Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism

J Neurochem. 2014 Mar;128(6):938-49. doi: 10.1111/jnc.12512. Epub 2013 Nov 14.


Atypical antipsychotic drugs (AAPDs) have been suggested to be more effective in improving cognitive impairment in schizophrenia than typical APDs, 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) D2 receptors antagonism, and direct or indirect 5-HT1A agonism, characterize almost all AAPDs. Blonanserin, an AAPD, has slightly greater affinity for D2 than 5-HT2A receptors. Using microdialysis and ultra performance liquid chromatography-mass spectrometry/mass spectrometry, we compared the abilities of the typical APD, haloperidol, three AAPDs, blonanserin, lurasidone, and olanzapine, and a selective 5-HT1A 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.

Keywords: UPLC-MS/MS; acetylcholine; antipsychotics; dopamine; glutamate; microdialysis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Antipsychotic Agents / pharmacology
  • Brain / drug effects*
  • Brain / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Dopamine / metabolism
  • Glutamic Acid / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Isoindoles / pharmacology*
  • Lurasidone Hydrochloride
  • Male
  • Microdialysis
  • Neurotransmitter Agents / metabolism*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Piperazines / pharmacology*
  • Piperidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology
  • Synaptic Transmission / drug effects*
  • Thiazoles / pharmacology*


  • Antipsychotic Agents
  • Isoindoles
  • Neurotransmitter Agents
  • Piperazines
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Thiazoles
  • Receptor, Serotonin, 5-HT1A
  • Glutamic Acid
  • blonanserin
  • Acetylcholine
  • Lurasidone Hydrochloride
  • Dopamine