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

• Published in: Psychopharmacology Vol. 232; no. 13; pp. 2251 - 2262
• Main Authors: Franklin, Kelle M., Hauser, Sheketha R., Lasek, Amy W., McClintick, Jeanette, Ding, Zheng-Ming, McBride, William J., Bell, Richard L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2015; Springer Nature B.V
• Subjects: Alcohol Drinking - drug therapy; Alcohol Drinking - genetics; Alcohol Drinking - metabolism; Alcohol use; Animals; Biomedical and Life Sciences; Biomedicine; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Dose-Response Relationship, Drug; Drug Delivery Systems - methods; Ethanol - administration & dosage; Female; Genetics; Male; Neurosciences; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Original Investigation; Pharmacology/Toxicology; Phosphodiesterase 4 Inhibitors - administration & dosage; Psychiatry; Rats; Rolipram - administration & dosage; Selective breeding; Species Specificity; Studies; Genetic predisposition; Interleukin 22 receptor; Animal model; Alcohol preference; High-alcohol consuming; Selective breeding
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-014-3852-3

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.