Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats

Neuropsychopharmacology. 2014 Jun;39(7):1722-31. doi: 10.1038/npp.2014.20. Epub 2014 Jan 29.

Abstract

A history of stress produces increases in rodent relapse-like alcohol self-administration behavior and regional brain gene expression of phosphodiesterase 10A (PDE10A), a dual-specificity cyclic adenosine monophosphate/cyclic guanosine monophosphate-inhibiting enzyme. Here, we tested the hypothesis that administration of TP-10, a specific PDE10A inhibitor, would reduce alcohol self-administration in conditions predisposing to elevated self-administration. TP-10 administration dose-dependently (0.562, 1.0 mg/kg; subcutaneously) reduced relapse-like alcohol self-administration regardless of stress history enhancement of relapse-like behavior. TP-10 also reduced alcohol self-administration in genetically alcohol-preferring rats, as well as in alcohol-non-dependent and -dependent rats. Effective systemic TP-10 doses did not alter alcohol pharmacokinetics, significantly reduce motor activity or intrabout operant response speed, or promote a conditioned place aversion. TP-10 also reduced saccharin self-administration, suggesting a general role for PDE10A in the self-administration of reinforcing substances. PDE10A inhibition in the dorsolateral striatum, but not the nucleus accumbens, reduced alcohol self-administration. Taken together, the results implicate dorsolateral striatum PDE10A in facilitating alcohol intake and support further investigation of PDE10A systems in the pathophysiology and potential treatment of substance use disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Alcohols / administration & dosage*
  • Analysis of Variance
  • Animals
  • Conditioning, Operant / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Administration Routes
  • Enzyme Inhibitors / pharmacology
  • Male
  • Motor Activity / drug effects
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrazoles / pharmacology
  • Quinolines / pharmacology
  • Rats
  • Rats, Wistar
  • Reinforcement Schedule
  • Reinforcement, Psychology*
  • Saccharin / administration & dosage*
  • Self Administration
  • Sweetening Agents / administration & dosage*
  • beta-Cyclodextrins / pharmacology

Substances

  • 2-(4-(pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)phenoxymethyl)quinoline succinic acid
  • Alcohols
  • Enzyme Inhibitors
  • Pyrazoles
  • Quinolines
  • Sweetening Agents
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • PDE10A protein, rat
  • Phosphoric Diester Hydrolases
  • Saccharin