The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats.
The highly potent and selective 5-HT(6) receptor antagonist SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide] has previously been demonstrated to improve retention significantly in a spatial water maze paradigm in adult rats. However, SB-271046 did not have any effect on task acquisition. As these apparently contradictory findings may be reconciled by a prime influence of SB-271046 on memory consolidation, the ability of this compound to reverse the discrete temporal action of a cholinergic antagonist in the 6-h period following passive avoidance training was investigated. SB-271046, given orally, by gavage, 30 min prior to training Wistar rats in a step-through, light-dark passive avoidance task, was found to reverse significantly the amnesia produced by administering scopolamine (0.8 mg/kg, intraperitoneal) in the 6-h post-training period. The effect was dose-dependent over a range of 3-20 mg/kg. Further, we investigated the cognition-enhancing effects of chronic SB-271046 administration (10 or 20 mg/kg/day; 40 days) on the acquisition and consolidation of a water maze spatial learning task in a population of 20-month-old Wistar rats with age-related learning deficits. Drug treatment progressively and significantly decreased platform swim angle and escape latencies over the five sequential trials on four consecutive daily sessions compared to vehicle-treated controls. SB-271046 also improved task recall as measured by significant increases in the searching of the target quadrant on post-training days 1 and 3, when the animals would have been substantially drug-free. This significant improvement of task recall suggests SB-271046, in addition to inducing symptomatic cognition-enhancing actions, also attenuates age-related decline in neural function.
Department of Pharmacology, Conway Institute, University College Dublin, Belfield, Ireland.
Andrew G
AG
Foley
Keith J
KJ
Murphy
Warren D
WD
Hirst
Helen C
HC
Gallagher
Jim J
JJ
Hagan
Neil
N
Upton
Frank S
FS
Walsh
Ciaran M
CM
Regan
D000284:Administration, Oral; D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D011985:Receptors, Serotonin / Q000378:metabolism*; D012601:Scopolamine; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013037:Spatial Behavior / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D013550:Swimming; D013876:Thiophenes / Q000494:pharmacology*
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D013876:Thiophenes; C097216:serotonin 6 receptor; D012601:Scopolamine; C117443:SB 271046