E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat.
OBJECTIVE
In rats, 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists improve learning and memory, but the effects of agonists are poorly defined. This study investigated the effects of 5-HT(6) receptor agonists and antagonists on a rodent model of recognition memory.


METHODS
Selective 5-HT(6) receptor agonists and antagonists were administered either alone, after a scopolamine-induced impairment, or combined with sub-effective doses of the acetylcholinesterase inhibitor, donepezil, or the glutamate NMDA receptor antagonist, memantine, in a novel object discrimination paradigm in adult rats.


RESULTS
After a 4-h inter-trial delay to induce natural forgetting, vehicle-treated rats spent an equivalent time exploring novel and familiar objects during the choice trial. The 5-HT(6) receptor agonists, E-6801 (1.25-10 mg/kg i.p.) and EMD-386088 (5-10 mg/kg i.p.), and antagonists, SB-271046 and Ro 04-6790 (5 and 10 mg/kg), along with donepezil (0.1-3 mg/kg) and memantine (5-20 mg/kg) all produced significant and mostly dose-dependent increases in novel object exploration, indicative of memory enhancement. Furthermore, sub-effective doses of E-6801 (1 mg/kg) when co-administered with either SB-271046 (3 mg/kg), donepezil (0.1 mg/kg) or memantine (5 mg/kg), and EMD-386088 (2 mg/kg) co-administered with SB-271046 (3 mg/kg) also significantly enhanced object-recognition memory. Additionally, using a 1-min inter-trial delay, E-6801 (2.5 and 5 mg/kg) was as effective as donepezil (0.3 and 1 mg/kg) in reversing a scopolamine-induced (0.5 mg/kg) impairment in object recognition.


CONCLUSIONS
This is the first study to demonstrate that E-6801, a potent 5-HT(6) receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission.
Kendall
Ian
I
Institute of Neuroscience, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham Medical School, Nottingham, UK.
Slotten
Helge A
HA
Codony
Xavier
X
Burgueño
Javier
J
Pauwels
Peter J
PJ
Vela
Jose M
JM
Fone
Kevin C F
KC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051381:Rats; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
C558329:6-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)imidazo(2,1-b)thiazole-5-sulfonamide; D007211:Indoles; D011950:Receptors, Cholinergic; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013844:Thiazoles; C097216:serotonin 6 receptor
Psychopharmacology (Berl). 2001 Nov;158(2):114-9
11702084
Pharmacol Biochem Behav. 2001 Jul-Aug;69(3-4):493-502
11509209
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):185-95
12551743
Neuropsychopharmacology. 2002 May;26(5):583-94
11927183
Science. 1992 Dec 18;258(5090):1903-10
1361685
J Pharmacol Exp Ther. 2004 Nov;311(2):677-82
15192085
J Med Chem. 1999 Jan 28;42(2):202-5
9925723
Neuropsychopharmacology. 2005 Dec;30(12):2169-79
15957009
Behav Brain Res. 2001 Jan 8;118(1):107-10
11163639
Neuropharmacology. 2006 Mar;50(4):412-20
16298400
J Pharmacol Exp Ther. 2005 Sep;314(3):1274-89
15951399
Neuropharmacology. 2008 Nov;55(6):1015-22
18655798
J Med Chem. 2000 Mar 9;43(5):1011-8
10715164
Psychopharmacology (Berl). 2009 Jan;202(1-3):111-23
18839151
J Pharmacol Exp Ther. 2003 Nov;307(2):682-91
12975483
J Neurosci. 2007 Apr 11;27(15):4201-9
17428998
Neuropsychopharmacology. 2004 Jan;29(1):93-100
14571256
Pharmacol Biochem Behav. 1994 Dec;49(4):859-69
7886099
Psychopharmacology (Berl). 2008 Jan;196(1):93-104
17922111
Br J Pharmacol. 2006 Aug;148(7):973-83
16783408
Eur Neuropsychopharmacol. 2007 Mar;17(4):277-88
16989988
Neuropharmacology. 2007 Apr;52(5):1274-83
17320917
Behav Brain Res. 2008 Dec 16;195(1):112-9
18191236
Pharmacol Biochem Behav. 2005 Jul;81(3):673-82
15964617
J Neurochem. 1996 Jan;66(1):47-56
8522988
J Pharmacol Toxicol Methods. 2007 Mar-Apr;55(2):144-50
16769227
Behav Brain Res. 2005 Jan 6;156(1):139-43
15474658
Br J Pharmacol. 2006 Aug;148(8):1133-43
16865095
Eur J Pharmacol. 1997 May 1;325(2-3):173-80
9163564
J Med Chem. 2005 Jan 27;48(2):353-6
15658848
Mol Pharmacol. 1993 Mar;43(3):320-7
7680751
Neuropharmacology. 2001 Dec;41(7):844-53
11684148
Trends Pharmacol Sci. 2008 Sep;29(9):482-92
19086256
Pol J Pharmacol. 2003 Sep-Oct;55(5):903-10
14704485
Neuropharmacology. 2007 Nov;53(6):699-723
17904591
J Pharmacol Exp Ther. 2004 Jun;309(3):1154-9
14764659
Curr Top Med Chem. 2002 Jun;2(6):643-54
12052198
J Comp Neurol. 1999 Aug 9;410(4):586-98
10398050
Br J Pharmacol. 1999 Apr;126(7):1537-42
10323584
Neuropsychopharmacology. 2001 Nov;25(5):662-8
11682249
Bioorg Med Chem Lett. 2005 Oct 1;15(19):4230-4
16055331
Neurosci Biobehav Rev. 2008 Aug;32(6):1087-102
18423591
J Comp Neurol. 1996 Jul 01;370(3):405-14
8799865
J Physiol Paris. 1996;90(5-6):337-8
9089508
Assay Drug Dev Technol. 2003 Apr;1(2):291-303
15090194
Drug Discov Today. 2006 Apr;11(7-8):283-99
16580970
Eur J Pharmacol. 2006 Dec 28;553(1-3):109-19
17069795
Brain Res Mol Brain Res. 1996 Apr;37(1-2):145-50
8738145
Neurobiol Learn Mem. 2006 Mar;85(2):132-8
16242977
Neurotox Res. 2004;6(2):153-8
15325968
Eur J Neurosci. 2006 Sep;24(5):1299-306
16987217
Drug News Perspect. 2001 Sep;14(7):396-400
12813582
J Med Chem. 2005 Mar 24;48(6):1781-95
15771424
Neuropharmacology. 2001 Aug;41(2):210-9
11489457
Biochem Biophys Res Commun. 1993 May 28;193(1):268-76
8389146
Psychopharmacology (Berl). 2005 Feb;177(4):381-90
15630588
Curr Drug Targets CNS Neurol Disord. 2004 Feb;3(1):59-79
14965245
Brain Res. 1999 Nov 20;847(2):221-30
10575091
Psychopharmacology (Berl). 2010 Jan;208(1):13-21
19902184
Pharmacol Biochem Behav. 2002 Apr;71(4):645-54
11888556
Psychopharmacology (Berl). 2003 Dec;170(4):358-67
13680084
Behav Brain Res. 2005 Apr 30;159(2):287-93
15817191
Neuroscience. 2007 Jul 13;147(3):778-85
17560041
Pharmacol Ther. 2005 Dec;108(3):320-33
16005519
Br J Pharmacol. 1998 Jun;124(3):556-62
9647481
Neuropharmacology. 2004 Aug;47(2):195-204
15223298
Neuropsychopharmacology. 2008 May;33(6):1323-35
17625499
Psychopharmacology (Berl). 2005 Sep;181(2):253-9
15846482
Br J Pharmacol. 2000 May;130(1):23-6
10780993
J Biol Chem. 2003 Nov 28;278(48):47610-21
13129934
J Pharmacol Exp Ther. 2002 Aug;302(2):731-41
12130738
Curr Opin Pharmacol. 2006 Feb;6(1):61-7
16368266
Behav Brain Res. 1988 Nov 1;31(1):47-59
3228475
Neurobiol Learn Mem. 2003 Sep;80(2):113-22
12932426
J Med Chem. 2003 Mar 27;46(7):1273-6
12646038
Pharmacol Biochem Behav. 2006 Oct;85(2):298-306
17045636
J Biol Chem. 2007 Feb 23;282(8):5496-505
17189269