Chronic antidepressant-like effect of EMD386088, a partial 5-HT6 receptor agonist, in olfactory bulbectomy model may be connected with BDNF and/or CREB signalling pathway.

Abstract

The removal of the olfactory bulbs has been attributed to behavioral changes and neuroplasticity manifesting themselves among others like increases in brain neurotrophin expression and neurogenesis. Earlier data presented that EMD386088, a 5-HT6 receptor partial agonist, exerts antidepressant-like properties after chronic administration in olfactory bulbectomy (OB) model as was it compared with amitriptyline (AMI). The aim of this study was to compare acute and chronic biochemical effects of EMD386088, administered in its antidepressant active (2.5mg/kg) and non-active (1.25mg/kg) doses, found in the open field test in OB rats, with those of AMI (10mg/kg). The levels of 5-HT6 receptor protein and selected neurotrophins in prefrontal cortex (PFC) and hippocampus (Hp) of rats have been examined. 5-HT6 receptor protein and selected neurotrophins: brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB), the product of the immediate early gene c-fos (cFos) protein levels were assessed using a Western blot analysis in PFC and Hp of bulbectomized rats after acute or chronic (14-day) EMD386088 or AMI intraperitoneal (ip) treatment. The acute treatment with EMD386088 caused significant increases in CREB and BDNF protein levels in PFC, and an increase in BDNF in Hp of OB rats, while AMI injection decreased CREB and did not change BDNF levels. After the chronic administration of EMD386088, the increasing levels of BDNF and CREB were still observed in PFC and Hp. The antidepressant-like effect of EMD386088 may be associated with the neuroplasticity activation in PFC and Hp in rats.