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The vasopressin V3 receptor (V3) is specifically expressed in pituitary corticotropes and mediates the stimulatory effect of vasopressin on adrenocorticotropic hormone (ACTH) release. The V3 gene is overexpressed in corticotrope pituitary tumours compared to normal pituitaries. We hypothesized that V3 overexpression might induce changes in corticotrope function and alter the regulation of the hypothalamic-pituitary-adrenal axis. Thus, we generated transgenic mice (POMV3) expressing the human V3 receptor in the pituitary under the control of rat pro-opiomelanocortin (POMC) promoter sequences. The transgene was efficiently transcribed and vasopressin binding was increased in both corticotropes and melanotropes. In-vitro ACTH release and inositol phosphate formation were unchanged in POMV3 pituitaries, but the responses to vasopressin were significatively increased. In vivo, basal circulating concentrations of ACTH in POMV3 mice were similar to those of controls but corticosterone concentrations were moderately increased. In addition, the levels of POMC mRNA in the transgenic pituitaries were comparable to those of control mice. Finally, POMV3 mice responded with a similar maximal increase of ACTH and corticosterone to a 20-min acute restraint stress. Together, these results show that hypophyseal V3 overexpression led to increased basal concentrations of corticosterone and suggest that the negative glucocorticoid feedback may be altered at the pituitary level.

The expression of the five somatostatin receptor subtypes, sst 1 - 5 was compared on tissue containing glial tumours (glioblastomas or oligodendrogliomas), medulloblastomas, and on normal human cortex. By semiquantitativereverse transcription coupled to polymerase chain reaction, the receptor expression profiles were high in cortex and in tissue containing oligodendrogliomas. It was moderate in medulloblastomas. Tissue containing glioblastomas displayed lower expression of somatostatin receptor subtypes, sst 1 and sst 3 being mostly expressed. By 1 2 5 I-Tyr 0 DTrp 8 somatostatin-14 or 1 2 5 I-Leu 8 DTrp 2 2 Tyr 2 5 somatostatin-28 autoradiography combined with synaptophysin immunohistochemistry, it was possible to differentiate between isolated tumoral cell component infiltrating the cerebral parenchyma (cortex or white matter) and tumoral tissue (without residual parenchyma) in glioblastomas or oligodendrogliomas. Glial tumoral tissue per se presented few somatostatin receptors. By contrast, medulloblastoma tumoral cells exhibited numerous octreotide sensitive somatostatin receptors, sst 2 immunocytochemistry demonstrated immunostaining of neuronal cells and neuropile; sst 2 and sst 3 immunostaining was identified on glioblastoma proliferating vessels endothelial cells and on medulloblastomas tumoral cells. Faint sst 2 immunostaining among glial tumoral cells was due to microglia, while glioma cells did not significantly stain. In summary, medulloblastoma tumoral cells express sst 2 /sst 3 receptors at a high level while glioma cells do not. In gliomas, sst expression is restricted to endothelial cells on proliferating vessels (displaying both sst 2 and sst 3 receptors), including parenchyma and reactive microglia (only sst 2 ). The differential expression of sst 2 /sst 3 receptors on gliomas and medulloblastomas has implications for the therapy of these tumours.

Somatostatin (SRIF) controls many physiological and pathological processes in the central nervous system but the respective roles of the five receptor isotypes (sst1-5) that mediate its effects are yet to be defined. In the present study, we attempted to identify functions of the sst2 receptor using mice with no functional copy of this gene (sst2 KO mice). In contrast with control 129Sv/C57Bl6 mice, sst2 mRNA was no longer detectable in the brain of sst2 KO mice; 125I-labeled Tyr0DTrp8-SRIF14 binding was also greatly reduced in almost all brain structures except for the hippocampal CA1 area, demonstrating that sst2 accounts for most SRIF binding in mouse brain. Invalidation of this subtype generated an increased anxiety-related behaviour in a number of behavioural paradigms, while locomotor and exploratory activity was decreased in stress-inducing situations. No major motor defects could be detected. sst2 KO mice also displayed increased release of pituitary ACTH, a main regulator of the stress response. Thus, somatostatin, via sst2 receptor isotype pathways, appears involved in the modulation of locomotor, exploratory and emotional reactivity in mice.

While the pharmacology of noradrenaline effects on growth hormone (GH) secretion has been extensively studied, the precise localization of noradrenergic neurons involved remains unclear. In the present work, we investigated whether A6 noradrenergic neurons located in the locus coeruleus can play a role in the rhythmic pattern of GH secretion or in the sensitivity of the hormone response to different external challenges. Three weeks after bilateral 6-hydroxydopamine injections (8μg/3μl) into the locus coeruleus, hypothalamic noradrenaline concentrations were reduced by 60%. Pulsatile GH secretory patterns were observed in unanaesthetized, freely moving control, sham-operated or locus coeruleus-lesioned male rats. The amplitude of the pulses and the area under the curves during the 6- or 12-h sampling period were twice as high in locus coeruleus-lesioned than in control and sham-operated rats. In contrast, trough levels of GH and intervals between GH peaks were similar in all groups. Prolactin, adrenocorticotrophin, thyroid-stimulating hormone and luteinizing hormone plasma levels were not affected by the lesion. GH responses to two centrally acting drugs i.e. clonidine (2.5, 5 and 10μg/100g body wt) and morphine (200μg/100g body wt) were also highly amplified in locus coeruleus-lesioned rats. In contrast, GH responses to two peptides directly acting on somatotrophs i.e. GH-releasing factor (0.05 and 1.25μg/100g body wt) and vasoactive intestinal peptide (1.5μg/100g body wt) were the same in sham-operated and lesioned animals. These data suggest that noradrenergic inputs from the locus coeruleus exert a selective inhibitory influence on GH secretion through centrally mediated mechanisms.