title: Blockade of 5-HT 1B receptors facilitates contextual aversive learning in mice by disinhibition of cholinergic and glutamatergic neurotransmission.
abstract: 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 (0.1-1.0mg/kg) before PA training impaired retention performance 24h later. Combined administration of anpirtoline with the selective 5-HT(1B) receptor antagonist NAS-181 (0.1-1.0mg/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 (0.1mg/kg), when administered prior to, but not after, scopolamine. In addition, NAS-181 attenuated PA impairments induced by MK-801 (0.3mg/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.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Therese M
authors.initials: TM
authors.lastname: Eriksson
authors.forename: Nather
authors.initials: N
authors.lastname: Madjid
authors.forename: Elin
authors.initials: E
authors.lastname: Elvander-Tottie
authors.forename: Oliver
authors.initials: O
authors.lastname: Stiedl
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.forename: Sven Ove
authors.initials: SO
authors.lastname: Ogren
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology*; D012601:Scopolamine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: C112429:2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine; D001578:Benzopyrans; D018680:Cholinergic Antagonists; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D010880:Piperidines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C058376:anpirtolin; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D012601:Scopolamine; D000109:Acetylcholine