Involvement of the Cyclic AMP-Responsive Element Binding Protein Gene Transcription Factor in Genetic Preference for Alcohol Drinking Behavior

Pandey, Subhash C.; Mittal, Navdha; Lumeng, Lawrence; Li, Ting‐Kai

doi:10.1097/00000374-199909000-00002

Cited by 18 publications

(25 citation statements)

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“…The basal protein levels of PKA-Cα were similar in the amygdaloid structures of P and NP rats. We reported earlier that CRE-DNA binding was lower in the nuclear extracts of whole amygdala, but not in the cortex, striatum, or hippocampus, of P compared with NP rats (34). These results suggest that there are innately lower protein levels of CREB and p-CREB in the amygdaloid, but not in the NAc, structures of P rats compared with NP rats.…”

Section: Discussionmentioning

confidence: 54%

“…More specifically, it has been found that CREB-haplodeficient mice have a higher preference to alcohol (31). Also, it was found that the expression and phosphorylation of CREB and cAMP-responsive element-DNA (CRE-DNA) binding are lower in the whole amygdala of P rats than NP rats (34). Neuropeptide Y (NPY) is one of several CREB-related target genes (27,31,35) and has been shown to play a role in anxiety and alcohol abuse (8,10,(36)(37)(38).…”

Section: Introductionmentioning

confidence: 99%

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Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism

Pandey¹,

Zhang²,

Roy³

et al. 2005

J. Clin. Invest.

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185

178

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We investigated the role of cAMP-responsive element-binding protein (CREB) in genetic predisposition to anxiety and alcohol-drinking behaviors using alcohol-preferring (P) and -nonpreferring (NP) rats. The levels of CREB, phosphorylated CREB, and neuropeptide Y (NPY) were innately lower in the central amygdala (CeA) and medial amygdala (MeA), but not in the basolateral amygdala (BLA), of P rats compared with NP rats. P rats displayed higher baseline anxiety-like behaviors and consumed higher amounts of alcohol compared with NP rats. Ethanol injection or voluntary intake reduced the higher anxiety levels in P rats. Ethanol also increased CREB function in the CeA and MeA, but not in the BLA, of P rats. Infusion of the PKA activator Sp-cAMP or NPY into the CeA decreased the alcohol intake and anxiety-like behaviors of P rats. PKA activator infusion also increased CREB function in the CeA of P rats. On the other hand, ethanol injection or voluntary intake did not produce any changes either in anxiety levels or on CREB function in the amygdaloid structures of NP rats. Interestingly, infusion of the PKA inhibitor Rp-cAMP into the CeA provoked anxiety-like behaviors and increased alcohol intake in NP rats. PKA inhibitor decreased CREB function in the CeA of NP rats. These novel results provide the first evidence to our knowledge that decreased CREB function in the CeA may be operative in maintaining the high anxiety and excessive alcohol-drinking behaviors of P rats.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism

Pandey¹,

Zhang²,

Roy³

et al. 2005

J. Clin. Invest.

Self Cite

185

178

View full text Add to dashboard Cite

show abstract

“…It has been shown that ethanol withdrawal after chronic ethanol exposure leads to significant reductions in CREB phosphorylation and NPY protein levels in various rat brain structures, and decreased CREB phosphorylation and NPY expression in the central amygdala (CeA) might be associated with anxietylike behaviors during ethanol withdrawal (Pandey et al, , 2003bZhang and Pandey, 2003). It has also been found that CREB expression and phosphorylation as well as NPY protein levels are lower in amygdaloid brain structures of alcoholpreferring (P) rats compared with alcohol-nonpreferring (NP) rats (Hwang et al, 1999;Pandey et al, 1999). Interestingly, P rats display more anxiety-like behaviors and have higher ethanol preference than NP rats Stewart et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Partial Deletion of the cAMP Response Element-Binding Protein Gene Promotes Alcohol-Drinking Behaviors

