BIMU 1 and RS 67333, two 5-HT4 receptor agonists, modulate spontaneous alternation deficits induced by scopolamine in the mouse.

The present study was conducted to determine the effects of two potent 5-HT4 receptor agonists, BIMU 1 (1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo (3.2.1)-oct-3-yl]-2-oxo-1H) benzimidazole-1-carboxamide hydrochloride; 1, 3, 10 mg/kg, i.p.) and RS 67333 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone; 0.25, 0.5, 1 mg/kg, i.p.) on the learning impairment induced by the muscarinic acetylcholine receptor antagonist, scopolamine (1 mg/kg) in mice. Working memory was examined by observing spontaneous alternation behavior in the Y-maze test. Both BIMU 1 (10 mg/kg) and RS 67333 (1 mg/kg) prevented the scopolamine-induced alternation deficits, whereas no effect could be evidenced on locomotor or emotional indices. The reversal actions of BIMU 1 and RS 67333 on this cognitive dysfunction were abolished by the selective 5-HT4 receptor antagonist GR 125487 (1-[2-[(methyl sulfonyl)-amino]-ethyl]-4-piperidinyl-methyl-5-fluoro-2-methoxy-1H-indole-3-carboxylate; 10 mg/kg, i.p.). When given alone at the same doses, none of the three serotonergic agents had any measurable effect. These results demonstrate the ability of 5-HT4 receptor agonists to reverse spontaneous working memory deficits and further confirm the therapeutic potential of such ligands in the treatment of cognitive alterations that associate short-term working memory disorders and cholinergic hypofunction.

New benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives as selective antagonists of 5-HT4 receptors: binding profile and pharmacological characterization.

A series of benzo[h][1,6]naphthyridine and azepino[3,2-c]quinoline derivatives were prepared and evaluated to determine the necessary requirements for high affinity on the 5-HT(4) receptors and high selectivity versus other receptors. The compounds were synthesized by substituting the chlorine atom of benzonaphthyridines and azepinoquinolines with various N-alkyl-4-piperidinylmethanolates. They were evaluated in binding assays with [(3)H]GR 113808 as the 5-HT(4) receptor radioligand. The affinity values (K(i) or inhibition percentages) depended upon the substituent on the aromatic ring on one hand and the substituent on the lateral piperidine chain on the other hand. A chlorine atom produced a marked drop in activity while a N-propyl or N-butyl group gave compounds with nanomolar affinities (1 < K(i) < 10 nM). Among the most potent ligands (3a, 4a, 5a), 4a was selected on the basis of its high affinity and selectivity for pharmacological screening and was evaluated in vivo in specific tests. This compound reveals itself as an antagonist/low partial agonist in the COS-7 cells stably expressing the 5-HT(4(a)) receptor. Derivative 4a also showed in vivo potent analgesic activity in the writhing test at very low doses.

Chronic ethanol consumption induces tolerance to the spatial memory impairing effects of acute ethanol administration in rats.

A large number of studies in rats have investigated the effects of acute and chronic ethanol administration on performance on many spatial learning and memory tasks. However, no study has addressed the problem of whether chronic ethanol consumption induces tolerance to acute ethanol-induced spatial memory deficits. In this study, we analyzed the behavioral effects of acute ethanol administration on spatial memory and locomotor activity in rats chronically intoxicated by ethanol. Male Sprague-Dawley rats were given as their only available liquid source a 10% (v/v) aqueous ethanol solution for 2 weeks before behavioral testing and during the 1-week behavioral testing period. They were treated intraperitoneally with 1.5 g/kg of ethanol 30 min before daily training in the Morris water maze, a spatial memory task sensitive to hippocampal damage. Our results demonstrate that learning and spatial memory of ethanol-consuming animals were not altered compared with control rats. Chronic ethanol consumption had no effect on spatial reference memory in terms of either the distance traveled to find the hidden platform during the acquisition phase of the experiment, or the time spent in the training quadrant during the retention trial. Acute ethanol administration impaired spatial memory in control rats and this impairment was reversed in chronic ethanol-consuming animals, revealing that chronic ethanol consumption did induce tolerance to the spatial memory deficits induced by acute ethanol injection, although plasma ethanol levels did not differ between the two groups. In contrast, chronic ethanol consumption did not induce tolerance to the acute ethanol-induced stimulatory locomotor activity measured in the same animals. Our results, therefore, indicate that chronic ethanol consumption induces tolerance to the cognitive impairing effects, but not to the locomotor stimulatory effects of acute ethanol administration in rats, suggesting that these two behavioral effects of ethanol do not share a common mechanism in the CNS.