The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release

Abstract

Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission. In the current study, the effects of partial nAChR agonist and 5-HT3 receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats. R3487/MEM3454, at doses of 0.1-10mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose-response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0mg/kg), completely blocked RG3487-induced (0.45mg/kg) DA but not ACh efflux, while the selective 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (1.0mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1mg/kg), but not typical APD haloperidol (0.1mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3mg/kg), olanzapine (1.0mg/kg), and quetiapine (30mg/kg), also produced additive effects on DA efflux. These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT3 receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia.