title: Nucleus incertus contributes to an anxiogenic effect of buspirone in rats: Involvement of 5-HT1A receptors.
abstract: The nucleus incertus (NI), a brainstem structure with diverse anatomical connections, is implicated in anxiety, arousal, hippocampal theta modulation, and stress responses. It expresses a variety of neurotransmitters, neuropeptides and receptors such as 5-HT1A, D2 and CRF1 receptors. We hypothesized that the NI may play a role in the neuropharmacology of buspirone, a clinical anxiolytic which is a 5-HT1A receptor partial agonist and a D2 receptor antagonist. Several preclinical studies have reported a biphasic anxiety-modulating effect of buspirone but the precise mechanism and structures underlying this effect are not well-understood. The present study implicates the NI in the anxiogenic effects of a high dose of buspirone. Systemic buspirone (3 mg/kg) induced anxiogenic effects in elevated plus maze, light-dark box and open field exploration paradigms in rats and strongly activated the NI, as reflected by c-Fos expression. This anxiogenic effect was reproduced by direct infusion of buspirone (5 μg) into the NI, but was abolished in NI-CRF-saporin-lesioned rats, indicating that the NI is present in neural circuits driving anxiogenic behaviour. Pharmacological studies with NAD 299, a selective 5-HT1A antagonist, or quinpirole, a D2/D3 agonist, were conducted to examine the receptor system in the NI involved in this anxiogenic effect. Opposing the 5-HT1A agonism but not the D2 antagonism of buspirone in the NI attenuated the anxiogenic effects of systemic buspirone. In conclusion, 5-HT1A receptors in the NI contribute to the anxiogenic effect of an acute high dose of buspirone in rats and may be functionally relevant to physiological anxiety.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117600, Singapore; Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore; Singapore Institute for Neurotechnology (SINAPSE), 117456, Singapore; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, 117456, Singapore.
authors.forename: Jigna Rajesh
authors.initials: JR
authors.lastname: Kumar
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117600, Singapore; Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore; Singapore Institute for Neurotechnology (SINAPSE), 117456, Singapore.
authors.forename: Ramamoorthy
authors.initials: R
authors.lastname: Rajkumar
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117600, Singapore; Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore; Singapore Institute for Neurotechnology (SINAPSE), 117456, Singapore.
authors.forename: Liying Corinne
authors.initials: LC
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117600, Singapore; Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore; Singapore Institute for Neurotechnology (SINAPSE), 117456, Singapore; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, 117456, Singapore. Electronic address: gavin_dawe@nuhs.edu.sg.
authors.forename: Gavin S
authors.initials: GS
authors.lastname: Dawe
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001007:Anxiety / Q000188:drug therapy* / Q000523:psychology; D002065:Buspirone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D057967:Infusions, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D014151:Anti-Anxiety Agents; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D002065:Buspirone
keywords: 5-HT(1A) receptors; Anxiogenic; Buspirone; D(2) receptors; Nucleus incertus