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, Kaushik; Pandey, Subhash C.

doi:10.1038/sj.npp.1300900

Cited by 39 publications

(29 citation statements)

References 84 publications

(114 reference statements)

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“…The effect of rolipram was verified by using Ro 20-1724, another selective PDE4 inhibitor, which decreased ethanol intake and preference to a similar extent as rolipram. Given that treatment with rolipram increases cAMP and phosphorylated cAMP response-element binding protein (pCREB) in the brain (Li et al 2009 2011; Schneider 1984) and that cAMP signaling plays an important role in the regulation of ethanol preference (Misra and Pandey 2006; Pandey et al 2004; Thiele et al 2000), these results suggest that pharmacological inhibition of PDE4 and subsequent increases in cAMP signaling in the brain may be responsible for the reduction of ethanol preference. To our knowledge, this is the first study to investigate the role of PDEs in regulating ethanol consumption.…”

Section: Discussionmentioning

confidence: 99%

“…It is established that cAMP-PKA signaling regulates ethanol intake in animal models (Misra and Pandey 2006; Pandey et al 2004, 2005; Thiele et al 2000). Stimulation of cAMP-PKA signaling decreases, whereas inhibition of this signaling pathway increases ethanol intake, although the actions appear to be brain region-specific (Misra and Pandey 2006; Pandey et al 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Stimulation of cAMP-PKA signaling decreases, whereas inhibition of this signaling pathway increases ethanol intake, although the actions appear to be brain region-specific (Misra and Pandey 2006; Pandey et al 2005). Consistent with these, null mutation of the regulatory IIβ subunit of PKA decreases cAMP-stimulated PKA activity and increases ethanol intake in mice (Thiele et al 2000).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of phosphodiesterase-4 decreases ethanol intake in mice

Chen

et al. 2011

Psychopharmacology

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Rationale Cyclic AMP (cAMP)-protein kinase A (PKA) signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown. Objective To examine whether PDE4 was involved in regulating ethanol intake. Methods The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram. Results Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking. Conclusions These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of phosphodiesterase-4 decreases ethanol intake in mice

Chen

et al. 2011

Psychopharmacology

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“…Ethanol preference was measured using the two-bottle free-choice paradigm used by us previously Misra and Pandey, 2006). Rats were bilaterally implanted with cannulas targeted 3 mm above the CeA, as described above.…”

Section: Studies With Normal Ratsmentioning

confidence: 99%

Effector Immediate-Early Gene Arc in the Amygdala Plays a Critical Role in Alcoholism

Pandey

Zhang²,

Ugale³

et al. 2008

J. Neurosci.

143

186

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The immediate early gene, activity-regulated cytoskeleton-associated protein (Arc), has been implicated in synaptic plasticity. However, the role of Arc in alcoholism is unknown. Here, we report that the anxiolytic effects of acute ethanol were associated with increased brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (trkB) expression, increased phosphorylation of extracellular signalregulated kinases 1/2 (Erk1/2), Elk-1, and cAMP responsive element-binding protein (CREB), increased Arc expression, and increased dendritic spine density (DSD) in both the central amygdala (CeA) and medial amygdala (MeA) but not in the basolateral amygdala (BLA) of rats. Conversely, the anxiogenic effects of withdrawal after long-term ethanol exposure were associated with decreased BDNF and trkB expression, decreased phosphorylation of Erk1/2, Elk-1, and CREB, decreased Arc expression, and decreased DSD in both the CeA and MeA but not in the BLA of rats. We also showed that BDNF infusion into the CeA normalized phosphorylation of Erk1/2, Elk-1, and CREB, and normalized Arc expression, thereby protecting against the onset of ethanol withdrawal-related anxiety. We further demonstrated that arresting Arc expression in the CeA decreased DSD, thereby increasing anxiety-like and alcohol-drinking behaviors in control rats. These results revealed that BDNF-Arc signaling and the associated DSD in the CeA, and possibly in the MeA, may be involved in the molecular processes of alcohol dependence and comorbidity of anxiety and alcohol-drinking behaviors.

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“…Enhanced PKA activity by the genetic deletion of the PKA inhibitory subunit, RIIβ, in mice induces the high ethanol consumption and low sensitivity to ethanol-induced sedation (Thiele et al 2000). Conversely, infusion of the PKA pathway inhibitor, Rp-cAMP, into the nucleus accumbens (NAc) shell significantly increased ethanol-drinking behavior in rats (Misra and Pandey 2006). Heterozygous CREB KO mice have increased alcohol-drinking behavior (Pandey et al 2004).…”

Section: Introductionmentioning

confidence: 97%