Review
Somatostatin and behaviour: The need for genetically engineered models

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Abstract

Somatostatin was originally characterised as a hypothalamic neurohormone responsible for the inhibition of pituitary Growth Hormone secretion. In mammals two genes encode for somatostatin-related peptides, somatostatin 14 and 28, and cortistatins, respectively. All peptides bind with similar affinities to the five cloned somatostatin receptors (sst), which belong to the GPCR family. Despite numerous studies, no clear behavioural function has yet been attributed to somatostatin-related peptides. This is due to the lack of good pharmacological tools (selective antagonists) and animal models. This review will focus on the recent development of such tools.

Introduction

The peptide somatostatin (SRIF) was characterised in 1972 [3] on the basis of its ability to inhibit Growth Hormone (GH) secretion from the anterior pituitary. Since that time, a great number of studies have attributed other physiological functions to this peptide, in accordance with its wide distribution in the peripheral nervous system and in the brain. In addition to its function in the regulation of GH release, it is now thought to be involved in the regulation of various exocrine and endocrine secretion from several organs, such as pancreas, gut, and thyroid gland [12], [13], [32]. Furthermore, it has been suggested that in the CNS, somatostatin serves as a neurotransmitter or neuromodulator which can influence motor activity and cognitive functions [11], [12], [31]. In this review, we will focus on the behavioural effects of somatostatin and discuss the recent development of more specific pharmacological and genetically engineered tools, which should provide a better understanding of the molecular mechanisms involved.

Section snippets

Somatostatin-related peptides

Mammalian somatostatin biosynthesis involves the post-translational proteolytic cleavage of a single precursor into two biologically active peptides SRIF-14 and SRIF-28. Recently a third peptide, sharing 11 residues with SRIF-14, was discovered in mammalian brain tissue and named cortistatin [6]. Cortistatin appears to be expressed in a more restricted manner in cortical and hippocampal regions, in comparison with SRIF [7] but it is not yet possible to differentiate between SRIF- and

Somatostatin receptors (sst)

At least five SRIF receptor subtypes (sst 1–5) mediate the diverse functional effects of SRIF and cortistatin in the CNS [6], [21]. All cloned SRIF receptors display similar affinities for the endogenous peptides [31]. They are linked to G-proteins that trigger multiple transmembrane signalling systems [2]. Autoradiographic receptor binding studies have shown a widespread but selective CNS distribution of SRIF binding sites in rodent and human brain using non-selective or sst2/sst3/sst5

Behavioural effects

A behavioural action of somatostatin was first observed in monkeys after injections of a large dose of somatostatin, which induced a tranquillising effect [40]. Later, several studies conducted in rodents suggested a role for the peptide in the control of locomotor activity as well as in learning and memory processes. Intraventricular injection of somatostatin in rats induced a marked behavioural excitation associated with a reduction in slow-wave and rapid eye movement sleep [19]. Injection of

New pharmacological tools

This consequent set of data reviewed above strongly suggests that somatostatinergic systems may play a role in the modulation of cognitive processes. This is also in keeping with the fact that 1) cortical and hippocampal somatostatin levels are diminished in patients with Alzheimer's disease [5] and 2) decrease in somatostatin expression has been correlated with cognitive impairment in ageing rats [10], [27], [28] and mutant mice [41]. Nevertheless, the conclusions drawn from injection-based

Genetically engineered animals

Another approach is based on the use of genetic models in which the gene coding for a given peptide or receptor subtype has been invalidated. At present, behavioural studies concerning somatostatin-related transgenic animals are scarce. The main observations reported in the literature are summarised in table I. Recently, using the first mice invalidated for a somatostatin receptor, the sst2 KO mice, we have shown that the sst2 receptor accounts for the majority (90 %) of central SRIF binding

Conclusion

It is probable that only the comparative study of the phenotype of mice invalidated for each somatostatin receptor, together with the use of selective agonists, will allow us to understand the general roles of somatostatin and to pinpoint the specific interventions of each receptor subtype. In the future, conditional knockout models as well as selective antagonists will also be needed to precisely demonstrate the role(s) of individual somatostatin receptors and peptides in brain functions.

Acknowledgments

This work was supported by INSERM and Merck. C. Viollet was a recipient of an INSERM/Merck fellowship.

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