Rationale: 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.
Objective: 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.
Method: 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).
Results: 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.
Conclusion: 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.