Lena Danovich1, Orly Weinreb, Moussa B H Youdim, Henry Silver. 1. Molecular Neuropsychiatry Unit, Shaar Menashe Brain Behavior Laboratory, Shaar Menashe MHC and Technion-Faculty of Medicine, Mobile Post, 38814, Haifa, Israel.
Abstract
INTRODUCTION: 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. FINDINGS: 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.
INTRODUCTION: 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. FINDINGS: 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.