The Effects of Novel, Selective 5-Hydroxytryptamine (5-HT)4 Receptor Ligands in Rat Spatial Navigation

doi:10.1016/S0028-3908(97)00055-5

Neuropharmacology

Volume 36, Issues 4–5, April–May 1997, Pages 689-696

https://doi.org/10.1016/S0028-3908(97)00055-5 Get rights and content

Abstract

Activation of central 5-hydroxytryptamine (5-HT₄) receptors may enhance cognitive performance. In the present study, the effects of two novel, potent and selective 5-HT₄ receptor agonists, RS 67333 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone) and RS 67506 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]-1-propanone), were studied in a rat model of spatial learning and memory; the Morris water maze. RS 67333 (0.1, 10 and 1000 μg/kg, intraperitoneally (i.p.)), a highly potent, selective and hydrophobic 5-HT₄ receptor agonist, reversed the decrements in cognitive performance induced by atropine (30 mg/kg, i.p.). By contrast, no effect was seen to RS 67506 (0.1, 10 and 1000 μg/kg, i.p.), a hydrophilic 5-HT₄ receptor agonist, of equivalent potency and selectivity to RS 67333. This differential effect may reflect the enhanced ability of RS 67333 to enter the CNS, with respect to RS 67506.

The ameliorative actions of RS 67333 on cognitive dysfunction were abolished by prior treatment with a selective 5-HT₄ receptor antagonist, RS 67532 [1-(4-amino-5-chloro-2-(3,5-dimethoxy benzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg, i.p.]. When given alone, or in naive rats, RS 67532 (0.1, 10 and 1000 μg/kg, i.p.), was without effect. None of the compounds tested affected the swim speed at any of the doses used. In separate locomotor studies, RS 67532 reduced activity at 1 and 10 mg/kg, i.p., although no effect was seen with RS 67333 or RS 67506 (0.01–10 mg/kg, i.p.).

Section snippets

Rats

Male rats (Sprague-Dawley, 250–300 g; Charles River, MA, U.S.A.) were housed in pairs in a climate controlled colony-room on a 12 hr light:12 hr dark cycle (illuminated from 7.00 a.m. to 7.00 p.m.), with water and food freely available.

Water maze

The water maze consisted of a black polyethylene tub (122 cm in diameter × 46 cm in height). A small glass Plexiglas platform (12 × 12 cm) positioned inside the tub, submerged 2 cm below the surface of the water, was the only structure within the reach of the

Morris water maze studies

Effects of atropine. In all studies, treatment with atropine produced a severe performance deficit in the water maze. These findings were similar to those seen in previous studies from our group using this paradigm (Fontana et al. (1995), Fontana et al. (1996)). Thus, the atropine treated group had significantly longer escape latencies than the vehicle treated group on each of the test days (F(1,15) = 10, p < 0.01 on day 1; F(1,14) = 58.6, p < 0.01 on day 2; Table 2; Fig. 2). With repeated

DISCUSSION

5-HT₄ receptor activation may play a role in cognition (see Bockaert et al. (1994)and Eglen et al. (1995a)for reviews). Few studies have been undertaken using selective 5-HT₄ receptor ligands, although Letty et al. (1997)have recently shown that activation of 5-HT₄ receptors improve rat social olfactory memory. In the present study, we have assessed the action of two selective and potent 5-HT₄ receptor agonists, RS 67333 and RS 67506, and a selective 5-HT₄ receptor antagonist RS 67532, in a rat

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The Effects of Novel, Selective 5-Hydroxytryptamine (5-HT)4 Receptor Ligands in Rat Spatial Navigation

Abstract

Section snippets

Rats

Water maze

Morris water maze studies

DISCUSSION

BioOrgan. Med. Chem. Lett.

BioOrgan. Med. Chem. Lett.

BioOrgan. Med. Chem. Lett.

BioOrgan. Med. Chem. Lett.

Trends Pharmac. Sci.

Neuropharmacology

Life Sci.

Neuropharmacology

BioOrgan. Med. Chem. Lett.

Neuropharmacology

J. Neurosci. Meth.

Neurobiol. Aging

Eur. J. Pharmacol.

cAMP-dependent, long lasting inhibition of a K+ current in mammalian neurons

Proc. natn Acad. Sci. U.S.A.

5-HT4 receptors: potential for therapeutic implications in neurology and psychiatry

CNS Drugs

Zacopride and BRL 24924 induce an increase in EEG-energy in rats

Br. J. Pharmac.

The Effects of Novel, Selective 5-Hydroxytryptamine (5-HT)₄ Receptor Ligands in Rat Spatial Navigation

cAMP-dependent, long lasting inhibition of a K⁺ current in mammalian neurons

5-HT₄ receptors: potential for therapeutic implications in neurology and psychiatry