The presynaptic component of the serotonergic system is required for clozapine's efficacy

Neuropsychopharmacology. 2011 Feb;36(3):638-51. doi: 10.1038/npp.2010.195. Epub 2010 Nov 3.

Abstract

Clozapine, by virtue of its absence of extrapyramidal side effects and greater efficacy, revolutionized the treatment of schizophrenia, although the mechanisms underlying this exceptional activity remain controversial. Combining an unbiased cheminformatics and physical screening approach, we evaluated clozapine's activity at >2350 distinct molecular targets. Clozapine, and the closely related atypical antipsychotic drug olanzapine, interacted potently with a unique spectrum of molecular targets. This distinct pattern, which was not shared with the typical antipsychotic drug haloperidol, suggested that the serotonergic neuronal system was a key determinant of clozapine's actions. To test this hypothesis, we used pet1(-/-) mice, which are deficient in serotonergic presynaptic markers. We discovered that the antipsychotic-like properties of the atypical antipsychotic drugs clozapine and olanzapine were abolished in a pharmacological model that mimics NMDA-receptor hypofunction in pet1(-/-) mice, whereas haloperidol's efficacy was unaffected. These results show that clozapine's ability to normalize NMDA-receptor hypofunction, which is characteristic of schizophrenia, depends on an intact presynaptic serotonergic neuronal system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation / methods
  • Action Potentials / drug effects
  • Adrenergic Uptake Inhibitors / pharmacology
  • Amphetamines / pharmacology
  • Animals
  • Antipsychotic Agents / pharmacology
  • Behavior, Animal / drug effects
  • Checkpoint Kinase 2
  • Clozapine / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Ketanserin / pharmacokinetics
  • Lysine / analogs & derivatives
  • Lysine / metabolism
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Motor Activity / drug effects
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques / methods
  • Phencyclidine / pharmacology
  • Presynaptic Terminals / drug effects*
  • Protein Binding / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / deficiency
  • Radioligand Assay / methods
  • Raphe Nuclei / cytology
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Reflex, Startle / drug effects
  • Reflex, Startle / physiology
  • Serotonin / metabolism*
  • Serotonin Antagonists / pharmacology*
  • Stereotyped Behavior / drug effects
  • Tritium / pharmacokinetics
  • Tryptophan Hydroxylase / metabolism

Substances

  • Adrenergic Uptake Inhibitors
  • Amphetamines
  • Antipsychotic Agents
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Serotonin Antagonists
  • Tritium
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • Ketanserin
  • Tryptophan Hydroxylase
  • Checkpoint Kinase 2
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 3
  • biocytin
  • Phencyclidine
  • Clozapine
  • Lysine
  • N-Methyl-3,4-methylenedioxyamphetamine
  • 4-iodo-2,5-dimethoxyphenylisopropylamine