Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4)

Kelle M. Franklin, Sheketha R. Hauser, Amy W. Lasek, Jeanette McClintick, Zheng-Ming Ding, William J. McBride, Richard L. Bell

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Rationale: Phosphodiesterase-4 (PDE4) and neuroimmune signaling have been posited to regulate alcohol drinking. Objectives: This study evaluated the involvement of PDE4 and Il22ra2 on ethanol (EtOH) intake by alcohol-preferring (P) and high-alcohol-drinking (HAD1) rats. Methods: Exp 1 determined the dose-response effects of PDE4 inhibitors, rolipram, and Ro 20-1724, on 2 h/day free-choice EtOH intake by adult P and HAD1 rats. Exps 2-3 examined the effects of repeated administration with the PDE4 inhibitors on EtOH or sucrose intake and locomotor behavior. Exp 4 determined Pde4-associated gene expression differences in subregions of the extended amygdala, between high- and low-alcohol-consuming rat lines. Exp 5 evaluated the effects of infusing short hairpin RNA to knock down Il22ra2 in the nucleus accumbens (NAc) shell on a 24-h free-choice EtOH drinking by P rats. Results: Administration of rolipram or Ro 20-1724 reduced EtOH intake by P rats; Ro 20-1724 reduced EtOH intake by HAD1 rats. Repeated rolipram or Ro 20-1724 exposure reduced EtOH intake by P and HAD1 rats. PDE4 inhibition induced motor impairment during the first hour of EtOH intake by P rats. Higher gene expression levels for PDE4A were found in the NAc shell of P vs NP rats. ShRNAs targeting Il22ra2 in the NAc shell significantly reduced chronic EtOH intake. Conclusions: PDE4 and neuroinflammatory/immune signaling pathways could represent molecular targets for the treatment of alcohol use disorders in genetically predisposed subjects. This study underscores the importance of testing compounds over multiple days and rat lines when determining efficacy to disrupt excessive alcohol intake.

Original languageEnglish (US)
Pages (from-to)2251-2262
Number of pages12
JournalPsychopharmacology
Volume232
Issue number13
DOIs
StatePublished - Jul 13 2015

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Type 4 Cyclic Nucleotide Phosphodiesterase
Alcohol Drinking
Alcohols
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone
Rolipram
Nucleus Accumbens
Phosphodiesterase 4 Inhibitors
Gene Expression
Amygdala
Small Interfering RNA
Drinking
Sucrose
Ethanol

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Franklin, Kelle M. ; Hauser, Sheketha R. ; Lasek, Amy W. ; McClintick, Jeanette ; Ding, Zheng-Ming ; McBride, William J. ; Bell, Richard L. / Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4). In: Psychopharmacology. 2015 ; Vol. 232, No. 13. pp. 2251-2262.
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abstract = "Rationale: Phosphodiesterase-4 (PDE4) and neuroimmune signaling have been posited to regulate alcohol drinking. Objectives: This study evaluated the involvement of PDE4 and Il22ra2 on ethanol (EtOH) intake by alcohol-preferring (P) and high-alcohol-drinking (HAD1) rats. Methods: Exp 1 determined the dose-response effects of PDE4 inhibitors, rolipram, and Ro 20-1724, on 2 h/day free-choice EtOH intake by adult P and HAD1 rats. Exps 2-3 examined the effects of repeated administration with the PDE4 inhibitors on EtOH or sucrose intake and locomotor behavior. Exp 4 determined Pde4-associated gene expression differences in subregions of the extended amygdala, between high- and low-alcohol-consuming rat lines. Exp 5 evaluated the effects of infusing short hairpin RNA to knock down Il22ra2 in the nucleus accumbens (NAc) shell on a 24-h free-choice EtOH drinking by P rats. Results: Administration of rolipram or Ro 20-1724 reduced EtOH intake by P rats; Ro 20-1724 reduced EtOH intake by HAD1 rats. Repeated rolipram or Ro 20-1724 exposure reduced EtOH intake by P and HAD1 rats. PDE4 inhibition induced motor impairment during the first hour of EtOH intake by P rats. Higher gene expression levels for PDE4A were found in the NAc shell of P vs NP rats. ShRNAs targeting Il22ra2 in the NAc shell significantly reduced chronic EtOH intake. Conclusions: PDE4 and neuroinflammatory/immune signaling pathways could represent molecular targets for the treatment of alcohol use disorders in genetically predisposed subjects. This study underscores the importance of testing compounds over multiple days and rat lines when determining efficacy to disrupt excessive alcohol intake.",
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Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4). / Franklin, Kelle M.; Hauser, Sheketha R.; Lasek, Amy W.; McClintick, Jeanette; Ding, Zheng-Ming; McBride, William J.; Bell, Richard L.

