Phosphodiesterase type 1 inhibition alters medial prefrontal cortical activity during goal-driven behaviour and partially reverses neurophysiological deficits in the rat phencyclidine model of schizophrenia

Abstract

Positive modulation of cAMP signalling by phosphodiesterase (PDE) inhibitors has recently been explored as a potential target for the reversal of cognitive and behavioural deficits implicating the corticoaccumbal circuit. Previous studies show that PDE type 1 isoform B (PDE1B) inhibition may improve memory function in rodent models; however, the contribution of PDE1B inhibition to impulsivity, attentional and motivational functions as well as its neurophysiological effects have not been investigated. To address this, we recorded single unit activity in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in Lister Hooded rats treated with the PDE1B inhibitor Lu AF64386 and tested in the 5-choice serial reaction time task (5-CSRTT). We also asked whether PDE1B inhibition modulates neurophysiological deficits produced by subchronic phencyclidine (PCP) treatment, a rat pharmacological model of schizophrenia. Lu AF64386 significantly affected behavioural parameters consistent with a reduction in goal-directed behaviour, however without affecting accuracy. Additionally, it reduced mPFC neuronal activity. Pre-treatment with PCP did not affect behavioural parameters, however it significantly disrupted overall neuronal firing while increasing phasic responses to reward-predicting cues and disrupting mPFC-NAc cross-talk. The latter two effects were reversed by Lu AF64386. These findings suggest PDE1B inhibition may be beneficial in disorders implicating a dysfunction of the mPFC-NAc network.