Oxcarbazepine and fluoxetine protect against mouse models of obsessive compulsive disorder through modulation of cortical serotonin and CREB pathway

Abstract

The serotonergic system is suggested to be dysregulated in obsessive compulsive disorder (OCD) as selective serotonin reuptake inhibitors have emerged as the mainstay in the treatment of this disorder. Oxcarbazepine (OXC), a second generation antiepileptic drug, enhances hippocampal serotonin (5-HT) levels. The aim of the present study was to screen the anti-OCD effects of OXC on marble burying behaviour (MBB) and 8-OHDPAT-induced disruption of alternation, two most studied paradigms of OCD, in rodents. Here we show that 8-OHDPAT (2.8 mg/kg) significantly increases spontaneous alternation behaviour (SAB) score in a T-maze. Fluoxetine (FLX), an SSRI on chronic administration (10mg/kg, 21 days) restored the increase in SAB induced by 8-OHDPAT in mice which is in line with the findings earlier reported for rats. Hence, we present the first mouse model of OCD induced by 2.8 mg/kg of 8-OHDPAT. Chronic administration (21 days) of OXC (20 and 40 mg/kg) also restored the SAB disrupted by 8-OHDPAT which was comparable to FLX. Likewise in MBB test, FLX and OXC significantly reduced the number of marbles buried. 8-OHDPAT induced OCD was associated with a concomitant decrease in basal 5-HT levels (88%) and depletion of basal CREB (32%) in the frontal cortex. Chronic treatment with FLX and OXC effectively mitigated the lowering effects of 8-OHDPAT on cortical 5-HT, and enabled an efficient recovery in basal CREB levels. Our results on FLX and OXC provide the indication that their anti-OCD effects in part, might be elicited through modulation of 5HT levels and CREB pathway.