Acceleration of onset of action in schedule-induced polydipsia: combinations of SSRI and 5-HT 1A and 5-HT 1B receptor antagonists

Abstract

Onset of action is a key unmet need in the treatment of depression. However, very few preclinical models in which the effects of antidepressants can be shown are suitable for screening for onset. In this context, previous literature suggests that a slow onset of action of selective serotonin reuptake inhibitors (SSRIs) is observed in schedule-induced polydipsia (SIP). The current investigation was performed to determine the latency to reduce SIP of the SSRI, fluoxetine, and of two treatments known to facilitate 5-HT neurotransmission to a greater extent than an SSRI alone. These treatments included interaction studies for fluoxetine+the 5-HT 1A antagonist, WAY 100635, and for fluoxetine+the 5-HT 1B partial agonist, GR 127935. Food-restricted rats were trained on a fixed interval schedule with drinking water freely available. Once water intake was stable, rats were randomly assigned to vehicle of treatment groups. Daily treatment was continued for 3 (interaction studies) or 18 days (fluoxetine alone study). Fluoxetine significantly reduced SIP after 5–6 days of treatment, with the maximal effect evidenced after 8 days. WAY 100635 and GR 127935 accelerated the onset of action of fluoxetine, with significant effects observed on treatment day 1. These data suggest that SIP may be useful to assess the onset of action of serotonin enhancers.