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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
µl 1 · 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
Copyright © 2001 Society for Neuroscience 0270-6474/01/2193207-08$05.00/0
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