title: The involvement of GABA(A) receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment.
abstract: There is evidence that combining selective serotonin reuptake inhibitor (SSRI) antidepressant and antipsychotic drugs may improve negative symptoms in schizophrenia and resistant symptoms in obsessive-compulsive and affective disorders. To examine the mechanism of action of this treatment we investigated the molecular modulation of γ-aminobutyric acid-A (GABA(A)) receptor components and biochemical pathways associated with GABA(A) receptor function following administration of the SSRI fluvoxamine (Flu) combined with the first-generation antipsychotic haloperidol (Hal) and compared it to the individual drugs and the atypical antipsychotic clozapine (Clz). We analysed prefrontal cortices of Sprague-Dawley rats injected intraperitoneally (i.p.) with the combination of Flu (10 mg/kg) and Hal (1 mg/kg), each drug alone, or Clz (10 mg/kg) after 30 min and 1 h. We found that haloperidol plus fluvoxamine (Hal-Flu) co-administration, and Clz, decreased the level of GABAAβ2/3 receptor subunit in the cytosolic fraction, and increased it in the membrane compartment in rat PFC. Flu or Hal alone did not produce changes in GABAAβ2/3 receptor protein expression. Additionally, Hal-Flu and Clz regulated molecular signalling pathways that modulate GABA(A) receptor function, including protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). In primary cortical culture, short-term treatment (15 min) with Hal-Flu combination and Clz increased GABAAβ subunit phosphorylation levels. Pretreatment of the cells with PKC inhibitor abolished the effect of the combined treatment, or Clz on phosphorylation of GABA(A) receptor. Inhibition of ERK2 did not alter the effect of drugs on GABA(A) receptor phosphorylation levels. Our findings provide evidence that the combined treatment regulates GABA(A) receptor function and does so via a PKC-dependent pathway.
authors.affiliation: Molecular Neuropsychiatry Unit, Shaar Menashe Brain Behavior Laboratory, Shaar Menashe MHC and Technion-Faculty of Medicine, Haifa, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Danovich
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.forename: Henry
authors.initials: H
authors.lastname: Silver
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D003024:Clozapine / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D004359:Drug Therapy, Combination; D016666:Fluvoxamine / Q000627:therapeutic use; D006220:Haloperidol / Q000627:therapeutic use; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D019964:Mood Disorders / Q000188:drug therapy*; D009771:Obsessive-Compulsive Disorder / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D003024:Clozapine; D004298:Dopamine; D016666:Fluvoxamine; D006220:Haloperidol; D019950:Mitogen-Activated Protein Kinase 1; D011493:Protein Kinase C; D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors