Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat.
OBJECTIVE
The beneficial effect of 5-HT6 receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT6 receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits.


METHODS
The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046.


RESULTS
Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046.


CONCLUSIONS
These data suggest a potential therapeutic role of 5-HT6 receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer's disease and schizophrenia.
Marcos
B
B
Department of Pharmacology, University of Navarra, Pamplona, Spain.
Chuang
T T
TT
Gil-Bea
F J
FJ
Ramirez
M J
MJ
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005702:Galantamine / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D015000:Yawning / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013876:Thiophenes; C097216:serotonin 6 receptor; D005702:Galantamine; D016291:Dizocilpine Maleate; D012601:Scopolamine; C117443:SB 271046