Involvement of sst2 somatostatin receptor in locomotor, exploratory activity and emotional reactivity in mice

Viollet, Cécile; Vaillend, Cyrille; Videau, Catherine; Bluet‐Pajot, Marie‐Thérèse; Ungerer, Arielle; L'Héritier, A.; Kopp, Caroline; Potier, Brigitte; Billard, Jean‐Marie; Schaeffer, James M.; Smith, Roy G.; Rohrer, Susan P.; Wilkinson, Hilary A.; Zheng, Hui; Epelbaum, Jacques

doi:10.1046/j.1460-9568.2000.00249.x

Cited by 104 publications

(70 citation statements)

References 45 publications

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“…In this study, we demonstrate that elevation in glucocorticoid levels in the Sst Ϫ/Ϫ mouse are associated with a significant increase in pituitary POMC expression, without a concomitant rise in hypothalamic CRH expression. These in vivo results, coupled with our present in vitro findings showing that SST can directly suppress POMC mRNA levels and ACTH release in primary mouse pituitary cell cultures and with the fact that pituitaries of sst2 knockout mice release more ACTH in vitro (47), strongly support the hypothesis that, at least in the mouse, endogenous SST can act as a corticotropin synthesis/release-inhibiting factor (14). The fact that the direct inhibitory actions of SST on POMC mRNA levels and ACTH release were also observed in primary pituitary cell cultures from a nonhuman primate suggests that endogenous SST may also play an important role in regulating corticotroph function in higher-order mammalian species, such as humans.…”

Section: Discussionsupporting

confidence: 82%

“…The inhibitory action of exogenous SST on ACTH release has prompted speculation regarding the role of endogenous SST as a corticotropin release-inhibiting factor (14). More recent observations support such a role, where pituitaries of sst2 knockout mice release more ACTH in vitro (47) and corticosterone levels are elevated in SST knockout mice (Sst Ϫ/Ϫ ) (50). Preliminary data generated by our laboratory have confirmed that basal corticosterone levels are elevated in both male and female Sst Ϫ/Ϫ mice (28).…”

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confidence: 99%

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Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways

Luque

Gahete²,

Hochgeschwender³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Corticosterone and total ghrelin levels are increased in somatostatin (SST) knockout mice (Sst Ϫ/Ϫ ) compared with SST-intact controls (Sst ϩ/ϩ ). Because exogenous ghrelin can increase glucocorticoids, the question arises whether elevated levels of ghrelin contribute to elevated corticosterone levels in Sst Ϫ/Ϫ mice. We report that Sst Ϫ/Ϫ mice had elevated mRNA levels for pituitary proopiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), whereas mRNA levels for hypothalamic corticotropin-releasing hormone (CRH) did not differ from Sst ϩ/ϩ mice. Furthermore, SST suppressed pituitary POMC mRNA levels and ACTH release in vitro independently of CRH actions. In contrast, it has been reported that ghrelin increases glucocorticoids via a central effect on CRH secretion and that n-octanoyl ghrelin is the form of ghrelin that activates the GHS-R1a and modulates CRH neuronal activity. Consistent with elevations in total ghrelin levels, Sst Ϫ/Ϫ mice displayed an increase in stomach ghrelin mRNA levels, whereas hypothalamic and pituitary expression of ghrelin was not altered. Despite the increase in total ghrelin levels, circulating levels of n-octanoyl ghrelin were not altered in Sst Ϫ/Ϫ mice. Because glucocorticoids and ghrelin increase in response to fasting, we examined the impact of fasting on the adrenal axis and ghrelin in Sst ϩ/ϩ and Sst Ϫ/Ϫ mice and found that endogenous SST does not significantly contribute to this adaptive response. We conclude that endogenous SST inhibits basal ghrelin gene expression in a tissue specific manner and independently and directly inhibits pituitary ACTH synthesis and release. Thus endogenous SST exerts an inhibitory effect on ghrelin synthesis and on the adrenal axis through independent pathways. somatostatin; adrenocorticotropic hormone; hypothalamic-pituitaryadrenal axis; corticotropin-releasing hormone; pituitary; stomach SOMATOSTATIN (SST), OR ITS SYNTHETIC ANALOGS, can reduce circulating adrenocorticotropic hormone (ACTH) and glucocorticoid levels in rats and humans in vivo (19,43,46). The inhibitory actions of SST are believed to be due, at least in part, to a direct effect on the pituitary. This hypothesis is supported by the fact that SST can block corticotropin-releasing hormone (CRH)-mediated ACTH release in cultures of primary rat pituitary cells, mouse pituitary tumor cells (AtT-20), and cultures of human corticotropinomas (20,25,44), where this effect appears to be mediated by the SST receptors sst2 and/or sst5 (20,43,44). Both the in vivo and in vitro inhibitory effects of SST on ACTH release can be masked by glucocorticoids, where glucocorticoids directly inhibit basal and CRH-mediated ACTH release (19,25). However, a recent study (20) demonstrates that an sst5 selective agonist can inhibit ACTH release in vitro in the presence of glucocorticoids. The inhibitory action of exogenous SST on ACTH release has prompted speculation regarding the role of endogenous SST as a corticotropin release-inhibiting factor (14). More recent observations suppo...

