title: Neuropathology markers and pathways associated with molecular targets for antipsychotic drugs in postmortem brain tissues: exploration of drug targets through the Stanley Neuropathology Integrative Database.
abstract: The atypical antipsychotics bind multiple receptor targets, including dopamine D₂ receptors (DRD2), 5-HT₂ receptors (HTR2A), α-2 adrenergic receptors (ADRA2A), and muscarinic receptors (CHRM1/4). Deficits in antipsychotic targets, their associated pathways, and the causal relationships between the various targets were explored using the Stanley Neuropathology Consortium Integrative Database (SNCID; http://sncid.stanleyresearch.org) and the Network Edge Orienting (NEO) software. There were brain region-specific deficits in the level of the antipsychotic targets, and the level of each target correlated with the mRNA level of the neurotrophic factor BDNF. While myelination was a common process correlated with both DRD2 mRNA levels and ADRA2A activity in the frontal cortex, metabolic processes were specifically correlated with DRD2 mRNA. Immune and inflammatory responses and apoptosis pathways were correlated with group II metabotropic glutamate receptors (GRM2), which are a target for the development of the next-generation antipsychotics. The NEO analysis revealed that HTR2A and GRM2 are likely to regulate BDNF levels in the hippocampus and frontal cortex, respectively, whereas DRD2 and ADRA2A activity are likely to be regulated by BDNF in the frontal cortex. BDNF may play an important role in mechanisms of action of the current antipsychotics and the next-generation antipsychotics that target GRM2. However, this data-mining approach indicates that the next-generation antipsychotics are likely to work through pathways that are distinct from those through which the current antipsychotics work. Exploratory analyses such as these may initiate future hypothesis-driven studies to reveal the mechanisms of action underlying the efficacy and side-effects of the antipsychotics.
authors.affiliation: Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD 20850, USA. kims@stanleyresearch.org
authors.forename: Sanghyeon
authors.initials: S
authors.lastname: Kim
authors.forename: Katerina
authors.initials: K
authors.lastname: Zavitsanou
authors.forename: George
authors.initials: G
authors.lastname: Gurguis
authors.forename: Maree J
authors.initials: MJ
authors.lastname: Webster
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D057225:Data Mining; D016208:Databases, Factual; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: C547768:ADRA2A protein, human; D014150:Antipsychotic Agents; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D065127:Dopamine D2 Receptor Antagonists; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2