Neurochemical arguments for the use of dopamine D receptor stimulation to improve cognitive impairment associated with schizophrenia.

BACKGROUND

Dopamine (DA) D receptors have been implicated in schizophrenia and the ability of some atypical antipsychotic drugs (APDs) to improve the cognitive impairment associated with schizophrenia (CIAS). Systemic administration of a D agonist, PD168077, at a sub-effective dose, together with a sub-effective dose of lurasidone, an atypical APD which is a weak D receptor antagonist, reversed the deficit in novel object recognition (NOR) in rats treated subchronically with phencyclidine (PCP), a rodent model of CIAS. Atypical APDs potentially stimulate DRs via their ability to enhance DA release in key brain areas related to cognition. However, some atypical APDs are relatively potent D antagonists at clinical dosages, including clozapine, and risperidone. The D antagonist, L745870, blocked the ability of clozapine, but not lurasidone, to reverse the NOR deficit in rats.

METHODS

The purpose of this study was to determine the effects of a selective D agonist and antagonist, alone, and as pretreatment with lurasidone, on neurotransmitter efflux in mouse medial prefrontal cortex (mPFC) and dorsal striatum (dSTR), using in vivo microdialysis.

RESULTS AND DISCUSSION

PD168077 alone, and in combination with sub-effective dose lurasidone, increased DA and acetylcholine (ACh) efflux in mPFC, but only DA efflux in dSTR. L745870 had no effect on neurotransmitter efflux on its own or on the ability of lurasidone to increase cortical or striatal neurotransmitter efflux. These results indicate D receptor agonism alone is sufficient to increase cortical DA and ACh efflux without interfering with the effects of lurasidone and possibly other atypical APDs on extracellular cortical DA and ACh levels. A D agonist may be useful for treating CIAS, especially as augmentation of those atypical APDs which are not potent D antagonists.