Pandey¹,

Roy²,

Zhang³

et al. 2004

J. Neurosci.

147

130

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The cAMP response element-binding protein (CREB) gene transcription factor has been shown to play a role in the synaptic plasticity associated with drug addictive behaviors; however, the causal role of the CREB gene in alcohol-drinking behaviors is unknown. The present investigation evaluated alcohol-drinking behaviors in mice that are haplodeficient in CREB as a result of targeted CREB (␣ and ⌬) gene disruption. It was found that CREB-haplodeficient (ϩ/Ϫ) mice have higher preference for ethanol but not for sucrose solution than wild-type (ϩ/ϩ) littermates. The functional aspects of the CREB gene transcription factor were also investigated by measuring the protein levels of phosphorylated CREB (p-CREB) and the expression of cAMP-inducible genes such as neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). Deletion of the CREB (␣ and ⌬) gene significantly decreases total CREB, p-CREB levels and the expression of NPY and BDNF in the brain structures of CREB-deficient (ϩ/Ϫ) mice. It was also found that CREB-deficient (ϩ/Ϫ) mice displayed more anxiety-like behaviors and that acute ethanol exposure produced anxiolytic effects and significantly increased protein levels of p-CREB and NPY in the central and medial but not in the basolateral amygdala of wild-type mice, but these effects are attenuated in CREB-deficient mice compared with wild-type mice. These results provide the first direct evidence that a haplodeficiency of the CREB gene is associated with increased alcohol-drinking behaviors. Furthermore, alcohol drinking and anxiety-like behaviors in CREBhaplodeficient mice may possibly be related to decreased expression of NPY and BDNF in the brains of these mice.

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“…However, other findings indicate that C57BL/6J mice are not anxious, consume large amounts of ethanol, and have lower basal levels of CREB, p-CREB, and NPY in the NAc shell but not in the amygdaloid structures compared with DBA/2J mice (Podhorna and Brown, 2002;Belknap et al, 1993;Misra and Pandey, 2003). On the other hand, alcohol preferring (P) rats consume large amounts of alcohol, are highly anxious, and have lower levels of CREB, p-CREB, and NPY in the central and medial amygdaloid but not in the NAc structures compared to alcohol non-preferring (NP) rats (Stewart et al, 1993;Li et al, 1993;Pandey et al, 1999bPandey et al, , 2003bPandey et al, , 2005Hwang et al, 1999). Interestingly, when PKA and CREB are lower in both NAc and amygdala such as in PKA (RII-b subunit) mutant and CREB haplodeficient mice, these mice have higher alcohol preference and display higher baseline anxiety levels as compared with littermate wild-type mice (Fee et al, 2003;Thiele et al, 2000;Pandey et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The Decreased Cyclic-AMP Dependent-Protein Kinase A Function in the Nucleus Accumbens: A Role in Alcohol Drinking but not in Anxiety-Like Behaviors in Rats

Misra

Pandey

2005

Neuropsychopharmacol

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The nucleus accumbens (NAc) brain structures have been implicated in the reward and reinforcing properties of ethanol. The present study investigated the role of nucleus accumbal cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling in alcohol drinking and anxiety-like behaviors of rats. It was found that infusion of PKA inhibitor (Rp-cAMP) into the NAc shell significantly increased the alcohol but not the sucrose intake, without modulating the anxiety-like behaviors, as measured by elevated plus maze test in rats. PKA inhibitor infusion into the NAc shell significantly decreased the protein levels of a-catalytic subunit of PKA (PKA-Ca) and phosphorylated cAMP response element-binding protein (p-CREB) as well as decreased the protein levels of neuropeptide Y (NPY) in the shell but not in the NAc core of rats. On the other hand, infusion of PKA activator (Sp-cAMP) or NPY alone into the NAc shell did not produce any changes in alcohol intake; however, when these agents were coinfused with PKA inhibitor, they significantly attenuated the increases in alcohol preference induced by pharmacological inhibition of PKA. Interestingly, PKA activator coinfusion with PKA inhibitor into the NAc shell significantly normalized the PKA inhibitor-induced decreases in the protein levels of PKA-Ca and p-CREB as well as of NPY in the NAc shell of rats. Taken together, these results provide the first evidence that decreased PKA function in the NAc shell is involved in alcohol drinking but not in anxiety-like behaviors of rats. Furthermore, decreased function of PKA may regulate alcohol drinking behaviors via CREB-mediated decreased expression of NPY in the NAc shell of rats.

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Involvement of the Cyclic AMP-Responsive Element Binding Protein Gene Transcription Factor in Genetic Preference for Alcohol Drinking Behavior

Abstract: Because P and NP rats are genetically bred for high and low alcohol drinking behavior, respectively, these results suggest the possibility that decreased expression of CREB protein in the amygdala may be associated with the high alcohol drinking behavior of P rats.

Cited by 18 publications

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Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism

Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism

Partial Deletion of the cAMP Response Element-Binding Protein Gene Promotes Alcohol-Drinking Behaviors

The Decreased Cyclic-AMP Dependent-Protein Kinase A Function in the Nucleus Accumbens: A Role in Alcohol Drinking but not in Anxiety-Like Behaviors in Rats

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