Role of cAMP response element-binding protein in the rat locus ceruleus

Regulation of neuronal activity and opiate withdrawal behaviors

Ming Hu Han, Carlos A. Bolaños, Thomas Green, Valerie G. Olson, Rachael L. Neve, Rong Jian Liu, George K. Aghajanian, Eric J. Nestler

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.

Original languageEnglish (US)
Pages (from-to)4624-4629
Number of pages6
JournalJournal of Neuroscience
Volume26
Issue number17
DOIs
StatePublished - 2006
Externally publishedYes

Fingerprint

Opiate Alkaloids
Cyclic AMP Response Element-Binding Protein
Locus Coeruleus
Neurons
Green Fluorescent Proteins
Morphine
Opioid-Related Disorders
Colforsin
Adenylyl Cyclases
Membrane Potentials
Transcription Factors

Keywords

  • Addiction
  • cAMP pathway
  • Dependence
  • Drug abuse
  • Morphine
  • Viral gene transfer

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Role of cAMP response element-binding protein in the rat locus ceruleus : Regulation of neuronal activity and opiate withdrawal behaviors. / Han, Ming Hu; Bolaños, Carlos A.; Green, Thomas; Olson, Valerie G.; Neve, Rachael L.; Liu, Rong Jian; Aghajanian, George K.; Nestler, Eric J.

In: Journal of Neuroscience, Vol. 26, No. 17, 2006, p. 4624-4629.

Research output: Contribution to journalArticle

Han, Ming Hu ; Bolaños, Carlos A. ; Green, Thomas ; Olson, Valerie G. ; Neve, Rachael L. ; Liu, Rong Jian ; Aghajanian, George K. ; Nestler, Eric J. / Role of cAMP response element-binding protein in the rat locus ceruleus : Regulation of neuronal activity and opiate withdrawal behaviors. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 17. pp. 4624-4629.
@article{7dda429474c24b738d31cbfd3a6664ed,
title = "Role of cAMP response element-binding protein in the rat locus ceruleus: Regulation of neuronal activity and opiate withdrawal behaviors",
abstract = "The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.",
keywords = "Addiction, cAMP pathway, Dependence, Drug abuse, Morphine, Viral gene transfer",
author = "Han, {Ming Hu} and Bola{\~n}os, {Carlos A.} and Thomas Green and Olson, {Valerie G.} and Neve, {Rachael L.} and Liu, {Rong Jian} and Aghajanian, {George K.} and Nestler, {Eric J.}",
year = "2006",
doi = "10.1523/JNEUROSCI.4701-05.2006",
language = "English (US)",
volume = "26",
pages = "4624--4629",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "17",

}

TY - JOUR

T1 - Role of cAMP response element-binding protein in the rat locus ceruleus

T2 - Regulation of neuronal activity and opiate withdrawal behaviors

AU - Han, Ming Hu

AU - Bolaños, Carlos A.

AU - Green, Thomas

AU - Olson, Valerie G.

AU - Neve, Rachael L.

AU - Liu, Rong Jian

AU - Aghajanian, George K.

AU - Nestler, Eric J.

PY - 2006

Y1 - 2006

N2 - The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.

AB - The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.

KW - Addiction

KW - cAMP pathway

KW - Dependence

KW - Drug abuse

KW - Morphine

KW - Viral gene transfer

UR - http://www.scopus.com/inward/record.url?scp=33646845782&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646845782&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.4701-05.2006

DO - 10.1523/JNEUROSCI.4701-05.2006

M3 - Article

VL - 26

SP - 4624

EP - 4629

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 17

ER -