Administration of selective 5-HT₆ receptor antagonists has been demonstrated to enhance cognition and attenuate age-related cognitive decline in rats (Foley, et al., 2004). The novel object recognition model is a task where animals are allowed to explore two identical objects and, after a suitable inter-trial interval (ITI), one of the objects is replaced with an object of identical size and shape but with a novel visual pattern. In this second trial, normal rats will show an exploratory bias towards the novel object. The present studies aimed to reverse the deficit induced by a 24 hour ITI by sub-chronic administration of the selective 5-HT₆ receptor antagonist, SB-399885.

Group-housed male Lister-hooded rats (333 - 413 g, n=12 per group) with free access to food and water, were held on a normal 12-hour light/dark cycle. The experimental procedure was based on that of King et al. (2004). Animals were habituated to the experimental arena for a 1 hour period 24 hours prior to the initial trial. In this trial animals were allowed to explore two identical objects for a 3 minute period. An inter-trial interval of 0.25, 1, 2, 3, 4, 6 or 24 hours was allowed prior to the 3 minute trial with the novel and familiar object. In a second experiment, animals were dosed orally twice a day with 1% methyl cellulose vehicle or SB-399885 (0, 1, 3 or 10 mg kg^-1) for 7 days. There was an interval of 24 hours between the two trials. On test days, the first SB-399885 dose was administered 3 hours prior to each animal’s trial. The time spent exploring the objects was scored by a trained observer. Data were analysed by ANOVA and Tukey’s test.

Increasing the ITI led to a significant deficit in novel object discrimination such that there was no significant difference between exploration of the familiar and the novel objects with an ITI of 4 hours or longer (Table 1). Sub-chronic SB-399885 treatment reversed the deficit in novel object recognition induced by a 24 hour ITI (Table 2).

Table 1. Time spent exploring either the familiar or novel objects in the second trial (s)

Table 2. Effect of SB-399885 (mg kg^-1) on novel object exploration

Mean ± s.e.m. * p < 0.05; ** p < 0.01, comparison between novel and familiar object.

The data support the hypothesis that 5-HT₆ receptor antagonists such as SB-399885 have potential utility in disorders characterized by cognitive decline.