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Tandospirone activates neuroendocrine and ERK (MAP kinase) signaling pathways specifically through 5-HT1A receptor mechanisms in vivo

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Abstract

Tandospirone, an azapirone, is a selective serotonin1A (5-HT1A) receptor agonist. The effects of tandospirone on plasma hormones and on mitogen-activated protein (MAP) kinase activity in the brain of male rats were studied. Tandospirone produced a time- and dose-dependent increase in plasma levels of oxytocin, adrenocorticotropin (ACTH), corticosterone, and prolactin. The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin, ACTH, and prolactin levels was 1.0 mg/kg (s.c.), while the minimal dose for corticosterone release was 3.0 mg/kg (s.c.). The ED50 of tandospirone was 1.3 mg/kg for oxytocin, 1.2 mg/kg for ACTH, 3.0 mg/kg for corticosterone, and 0.24 mg/kg for prolactin. Pretreatment with the specific 5-HT1A receptor antagonist WAY 100,635 (0.3 mg/kg, s.c.) completely blocked the effects of tandospirone on plasma levels of oxytocin, ACTH, and corticosterone but shifted the dose–response curve for prolactin to the right. Tandospirone injection (10 mg/kg, s.c.) stimulated the MAP kinase signaling cascade, specifically the phosphorylation of p42/44 extracellular signal-regulated kinase (ERK). Western blot analysis revealed a significant increase in phosphorylated ERK (p-ERK) levels in the hypothalamic paraventricular nucleus (PVN) as well as the dorsal raphé nucleus 5 min following tandospirone injection. These increases were blocked by pretreatment with WAY 100,635 (0.3 mg/kg). The results are the first evidence that systemic 5-HT1A receptor agonist administration produces a rapid increase in p-ERK levels in vivo, providing further insight into the signaling mechanisms of the 5-HT1A receptor.

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Abbreviations

ACTH:

Adrenocorticotropin

CRH:

Corticotropin-releasing hormone

ERK:

Extracellular signal-regulated kinase

MAP:

Mitogen-activated protein

PVN:

Paraventricular nucleus

p-ERK:

Phosphorylated extracellular signal-regulated kinase

5-HT:

Serotonin1A

5-HT1Areceptor:

Serotonin1Areceptor

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Acknowledgements

Unfortunately, during the preparation of this manuscript Louis “Loek” D. Van de Kar passed away. Loek’s love of science has been passed on to all who have been fortunate enough to work with him. He will be missed greatly. The authors gratefully acknowledge Dr. Julie Hensler for her helpful discussions and critical review of the manuscript. The authors would like to thank Vorarudee Charumas for her technical assistance and thoughtful questions. This research was supported in part by USPHS MH 58448 and NS34153

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  1. Nicole R. Sullivan

    Present address: Wyeth Neurosciences, 8000, Princeton, NJ, 08543, USA

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  1. Center for Serotonin Disorders Research and Department of Pharmacology, Stritch School of Medicine, Loyola University of Chicago, 2160 South First Avenue, Maywood, IL, 60153, USA

    Nicole R. Sullivan, James W. Crane, Katerina J. Damjanoska, Gonzalo A. Carrasco, Deborah N. D’Souza, Francisca Garcia & Louis D. Van de Kar

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Sullivan, N.R., Crane, J.W., Damjanoska, K.J. et al. Tandospirone activates neuroendocrine and ERK (MAP kinase) signaling pathways specifically through 5-HT1A receptor mechanisms in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 371, 18–26 (2005). https://doi.org/10.1007/s00210-004-1005-7

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