Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex
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5-HT6 receptor antagonists improve cognitive processes in rodents. However, their site(s) of action remains unexplored and their influence upon social memory has been little investigated.
We examined the influence of 5-HT6 receptor ligands upon social memory in rats by use of systemic or local administration into the frontal cortex (FCX), striatum, or nucleus basalis magnocellularis (NBM).
Materials and methods
The social recognition test is based upon the ability of an adult rat to recognize a younger conspecific during the second of two 5-min sessions. In a procedure without an inter-session interval, the actions of drugs alone and the ability to reverse “amnesia” induced by the muscarinic antagonist, scopolamine (1.25 mg/kg, s.c.), were examined. The potential promnesic effect of drugs was also investigated in another procedure where a spontaneous deficit of recognition was induced by a 120-min inter-session interval.
The 5-HT6 receptor agonist, WAY-181187 (10.0 mg/kg, i.p.), significantly impaired social recognition. This effect was abolished by the 5-HT6 receptor antagonists, SB-271046 (20.0 mg/kg, i.p.) and SB-258585 (10.0 mg/kg, i.p.). These agents also abolished scopolamine-induced amnesia (10.0 and 2.5 mg/kg, i.p., respectively) and reversed the delay-induced deficit (10.0–20.0 and 2.5–10.0 mg/kg, i.p., respectively). WAY-181187 into the FCX significantly impaired social recognition (0.16–0.63 μg/side). Conversely, SB-271046 into the FCX (2.5–5.0 μg/side), but neither into the striatum nor the NBM, significantly reversed spontaneous deficit.
These results indicate that 5-HT6 receptors modulate social recognition by actions in the FCX and underpin their pertinence as targets for the treatment of psychiatric disorders in which cognitive function is compromised.
Keywords5-HT6 receptor Social recognition Scopolamine Microinfusion Frontal cortex Striatum Nucleus basalis magnocellularis
- Bentley JC, Sleight AJ, Marsden CA, Fone KCF (1997) 5-HT6 antisense oligonucleotide I.C.V. affects rat performance in the water maze and feeding. J Psychopharmacol 11:255Google Scholar
- Bromidge SM, Brown AM, Clarke SE, Dodgson K, Gager T, Grassam HL, Jeffrey PM, Joiner GF, King FD, Middlemiss DN, Moss SF, Newman H, Riley G, Routledge C, Wyman P (1999) 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophene-sulfonamide (SB-271046): a potent, selective, and orally bioavailable 5-HT6 receptor antagonist. J Med Chem 42:202–205PubMedCrossRefGoogle Scholar
- Callahan PM, Ilch CP, Rowe WB, Tehim A (2004) Characterization of the selective 5-HT6 receptor antagonist SB 271046 in behavioral models of cognition. Soc Neurosci Abstr 30:776.19Google Scholar
- Chudasama Y, Passetti F, Rhodes SEV, Lopian D, Desai A, Robbins TW (2003) Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146:105–119PubMedCrossRefGoogle Scholar
- Foley AG, Murphy KJ, Hirst WD, Gallagher HC, Hagan JJ, Upton N, Walsh FS, Regan CM (2004) The 5-HT6 receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology 29:93–100PubMedCrossRefGoogle Scholar
- Hirst WD, Stean TO, Rogers DC, Sunter D, Pugh P, Moss SF, Bromidge SM, Riley G, Smith DR, Barlett S, Heidbreder CA, Atkins AR, Lacroix LP, Dawson LA, Foley AG, Regan CM, Upton N (2006) SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. Eur J Pharmacol 553:109–119PubMedCrossRefGoogle Scholar
- King MV, Sleight AJ, Fone KCF, Marsden CA (2006) A 5-HT6 receptor agonist prolongs memory in the novel object discrimination (NOD) task. J Psychopharmacol 20:A66Google Scholar
- Lee KH, Brown WH, Egleston PN, Green RDJ, Farrow TFD, Hunter MD, Parks RW, Wilkinson ID, Spence SA, Woodruff PWR (2006) A functional magnetic resonance imaging study of social recognition in schizophrenia during an acute episode and after recovery. Am J Psychiatry 163:1926–1933PubMedCrossRefGoogle Scholar
- Lindner MD, Hodges DB, Hogan JB, Orie AF, Corsa JA, Barten DM, Polson C, Robertson BJ, Guss VL, Gillman KW, Starrett JE, Gribkoff VK (2003) An assessment of the effects of serotonin6 (5-HT6) receptor antagonists in rodent models of learning. J Pharmacol Exp Ther 307:682–691PubMedCrossRefGoogle Scholar
- Loiseau F, Millan MJ, Dekeyne A (2007) The D1 receptor agonist, SKF81297, and the D3 receptor antagonist, S33084, enhance social recognition in rat: implication of the frontal cortex. Behav Pharmacol 18:S50–S51Google Scholar
- Millan MJ, Gobert A, Roux S, Porsolt RD, Meneses A, Carli M, Di Cara B, Jaffard R, Rivet J-M, Lestage P, Mocaer E, Péglion JL, Dekeyne A (2004) The serotonin1A receptor partial agonist, S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine], enhances cholinergic transmission and cognitive function in rodents: a combined neurochemical and behavioral analysis. J Pharm Exp Ther 311:190–203CrossRefGoogle Scholar
- Mitchell ES, Hoplight BJ, Lear SP, Neumaier JF (2006) BGC20–761, a novel tryptamine analog, enhances memory consolidation and reverses scopolamine-induced memory deficit in social and visuospatial memory tasks through a 5-HT6 receptor-mediated mechanism. Neuropharmacology 50:412–420PubMedCrossRefGoogle Scholar
- Paxinos G, Watson W (1994) The rat brain stereotaxic coordinates. Academic, SydneyGoogle Scholar
- Riemer C, Borroni E, Levet-Trafit B, Martin JR, Poli S, Porter RHP, Bös M (2003) Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. J Med Chem 46:1273–1276PubMedCrossRefGoogle Scholar
- Schechter LE, Li Q, Smith DL, Zhang G, Shan Q, Platt B, Brandt MR, Dawson LA, Cole D, Bernotas R, Robichaud A, Rosenzweig-Lipson S, Beyer CE (2007) Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology (in press) DOI 10.1038/sj.npp-1301503
- Schreiber R, Vivian J, Hedley L, Szczepanski K, Secchi RL, Zuzow M, van Laarhoven S, Moreau JL, Martin JR, Sik A, Blokland A (2006) Effects of the novel 5-HT6 receptor antagonist Ro4368554 in rat models for cognition and sensorimotor gating. Eur Neuropsychopharmacol 30:2169–2179Google Scholar