טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentDanovich Ilana
SubjectThe Molecular Mechanism of Pharmacodynamic Interactions
between Psychoactive Drugs: Interactions between
Antidepressants and Antipsychotic Drugs
DepartmentDepartment of Medicine
Supervisors Professor Henry Silver
Professor Emeritus Moussa Youdim
Dr. Orly Weinreb
Full Thesis textFull thesis text - English Version


Abstract

Adding selective serotonin reuptake inhibitor (SSRI) antidepressants (e.g. fluvoxamine) to antipsychotics (e.g. haloperidol) can improve negative symptoms of schizophrenia. The biochemical mechanisms mediating this clinical response remain obscure. We hypothesized that the unique molecular changes produced by  antipsychotic-SSRI combined treatment, different those of individual drug treatments, and common to the changes induced by atypical antipsychotic clozapine, may be involved in the mechanism of improving negative symptoms. Since previous findings indicated a possible involvement of γ-aminobutyric acid (GABA) system in the mechanism of action of the combined treatment, we concentrated on GABA-A receptor regulation, and molecules associated with the GABA-A receptor: protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). Chronic treatment with haloperidol-fluvoxamine (HALO-FLU), but not each drug alone, decreased GABA-Aβ2/3 receptor expression, and caused receptor translocation from the membranal to the cytosolic compartment in rat prefrontal cortex (PFC). This was accompanied by decrease in GABA function, as shown in muscimol-induced loss of righting reflex. Acute HALO-FLU treatment  increased GABA-Aβ2/3 receptor in membranal and decreased in cytosolic compartment of rat PFC, and decreased dopamine content in PFC. In primary cortical neuronal cultures, short-term treatment with HALO-FLU combination increased GABA-Aβ2/3 receptor phosphorylation. Pretreatment of the cells with inhibitor of PKC, but not of ERK2, abolished the effect of the combined treatment on phosphorylation of GABA-A receptor. PKC and ERK2 posphorylation was differently regulated by the drug combination than by individual treatments both in rats and in primary cortical cultures. Glycogen synthase-3β (GSK-3β) was increased by HALO-FLU combination in PFC of acutely treated rats.  Clozapine effected GABA-A receptors, PKC, ERK2 and GSK-3β similarly as HALO-FLU combination, implying that the regulation of GABA-A receptors and its associated molecular signaling pathways might be important to the mechanism of negative symptom amelioration. The molecular effects of the antipsychotic-SSRI clinical treatment were examined in peripheral mononuclear (PMN) cells and plasma of schizophrenia patients exhibiting negative symptoms following FLU augmentation of antipsychotic treatment. We demonstrated alterations in mRNA encoding for GABA-Aβ3 and serotoninergic (5-HT2A, 5-HT7) receptors, PKCβ2, and brain-derived neurotrophic factor (BDNF) in PMN cells of schizophrenia patients, and an increase in BDNF plasma levels. The gene alterations in PMN cells were intercorrelated, and some correlated with clinical symptoms.

Our findings provide new knowledge about the molecular mechanisms of the clinical effect of antipsychotic-SSRI treatment and might contribute to improvement of therapies for schizophrenia and a range of psychiatric conditions treated with this drug combination.