Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5‐<scp>HT</scp>)_2A and <scp>DA</scp> D₂ antagonism and 5‐<scp>HT</scp>_1A partial agonism

Abstract

Abstract Atypical antipsychotic drugs ( AAPD s) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APD s, a conclusion supported by differences in receptor affinities and neurotransmitter efflux in the cortex and the hippocampus. More potent serotonin (5‐ HT ) 2A than dopamine ( DA ) D 2 receptors antagonism, and direct or indirect 5‐ HT 1A agonism, characterize almost all AAPD s. Blonanserin, an AAPD , has slightly greater affinity for D 2 than 5‐ HT 2A receptors. Using microdialysis and ultra performance liquid chromatography‐mass spectrometry/mass spectrometry, we compared the abilities of the typical APD , haloperidol, three AAPD s, blonanserin, lurasidone, and olanzapine, and a selective 5‐ HT 1A partial agonist, tandospirone, and all, except haloperidol, were found to ameliorate the cognitive deficits produced by the N ‐methyl‐d‐aspartate antagonist, phencyclidine, altering the efflux of neurotransmitters and metabolites in the rat cortex and nucleus accumbens. Blonanserin, lurasidone, olanzapine, and tandospirone, but not haloperidol, increased the efflux of cortical DA and its metabolites, homovanillic acid and 3,4‐dihydroxyphenylacetic acid. Olanzapine and lurasidone increased the efflux of acetylcholine; lurasidone increased glutamate as well. None of the compounds significantly altered the efflux of 5‐ HT or its metabolite, 5‐hydroxyindole acetic acid, or GABA , serine, and glycine. The ability to increase cortical DA efflux was the only shared effect of the compounds which ameliorates the deficit in cognition in rodents following phencyclidine. image Abnormalities in dopaminergic, glutamatergic, gamma‐aminobutyric acid (GABAergic), cholinergic, and noradrenergic activity in the medial prefrontal cortex and hippocampus have been implicated in the pathophysiology of the cognitive impairment in schizophrenia. Using in vivo microdialysis and UPLC‐MS/MS assay method, the effect of multiple antipsychotics with different binding properties on the efflux of neurotransmitters including acetylcholine (ACh), dopamine (DA), and metabolites, serotonin, serine, glycine, glutamate (Glu) and GABA in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been studied in rats. Related mechanisms of receptors and neurotransmitter efflux have been discussed.