The involvement of GABAA 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.

Chronic treatment with serotonin reuptake inhibitor antidepressant (SSRI) combined with an antipsychotic regulates GABA-A receptor in rat prefrontal cortex

“…The effect of chronic HALO-FLU combined treatment on GABA-A Rβ2/3 receptor in rat PFC Acute studies in our laboratory showed that HALO-FLU combined affected GABA-A receptors differently than each drug given alone (Danovich et al 2011;Chertkow et al 2006). Figure 1 shows the effect of chronic treatment on the GABA-Aβ2/3 receptor expression levels and cellular distribution in rat PFC.…”

“…The effect of chronic HALO-FLU combined treatment on PKC and ERK2 phosphorylation in rat PFC Next, we examined changes in the activation of MAPK/ ERK signaling pathways, as PKC and ERK2 are known to be involved in the regulation of GABA-A receptor and might be influenced by psychotropics (Danovich et al 2011). It is shown in Fig.…”

“…Recently, we reported that acute HALO-FLU coadministration, but not each drug alone, decreased levels of GABA-Aβ2/3 receptor in the cytosolic fraction and increased it in the membranal compartment in rat PFC (Danovich et al 2011). Furthermore, in primary cortical culture, short-term (15 min) treatment with HALO-FLU increased GABA-Aβ2/3 phosphorylation levels (Danovich et al 2011).…”

“…Treatment duration was chosen to correspond to onset of clinical response (Silver et al 2003b). Previous studies showed that the doses used produced in rat serum drug levels in ranges considered therapeutic in humans (Chertkow et al 2006) and that levels of HALO or FLU in rat brain and serum do not differ significantly whether administered in combination or in monotherapy (Danovich et al 2011;Chertkow et al 2006).…”

“…Recent studies in our laboratory (Danovich et al 2011) have shown that acute administration of haloperidol (HALO) combined with fluvoxamine (FLU) regulated subcellular distribution and expression levels of γ-amino butyric acid-A (GABA-A) β2/3 and its phosphorylation by protein kinase C (PKC) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signal transduction pathways in rat prefrontal cortex (PFC) (Brandon et al 2000;Kalluri and Ticku 2002;Zheng et al 2007Zheng et al , 2009). These changes were not observed when haloperidol or fluvoxamine were administered alone, but did occur after treatment with clozapine, an atypical antipsychotic that can also improve negative symptoms.…”