title: 5-HT1A receptor agonist flesinoxan enhances Fos immunoreactivity in rat central amygdala, bed nucleus of the stria terminalis and hypothalamus.
abstract: 5-Hydroxytryptamine-1A (5-HT1A) receptor agonists, including flesinoxan, reduce anxiety and activate the hypothalamus-pituitary-adrenal (HPA) axis under basal conditions. In order to investigate the underlying neural mechanisms we investigated immunoreactivity for the immediate early gene protein product Fos (Fos-ir) in rat brains 1 h after flesinoxan treatment (0.0, 0.3 or 3.0 mg/kg p.o.). Typically, 5-HT1A receptor-containing brain areas, such as the dorsal raphe nuclei, hippocampus, septum, diagonal band and the cortical and basomedial amygdala, do not show Fos-ir. Apparently, binding of flesinoxan at the 5-HT1A receptor does not directly lead to activation of c-fos in the cell, probably due to its negative coupling to adenylate cyclase. However, in typically non-5HT1A receptor-containing brain areas Fos-ir is increased due to flesinoxan treatment, as in the paraventricular nucleus of the hypothalamus (PVN), the dorsolateral part of the bed nucleus of the stria terminalis (BNSTdl) and the central amygdala (CeA). Flesinoxan-treated rats also exhibited higher plasma corticosterone levels than vehicle-treated animals, which suggests the involvement of corticotropin-releasing hormone (CRH) or vasopressin in the hypothalamus. After double immunolabelling (Fos/CRH or Fos/vasopressin), every CRH neuron detected in the PVN also contained Fos. Moreover, a significant correlation existed between the number of Fos-ir neurons in the PVN and the plasma corticosterone level. Hardly any Fos/vasopressin double labelling was visible in the PVN. Accordingly, flesinoxan exerts its activating effects on the HPA axis via CRH neurons in the PVN. These effects are trans-synaptically mediated by other brain areas, such as the CeA and BNSTdl, which also show increased Fos-ir.
authors.affiliation: Department of Psychopharmacology, Faculty of Pharmacy, Rudolf Magnus Institute for Neurosciences, Utrecht University, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Compaan
authors.forename: L
authors.initials: L
authors.lastname: Groenink
authors.forename: J
authors.initials: J
authors.lastname: van der Gugten
authors.forename: R A
authors.initials: RA
authors.lastname: Maes
authors.forename: B
authors.initials: B
authors.lastname: Olivier
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000032:analysis; D016762:Genes, fos; D007031:Hypothalamus / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D015999:Multivariate Analysis; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009928:Organ Specificity; D010879:Piperazines / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013788:Thalamus / Q000378:metabolism; D014667:Vasopressins / Q000032:analysis
chemical_list: D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D014667:Vasopressins; C056895:flesinoxan; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone