The novel object discrimination (NOD) task is a two-trial test of non-spatial recognition memory, dependent on brain areas known to express 5-HT₆ receptors (Steckler et al. 1998). The selective 5-HT₆ receptor antagonist Ro 04-6790 (Sleight et al. 1998) prolongs memory in this task by enhancing consolidation, an effect blocked by the non-competitive NMDA receptor antagonist MK-801 (King et al. 2004). Ro 04-6790 also reverses scopolamine-induced deficits in NOD (Woolley et al. 2003), and these behavioural findings are consistent with the ability of 5-HT₆ receptor antagonists to increase central glutamate (Dawson et al. 2001) and ACh release (Shirazi-Southall et al. 2002; Reimer et al. 2003). Increased excitatory neurotransmission in response to 5-HT₆ receptor antagonists may be explained by the presence of excitatory 5-HT₆ receptors on GABAergic interneurones (Woolley et al. 2000). In the present study NOD was impaired by the GABA uptake inhibitor SKF89976A (Borden et al. 1994) or diazepam, whose effects should be attenuated by the decrease in GABA release predicted if 5-HT₆ receptors are present on GABAergic interneurones. The ability of Ro 04-6790 to reverse these cognitive impairments was investigated.

NOD was performed as described previously (King et al. 2004). Male Lister-hooded rats (120-200g, n=11-12 per group) were habituated (60min, -24h) to individual test arenas then received two 3min trials separated by a 2h interval; ‘familiarisation’ with two identical objects, and ‘choice’ with one familiar and one novel. Pre-treatment with SKF89976A (10, 20mg/kg), diazepam (2, 4mg/kg), or vehicle control (1ml/kg water or 0.5% w/v methylcellulose) i.p. occurred 40min prior to familiarisation, followed 20min later by Ro 04-6790 (10mg/kg) or 1ml/kg saline i.p. 7d later each rat received the opposite drug/vehicle combination to serve as its own control. Student’s paired t-test was used to compare the time at the two objects in each trial.

No group showed an object preference during familiarisation. Vehicle treated rats spent longer (P<0.01) exploring the novel than the familiar object during the choice trial, and SKF89976A and diazepam abolished this discrimination. Ro 04-6790 alone had no effect due to lack of an initial impairment (Woolley et al 2003), but successfully reversed both the SKF89976A (10mg/kg; P<0.01) and diazepam (2mg/kg; P<0.05) induced deficits. These data support the hypothesis that modulation of GABAergic neurotransmission underlies the cognitive effects of 5-HT₆ receptor antagonists.

Borden et al. 1994 Eur. J. Pharmacol. 269 219
Dawson et al. 2001 Neuropsychopharmacol. 25, 662
King et al. 2004 Neuropharmacol. In Press
Reimer et al. 2003 J. Med. Chem. 46 1273
Shirazi-Southall et al. 2002 Neuropsychopharmacol. 26 583
Sleight et al. 1998 Brit. J. Pharmacol. 124, 556
Steckler et al. 1998 Prog. Neurobiol. 54 313
Woolley et al. 2000 Brit. J. Pharmacol. 131S, 238P
Woolley et al. 2003 Psychopharmacol. 170, 358

This work is sponsored by F. Hoffmann-La Roche, who also provided Ro 04-6790