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways

Luque

Gahete²,

Hochgeschwender³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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“…We used four strains of mice in this study: somatostatin receptor subtype 2 (SST 2 ) knock-outs, SST 3 knock-outs, SST 4 knock-outs, and wild-type mice. SST 2 knock-out mice were provided by Merck Pharmaceuticals (Whitehouse Station, NJ) and have been characterized phenotypically (Viollet et al, 2000;Dutar et al, 2002). We did limited studies on SST 2 / SST 4 double knock-outs, which were bigenic crosses between the SST 2 and SST 4 knock-outs.…”

Section: Methodsmentioning

confidence: 99%

Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures

Qiu

Zeyda²,

Johnson³

et al. 2008

J. Neurosci.

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The K ϩ M-current (I M , Kv7) is an important regulator of cortical excitability, and mutations in these channels cause a seizure disorder in humans. The neuropeptide somatostatin (SST), which has antiepileptic properties, augments I M in hippocampal CA1 pyramidal neurons. We used SST receptor knock-out mice and subtype-selective ligands to investigate the receptor subtype that couples to I M and mediates the antiepileptic effects of SST. Using pentylenetetrazole as a chemoconvulsant, SST 2 , SST 3 , and SST 4 receptor knock-out mice all had shorter latencies to different seizure stages and increased seizure severity when compared with wild-type mice. However, the most robust differences were observed in the SST 4 knock-outs. When seizures were induced by systemic injection of kainate, only SST 4 knock-outs showed an increase in seizure sensitivity. We next examined the action of SST and subtype-selective SST agonists on electrophysiological parameters in hippocampal slices of wild-type and receptor knock-out mice. SST 2 and SST 4 appear to mediate the majority of SST inhibition of epileptiform activity in CA1. SST lacked presynaptic effects in mouse CA1, in contrast to our previous findings in rat. SST increased I M in CA1 pyramidal neurons of wild-type and SST 2 knock-out mice, but not SST 4 knock-out mice. Using M-channel blockers, we found that SST 4 coupling to M-channels is critical to its inhibition of epileptiform activity. This is the first demonstration of an endogenous enhancer of I M that is important in controlling seizure activity. SST 4 receptors could therefore be an important novel target for developing new antiepileptic and antiepileptogenic drugs.

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“…for sst1 -sst4 (18) and for sst5 (19)) but the most studied remain sst2 and sst5 KO mice. The studies of sst2 gene KO mice indicated that this receptor displays specific central actions such as fine motor control (20), modulation of spatial learning (21), exploratory activity and emotional reactivity (22). Among the peripheral actions of SRIF, sst2 receptor appears specifically involved in the inhibition of gastric acid secretion (23,24).…”

Section: Somatostatin (Sst) Receptor Familymentioning

confidence: 99%

Novel modalities of somatostatin actions

Krantic

Goddard²,

Saveanu³

et al. 2004

European Journal of Endocrinology

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The first part of this contribution reviews the current knowledge about endocrine and neuromodulatory actions of somatostatin. These biological actions are exerted according to endocrine, paracrine and autocrine modes of action and involve five distinct types of membrane receptors belonging to the 'super-family' of G-protein-coupled receptors. A new concept concerning a juxtacrine mode of action has recently been introduced to refer to the intervention of cytokines and growth factors in direct, cell-to-cell communication. The evidence in favor of juxtacrine actions of somatostatin will be presented in the second part of this review and illustrated by our own results on macrophage-lymphocyte T interactions in the immune system and spermatogonia -Sertoli cell interactions in mammalian testis. Another phenomenon such as ligand-induced somatostatin receptor homo-and hetero-dimerization resulting in 'poly'-receptors (with characteristics different from those of each of the two receptors forming the complex) is also at the origin of a novel mode of somatostatin action. The latter will be illustrated by the data obtained on human pituitary adenomas with somatostatin analogs specific for either 'poly'-receptor or relevant individual receptors. The arguments in favor of the analogous mode of actions among different families of chemical messengers such as peptides, cytokines and growth factors are discussed in the concluding section. The emerging unifying concepts on such functional analogies might provide a useful basis for the development of synthetic analogs not only for bioactive peptides but also for other types of chemical messengers.European Journal of Endocrinology 151 643-655

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Involvement of sst2 somatostatin receptor in locomotor, exploratory activity and emotional reactivity in mice

Cited by 104 publications

References 45 publications

Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways

Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways

Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures

Novel modalities of somatostatin actions

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