Blockade of 5-HT_1B receptors facilitates contextual aversive learning in mice by disinhibition of cholinergic and glutamatergic neurotransmission

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• 作者：Therese M. Eriksson ; Nather Madjid ; Elin Elv ; er-Tottie ; Oliver Stiedl ; Per Svenningsson ; Sven Ove Ö ; gren
• 关键词：Contextual learning ; Memory ; Passive avoidance ; 5-HT_1B receptor ; Acetylcholine ; Glutamate
• 刊名：Neuropharmacology
• 出版年：2008
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：June 2008
• 卷：54
• 期：7
• 页码：1041-1050
• 文件大小：519 K

摘要

Serotonergic (5-HT) neurotransmission plays a role in learning and memory processes, but the physiological role of various receptor subtypes is not well characterised. Among these, 5-HT_1B receptors are located as autoreceptors on 5-HT axons and heteroreceptors on non-serotonergic terminals. This study examined the role of the 5-HT_1B receptor in one-trial aversive contextual learning using the passive avoidance (PA) task in NMRI mice. Subcutaneous administration of the 5-HT_1B receptor agonist anpirtoline (0.1–1.0 mg/kg) before PA training impaired retention performance 24 h later. Combined administration of anpirtoline with the selective 5-HT_1B receptor antagonist NAS-181 (0.1–1.0 mg/kg) fully blocked the impairments. Administration of NAS-181 alone dose-dependently improved PA retention performance. This facilitatory effect was blocked by subthreshold doses of both the muscarinic antagonist scopolamine (0.03 mg/kg) and the NMDA receptor antagonist MK-801 (0.03 mg/kg). NAS-181 also fully blocked the PA impairments induced by an amnesic dose of scopolamine (0.1 mg/kg), when administered prior to, but not after, scopolamine. In addition, NAS-181 attenuated PA impairments induced by MK-801 (0.3 mg/kg). These findings indicate that 5-HT_1B receptors are activated at basal levels of 5-HT transmission. The facilitatory effect of NAS-181 involved alleviation of an inhibitory 5-HT tone mediated via 5-HT_1B receptors on cholinergic and glutamatergic transmission. This disinhibition is expected to occur in neuronal circuits involved in contextual learning including the hippocampus and interconnected cortico-limbic regions. Blockade of brain 5-HT_1B heteroreceptors may represent a novel therapeutic strategy for restoration of deficient cholinergic and glutamatergic neurotransmission contributing to memory disorders.