Multiple intracellular effectors modulate physiological functions of the cloned somatostatin receptors.

Somatostatin is a peptide widely distributed in both the central nervous system (CNS) and peripheral tissues. It is found as two bioactive peptides of 14 and 28 amino acids, the latter being an N-terminalextended form (Reichlin 1983a). The name somatostatin comes from its initial discovery as an inhibitor of growth hormone (GH) release from anterior pituitary cells (Brazeau et al. 1973). Since then, numerous other physiological activities of somatostatin have been discovered associated with differing peptide and receptor localization (Reichlin 1983a,b). Besides GH, somatostatin is also able to inhibit secretion of prolactin (PRL) and thyroid-stimulating hormone (TSH) (Reichlin 1983a). In the CNS, the highest somatostatin concentrations have been detected in the hypothalamus in the tuberoinfundibular neurons where, acting as a neurohormone, the peptide regulates the hypothalamic–hypophyseal axis (Schettini 1991). Somatostatin-containing neurons are also present in many other areas of the brain, such as the cerebral cortex, the limbic system (including the hippocampus and the amygdala) and the nigro-striatal pathway (Schettini 1991). In these areas somatostatin acts as a true neurotransmitter or as a neuromodulator of release of neurotransmitters such as acetylcholine (Gray et al. 1990) and dopamine (Thal et al. 1986). In the past few years clinical and post-mortem observations on Alzheimer’s patients, as well as experimental studies in animal models, have suggested that this peptide may be an important regulator of cognitive functions (Schettini 1991). In support of this are the observations that the concentration of somatostatin in the brain (Davies et al. 1980) and cerebrospinal fluid (Atack et al. 1988) is reduced in patients with Alzheimer’s dementia, neuritic plaques contain somatostatin (Morrison et al. 1985), neurofibrillary tangles have been identified in somatostatinergic neurons (Roberts et al. 1985) and a strict correlation has been demonstrated between somatostatin levels and cognitive performance in patients affected by Alzheimer’s disease (Tamminga et al. 1987). In animal models, depletion of rat brain somatostatin by cysteamine administration (a thiol-containing agent the action of which mimics the natural decline in somatostatin content in aged animals (Florio et al. 1991)) caused memory loss as assessed by many different behavioural paradigms, including active and passive avoidance tests (Vecsei et al. 1984, Harotunian et al. 1987, Schettini et al. 1988a, Florio et al. 1988), the Morris swim test (Fitzgerald & Dokla 1989) and the eight-arm radial maze (Sessions et al. 1989). In the peripheral nervous system, somatostatin is produced by ä-cells of the pancreas where it plays an important role in the control of both insulin and glucagon secretion (Koerker et al. 1974). Somatostatin is also produced in the gastroenteric tract, mainly in the antral portion of the stomach where it controls the release of enteric hormones (vasoactive intestinal peptide, cholecystokinin (CCK), motilin and secretin) as well as gastric acid secretion (Reichlin 1983b). Finally, somatostatin has been recently demonstrated to play an important role as an endogenous inhibitor of cell proliferation in various normal and neoplastic tissues, and somatostatin analogues are now being used for the treatment of different human tumours (Schally 1988, Reubi & Laissue 1995). The wide range of tissues releasing or responding to somatostatin and the variety of physiological 89