In: Psychopharmacology, Vol. 232, No. 13, 13.07.2015, p. 2251-2262.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4)

AU - Franklin, Kelle M.

AU - Hauser, Sheketha R.

AU - Lasek, Amy W.

AU - McClintick, Jeanette

AU - Ding, Zheng-Ming

AU - McBride, William J.

AU - Bell, Richard L.

PY - 2015/7/13

Y1 - 2015/7/13

N2 - Rationale: Phosphodiesterase-4 (PDE4) and neuroimmune signaling have been posited to regulate alcohol drinking. Objectives: This study evaluated the involvement of PDE4 and Il22ra2 on ethanol (EtOH) intake by alcohol-preferring (P) and high-alcohol-drinking (HAD1) rats. Methods: Exp 1 determined the dose-response effects of PDE4 inhibitors, rolipram, and Ro 20-1724, on 2 h/day free-choice EtOH intake by adult P and HAD1 rats. Exps 2-3 examined the effects of repeated administration with the PDE4 inhibitors on EtOH or sucrose intake and locomotor behavior. Exp 4 determined Pde4-associated gene expression differences in subregions of the extended amygdala, between high- and low-alcohol-consuming rat lines. Exp 5 evaluated the effects of infusing short hairpin RNA to knock down Il22ra2 in the nucleus accumbens (NAc) shell on a 24-h free-choice EtOH drinking by P rats. Results: Administration of rolipram or Ro 20-1724 reduced EtOH intake by P rats; Ro 20-1724 reduced EtOH intake by HAD1 rats. Repeated rolipram or Ro 20-1724 exposure reduced EtOH intake by P and HAD1 rats. PDE4 inhibition induced motor impairment during the first hour of EtOH intake by P rats. Higher gene expression levels for PDE4A were found in the NAc shell of P vs NP rats. ShRNAs targeting Il22ra2 in the NAc shell significantly reduced chronic EtOH intake. Conclusions: PDE4 and neuroinflammatory/immune signaling pathways could represent molecular targets for the treatment of alcohol use disorders in genetically predisposed subjects. This study underscores the importance of testing compounds over multiple days and rat lines when determining efficacy to disrupt excessive alcohol intake.

AB - Rationale: Phosphodiesterase-4 (PDE4) and neuroimmune signaling have been posited to regulate alcohol drinking. Objectives: This study evaluated the involvement of PDE4 and Il22ra2 on ethanol (EtOH) intake by alcohol-preferring (P) and high-alcohol-drinking (HAD1) rats. Methods: Exp 1 determined the dose-response effects of PDE4 inhibitors, rolipram, and Ro 20-1724, on 2 h/day free-choice EtOH intake by adult P and HAD1 rats. Exps 2-3 examined the effects of repeated administration with the PDE4 inhibitors on EtOH or sucrose intake and locomotor behavior. Exp 4 determined Pde4-associated gene expression differences in subregions of the extended amygdala, between high- and low-alcohol-consuming rat lines. Exp 5 evaluated the effects of infusing short hairpin RNA to knock down Il22ra2 in the nucleus accumbens (NAc) shell on a 24-h free-choice EtOH drinking by P rats. Results: Administration of rolipram or Ro 20-1724 reduced EtOH intake by P rats; Ro 20-1724 reduced EtOH intake by HAD1 rats. Repeated rolipram or Ro 20-1724 exposure reduced EtOH intake by P and HAD1 rats. PDE4 inhibition induced motor impairment during the first hour of EtOH intake by P rats. Higher gene expression levels for PDE4A were found in the NAc shell of P vs NP rats. ShRNAs targeting Il22ra2 in the NAc shell significantly reduced chronic EtOH intake. Conclusions: PDE4 and neuroinflammatory/immune signaling pathways could represent molecular targets for the treatment of alcohol use disorders in genetically predisposed subjects. This study underscores the importance of testing compounds over multiple days and rat lines when determining efficacy to disrupt excessive alcohol intake.

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