Anxiolytic and anti-stress effects of brain prolactin: Improved efficacy of antisense targeting of the prolactin receptor by molecular modeling

We provide the first evidence that prolactin is a neuromodulator of behavio ral and neuroendocrine stress coping in the rat. In virgin female and male rats, intracerebral infusion of ovine prolactin (oPRL) into the lateral cer ebral ventricle (intracerebroventricular) exerted an anxiolytic effect on t he elevated plus-maze in a dose-dependent manner (0.1 and 1.0 mug/5 mul; 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 <mu>g . 0.5 mu l(-1) . hr(-1); 5 d) increased anxiety-related behavior on the plus-maze co mpared with mixed bases-treated and vehicle-treated rats (p < 0.01), again demonstrating an anxiolytic effect of PRL acting at brain level. Furthermor e, in jugular vein-catheterized female rats, the stress-induced increase of corticotropin secretion was decreased after chronic intracerebroventricula r infusion of oPRL (osmotic minipump, 1.0 <mu>g . 0.5 mul(-1) . hr(-1); 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-adr enal (HPA) axis by prolactin. The antisense ODN sequence was selected on th e basis of secondary structure molecular modeling of the target mRNA to imp rove antisense ODN-mRNA hybridization. Receptor autoradiography confirmed t he expected improvement in the efficacy of downregulation of prolactin rece ptor expression [empirically designed antisense, 30%; p> 0.05, not signific ant; adjustment of target position after mRNA modeling, 72%; p< 0.05). Take n together, prolactin acting at brain level has to be considered as a novel regulator of both emotionality and HPA axis reactivity.