Selective inhibition of phosphodiesterase 10A impairs appetitive and aversive conditioning and incentive salience attribution

• Selective PDE10A inhibitor MP10 impaired intensive operant responding in mice.
• It also affected cue-based conditioning as well as instrumentally conditioned reinforcement.
• MP10 dose-dependently enhanced striatal expression of the immediate early gene Zif268.
• PDE10A-dependentstriatal signaling thus controls specific reward-motivated behaviors.
• PDE10A could be a drug target for psychopathologies that affect reward-motivated behavior.

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.