title: Selective inhibition of phosphodiesterase 10A impairs appetitive and aversive conditioning and incentive salience attribution.
abstract: The pharmacological effect of the selective PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline succinic acid (MP-10) on aversively and appetitively motivated behavior in C57BL/6J mice was examined. MP-10 dose-dependently impaired performance on a highly demanding reward schedule during appetitive conditioning. The compound further affected cue-based, but not contextual aversive conditioning. Finally, dose-dependent impaired performance in an instrumentally conditioned reinforcement (ICR) task was found. This suggests that the observed behavioral effects of MP-10 can be at least partially ascribed to impaired incentive salience attribution. MP-10 administration dose-dependently enhanced striatal expression of the immediate early gene Zif268, which suggest that MP-10 affects the studied motivated behaviors by enhancing PDE10A-regulated striatal signaling. Striatal signaling thus appears to be crucial in processes that control reward-motivated behavior in general, and incentive salience attribution in particular. Continued research will prove valuable towards a better understanding of psychopathologies that affect reward-motivated behaviors, such as drug addiction and schizophrenia.
authors: Laboratory of Biological Psychology, Leuven Institute for Neuroscience & Disease (LIND), University of Leuven, Tiensestraat 102, BE-3000 Leuven, Belgium.
authors: Elisabeth
authors: E
authors: Piccart
authors: Janssen R&D, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors: Xavier
authors: X
authors: Langlois
authors: Janssen R&D, a division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors: Greet
authors: G
authors: Vanhoof
authors: Laboratory of Biological Psychology, Leuven Institute for Neuroscience & Disease (LIND), University of Leuven, Tiensestraat 102, BE-3000 Leuven, Belgium. Electronic address: rudi.dhooge@ppw.kuleuven.be.
authors: Rudi
authors: R
authors: D'Hooge
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects*; D001362:Avoidance Learning / Q000187:drug effects*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004597:Electroshock / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011804:Quinolines
keywords: Incentive salience attribution; MP-10; Medium spiny neurons; Operant conditioning; Selective PDE10A Antagonist; Striatum