title: Phosphodiesterase 10A regulates alcohol and saccharin self-administration in rats.
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.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Logrip
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Vendruscolo
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Zorrilla
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000438:Alcohols / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012439:Saccharin / Q000008:administration & dosage*; D012646:Self Administration; D013549:Sweetening Agents / Q000008:administration & dosage*; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: C528913:2-(4-(pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)phenoxymethyl)quinoline succinic acid; D000438:Alcohols; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D013549:Sweetening Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases; D012439:Saccharin