sb-271046 and Memory-Disorders

Schizophrenia is a serious mental disorder that affects 1% of the world's population. Although various therapeutic tools have been developed since the appearance of the first generation of antipsychotics, the effect of these agents does not manage to attenuate a significant part of psychotic symptoms. Ketamine is an anesthetic agent able to produce psychotic-like symptoms through the antagonism of the glutamatergic N-methyl-d-aspartic acid (NMDA) receptors (NMDARs). This drug has been widely used to study new pharmacological tools with potential antipsychotic properties. On the contrary, it is known that the 5-HT6 receptor agonist and antagonist drugs induce procognitive, anxiolytic and antidepressant effects in different preclinical models. Therefore, the aim of this study was to evaluate the behavioral actions of the 5-HT6 receptors' agonist E-6837 and the antagonist SB-271046, in ICR-CD1 mice previously treated with a subchronic ketamine scheme (10 mg/kg i.p. daily for 5 days). Results showed that repeated administration of ketamine induced recognition memory deficit, anxiogenic effects, obsessive-compulsive behaviors and stereotyped movements. The acute administration of both 5-HT6 agents reversed the memory deficit and induced a decrease in anxiety, whereas SB-271046 administration produced a decrease in climbing behavior. The injection of either of these 5-HT6 drugs had no effect in the light-dark test. Surprisingly, when these drugs were injected together with ketamine, anxiogenic actions were produced. Current findings suggest that both agonist and antagonist 5-HT6 drugs play an important role in modulating psychotic-like symptoms induced by the subchronic blockade of NMDAR.

Topics: Animals; Antipsychotic Agents; Humans; Indoles; Ketamine; Memory Disorders; Mice; Mice, Inbred ICR; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sulfonamides; Thiophenes

Blockade of 5-HT6 receptors (5-HT6R) is known to improve cognitive performances in the rodent. This improvement has been hypothesized to be the result, at least in part, of a modulation of the cholinergic neurotransmission.. We assessed the effects of 5-HT6R blockade on selected types of memory relevant to functional deficits of ageing and neurodegenerative diseases, in mice that present a scopolamine-induced cholinergic disruption of memory.. Following the selection of an adequate dose of scopolamine to induce cognitive deficits, we have studied the effects of the selective 5-HT6R antagonist SB-271046, alone or in combination with scopolamine, on working memory (spontaneous alternation task in the T-maze), recognition memory (place recognition) and aversive learning (passive avoidance).. SB-271046 alone failed to affect working memory, recognition memory and aversive learning performances. In contrast, SB-271046 was able to reverse the scopolamine-induced deficits in working memory (only at 30 mg kg⁻¹) and those of acquisition and retrieval of aversive learning (dose-dependent effect); scopolamine-induced deficits in episodic-like memory (acquisition and retrieval) were partially counteracted by 5-HT6R blockade.. The modulation between 5-HT6R and the cholinergic system appears to be predominant for working memory and aversive learning, but not for other types of memory (i.e. episodic-like memory). Interactions between 5-HT6R and alternative neurotransmission systems (i.e. glutamatergic system) should be further studied. The respective involvement of these interactions in the memory disorders related to ageing and neurodegenerative diseases is of pivotal importance regarding the possible use of 5-HT6R antagonists in the treatment of memory disorders in humans.

Topics: Animals; Avoidance Learning; Cholinergic Antagonists; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Memory Disorders; Memory, Short-Term; Mice; Receptors, Serotonin; Scopolamine; Serotonin Antagonists; Sulfonamides; Thiophenes

Studies have shown that the blockade of 5-HT6 receptors (5-HT6R) can improve memory processes and reverse age-related spatial episodic like memory deficits. Since normal aging in the human is associated with a decline in episodic and working memory, we assessed the effect of the 5-HT6R blockade (SB-271046) on recognition memory (object recognition task) (a component of episodic like memory) in parallel to working memory (spontaneous alternation task in the T-maze) performances in young, adult, aged and senescent mice. Deficits in consolidation of non spatial recognition memory that were observed in 17- and 21-month-old mice were found to be reversed by 5-HT6R blockade. Deficits in working memory performances were only apparent as late as at 25 months of age; again, these deficits were reversed by 5-HT6R blockade. This study revealed in the mouse that, as in humans, working memory is more lately altered than recognition memory during aging and that such memory deficits could be counteracted by the use of 5-HT6R antagonists.

Topics: Age Factors; Analysis of Variance; Animals; Exploratory Behavior; Female; Memory Disorders; Memory, Short-Term; Mice; Neuropsychological Tests; Reaction Time; Receptors, Serotonin; Recognition, Psychology; Serotonin Antagonists; Sulfonamides; Thiophenes