title: Chronic treatment with serotonin reuptake inhibitor antidepressant (SSRI) combined with an antipsychotic regulates GABA-A receptor in rat prefrontal cortex.
abstract: BACKGROUND
  The combination of selective serotonin reuptake inhibitor (SSRI) antidepressants and antipsychotics is currently used for the treatment of negative symptoms of schizophrenia. However, the biochemical mechanism mediating the clinical effectiveness of this treatment remains obscure. Previously, we have reported that acute haloperidol (HALO)-fluvoxamine (FLU) in vivo and in vitro treatment regulated GABA-Aβ2/3 receptor subunits, and protein kinase C (PKC) and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) signaling pathways.
  
  
  RESULTS
  In the present study, we demonstrated that chronic HALO-FLU treatment, but not each drug alone, significantly decreased GABA-Aβ2/3 receptor expression (25 ± 6.2% vs. control) and caused receptor translocation from the membrane to the cytosol in rat prefrontal cortex. Phosphorylation of PKC and ERK2 was affected differently by HALO-FLU combination than by the individual drug treatments. HALO and FLU each given alone increased PKC phosphorylation levels (29 ± 15% and 40 ± 11.8%, vs. control, respectively) and did not affect ERK2 phosphorylation, while HALO-FLU combined treatment did not alter PKC phosphorylation levels and significantly decreased ERK2 phosphorylation levels (58 ± 4.4% vs. control). GABA-A receptor downregulation in the brain was accompanied by a decrease in GABA-A function, as shown in muscimol-induced loss of righting reflex (22 ± 9.8 min).
  
  
  CONCLUSIONS
  We provide a brief heuristic overview of our preclinical and clinical studies with the SSRI-antipsychotic combination and argue that the finding that it causes similar dynamic changes in laboratory and clinical domains, specifically in GABA-A β2/3 receptor and PKC, strongly supports the hypothesis that the GABA-A receptors and their regulatory systems are involved in the molecular mechanisms underlying the clinical effectiveness of SSRI augmentation.
authors: Molecular Neuropsychiatry Unit, Shaar Menashe Brain Behavior Laboratory, Shaar Menashe MHC and Technion-Faculty of Medicine, Mobile Post, 38814, Haifa, Israel.
authors: Lena
authors: L
authors: Danovich
authors: Orly
authors: O
authors: Weinreb
authors: Moussa B H
authors: MB
authors: Youdim
authors: Henry
authors: H
authors: Silver
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors