Effects of 5‐HT₆ receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat

Abstract

Background and purpose: The beneficial effect of 5-HT 6 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-HT 6 receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergicmediated) deficits. Experimental approach: 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. Key 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 and implications: These data suggest a potential therapeutic role of 5-HT 6 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.

Chronic activation of 5-HT4 receptors or blockade of 5-HT6 receptors improve memory performances

“…While never investigated after chronic activation of 5-HT 4 R before, this result is in accordance with a study assessing locomotor activity after chronic treatment with SB-271046 [58].…”

Inhibition of Nicotine Dependence by Curcuminoid Is Associated with Reduced Acetylcholinesterase Activity in the Mouse Brain

“…Thus, it is possible that AChE inhibition by curcuminoid may increase or enhance the interoceptive cues of nicotine by activating α4β2 nAChRs and reducing subsequent nicotine consumption. Additionally, proposed that the effect of acute AChE inhibition on nicotine self-administration in rats indicates that increased cholinergic transmission is a prerequisite for the elimination of nicotine reinforcement [37] and repairing cognitive impairment [38].…”

Amyloid beta: structure, biology and structure-based therapeutic development

“…Voltage-gated calcium channel blockers, such as verapamil, diltiazem, isradipine and nimodipine, protect cultured neurons from Aβ-induced toxicity and thus could be potential candidates for treating Alzheimer's disease [324] . The 5-HT6 receptor antagonist idalopirdine, in combination with a cholinesterase inhibitor, may also increase cognitive function [325] . Huperzine A [326,327] , 2,2',4'-trihydroxychalcone (TDC) [328] and bis(7)-cognitin [329] exhibit neuroprotective effects.…”