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The Journal of Neuroscience, May 1, 2001, 21(9):3207-3214

Anxiolytic and Anti-Stress Effects of Brain Prolactin: Improved Efficacy of Antisense Targeting of the Prolactin Receptor by Molecular Modeling

Luz Torner, Nicola Toschi, Agnes Pohlinger, Rainer Landgraf, and Inga D. Neumann

Max Planck Institute of Psychiatry, 80804 Munich, Germany

We provide the first evidence that prolactin is a neuromodulator of behavioral and neuroendocrine stress coping in the rat. In virgin female and male rats, intracerebral infusion of ovine prolactin (oPRL) into the lateral cerebral ventricle (intracerebroventricular) exerted an anxiolytic effect on the elevated plus-maze in a dose-dependent manner (0.1 and 1.0 µg/5 µl; p < 0.01). In contrast, downregulation of the expression of the long form of brain prolactin receptors by chronic intracerebroventricular infusion of an antisense oligodeoxynucleotide (ODN) (osmotic minipump, 0.5 µg · 0.5 µl¹ · hr¹; 5 d) increased anxiety-related behavior on the plus-maze compared with mixed bases-treated and vehicle-treated rats (p < 0.01), again demonstrating an anxiolytic effect of PRL acting at brain level. Furthermore, in jugular vein-catheterized female rats, the stress-induced increase of corticotropin secretion was decreased after chronic intracerebroventricular infusion of oPRL (osmotic minipump, 1.0 µg · 0.5 µl¹ · hr¹; p < 0.05) and, in contrast, was further elevated by antisense targeting of the brain prolactin receptors (p < 0.01). This provides evidence for a receptor-mediated attenuation of the responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis by prolactin. The antisense ODN sequence was selected on the basis of secondary structure molecular modeling of the target mRNA to improve antisense ODN-mRNA hybridization. Receptor autoradiography confirmed the expected improvement in the efficacy of downregulation of prolactin receptor expression [empirically designed antisense, 30%; p > 0.05, not significant; adjustment of target position after mRNA modeling, 72%; p < 0.05). Taken together, prolactin acting at brain level has to be considered as a novel regulator of both emotionality and HPA axis reactivity.

Key words: ACTH; anxiety; choroid plexus; plus-maze; HPA axis; mRNA secondary structure

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2193207-08$05.00/0

This article has been cited by other articles:

				D. A. Slattery and I. D. Neumann No stress please! Mechanisms of stress hyporesponsiveness of the maternal brain J. Physiol., January 15, 2008; 586(2): 377 - 385. [Abstract] [Full Text] [PDF]

				I. C. Kokay, P. M. Bull, R. L. Davis, M. Ludwig, and D. R. Grattan Expression of the long form of the prolactin receptor in magnocellular oxytocin neurons is associated with specific prolactin regulation of oxytocin neurons Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2006; 290(5): R1216 - R1225. [Abstract] [Full Text] [PDF]

				T. Fujikawa, H. Soya, K. L. K. Tamashiro, R. R. Sakai, B. S. McEwen, N. Nakai, M. Ogata, I. Suzuki, and K. Nakashima Prolactin Prevents Acute Stress-Induced Hypocalcemia and Ulcerogenesis by Acting in the Brain of Rat Endocrinology, April 1, 2004; 145(4): 2006 - 2013. [Abstract] [Full Text] [PDF]

				I. D. Neumann, O. J. Bosch, N. Toschi, L. Torner, and A. J. Douglas No Stress Response of the Hypothalamo-Pituitary-Adrenal Axis in Parturient Rats: Lack of Involvement of Brain Oxytocin Endocrinology, June 1, 2003; 144(6): 2473 - 2479. [Abstract] [Full Text] [PDF]

				M. Heinrichs, G. Meinlschmidt, I. Neumann, S. Wagner, C. Kirschbaum, U. Ehlert, and D. H. Hellhammer Effects of Suckling on Hypothalamic-Pituitary-Adrenal Axis Responses to Psychosocial Stress in Postpartum Lactating Women J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4798 - 4804. [Abstract] [Full Text] [PDF]

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