma /Gsalpha Stimulation of Adenylyl Cyclase: Relevance to Opioid Tolerance
Mol. Pharmacol.,
October 1, 1998;
54(4):
655 - 662.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
L. J. Punch, D. W. Self, E. J. Nestler, and J. R. Taylor
Opposite Modulation of Opiate Withdrawal Behaviors on Microinfusion of a Protein Kinase A Inhibitor Versus Activator into the Locus Coeruleus or Periaqueductal Gray
J. Neurosci.,
November 1, 1997;
17(21):
8520 - 8527.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. J. Nestler and G. K. Aghajanian
Molecular and Cellular Basis of Addiction
Science,
October 3, 1997;
278(5335):
58 - 63.
[Abstract]
[Full Text]
|
|
|
|
