SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

“…However, by comparing directly the percent time spent in the new arm with reference to a random exploration (random choice level of 33.33%) for the 60-min ITI (Figures 4a and b), one can conclude there is a rather small effect of SB-271046 on both 12-and 18-month-old mice. Though no other work has evaluated the effect of 5-HT6R blockade on the consolidation of spatial recognition memory in aged animals, our results are consistent with previous studies in the rat that demonstrate an improvement of task acquisition and recall in a spatial learning paradigm in 20-and 22-month-old rats following acute or chronic 5-HT6R antagonism (Foley et al, 2004;Hirst et al, 2006). These age-related deficits, consistent with previous studies on spatial memory (Bach et al, 1999;Barnes, 1979;Pelleymounter, 1988, Gower andLamberty, 1993;Granger et al, 1996), are attributable to dysfunctions in memory processes on the basis that impaired locomotor activity in the two-trial place recognition test in the Y-maze could not be mistaken for a memory deficit because the test is based on the choice between a novel place and familiar places (Dellu et al, 1992(Dellu et al, , 2000 and the percentage of time spent in exploration is used as the measure.…”

“…Thus, we first evaluated in young adult mice the effects of selective blockade of 5-HT6R by SB-271046 (Bromidge et al, 1999;Routledge et al, 2000) on acquisition, consolidation, and retrieval of spatial recognition memory in the two-trial place recognition task in the Y-maze (Dellu et al, 1992(Dellu et al, , 2000. Because (1) aging is associated with spatial learning impairment attributed to deficiency of information consolidation in the hippocampus (Barnes, 1979;Friedman et al, 2007;Gallagher et al, 1993), (2) memory consolidation has been associated with changes in 5-HT6R levels (Meneses et al, 2007), and (3) very few studies have evaluated the role of 5-HT6R in spatial memory in aged rodents (Foley et al, 2004;Hirst et al, 2006), we also investigated, in a second set of experiments, the effects of blockade of 5-HT6R on consolidation of spatial recognition memory in adult and aged mice.…”

“…Such a hypothesis is further supported by experimental studies showing that 5-HT6R antagonism promotes cognitive processes in the rat. In the Morris water maze paradigm, the selective 5-HT6R antagonists Ro 04-6790, SB-271046, SB-357134, and SB-399885 improved spatial reference memory retrieval in adult rats (Rogers and Hagan, 2001;Stean et al, 2002;Woolley et al, 2001) as well as the acquisition and retrieval of spatial reference memory in aged rats (Foley et al, 2004;Hirst et al, 2006). In the object discrimination task, Ro 04-6790 and SB-271046 increased the acquisition and consolidation of recognition memory in adult rats King et al, 2004), whereas BGC20-761, another 5-HT6R antagonist improved the consolidation of recognition memory in mature rats (Mitchell et al, 2006).…”

Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

“…Furthermore, 5-HT 6 receptor antagonists have been reported to increase the extracellular levels of acetylcholine in hippocampus and cortex and counteract cognitive impairment induced by muscarinic receptor blockade. Thus, inhibition of cholinergic function may interfere with the expression of effects mediated by 5-HT 6 receptor antagonism (see Mitchell and Neumaier, 2005;Hirst et al, 2006).…”

Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

“…In particular, it is widely reported to be located in brain regions associated with learning and memory such as the cerebral cortex, the hippocampus and the striatum 6 . It has been demonstrated that antagonism of the 5-HT 6 receptor modulates the release of a wide variety of neurotransmitters including elevation of extracellular levels of both glutamate and acetylcholine in brain regions such as the medial prefrontal cortex and the hippocampal formation 7,8 . This modulatory activity suggests potential utility for 5-HT 6 receptor antagonists in the treatment of cognitive impairments associated with Alzheimer's disease and schizophrenia.…”