Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Jul 1.
Published in final edited form as: Horm Behav. 2015 May 27;73:15–22. doi: 10.1016/j.yhbeh.2015.05.009

The role of brain somatostatin receptor 2 in the regulation of feeding and drinking behavior

Andreas Stengel 1, Hiroshi Karasawa 2, Yvette Taché 2,*
PMCID: PMC4546908  NIHMSID: NIHMS694930  PMID: 26026616

Abstract

Somatostatin was discovered four decades ago as hypothalamic factor inhibiting growth hormone release. Subsequently, somatostatin was found to be widely distributed throughout the brain and to exert pleiotropic actions via interaction with five somatostatin receptors (sst1-5) that are also widely expressed throughout the brain. Interestingly, in contrast to the predominantly inhibitory actions of peripheral somatostatin, the activation of brain sst2 signaling by intracerebroventricular injection of stable somatostatin agonists potently stimulates food intake and independently, drinking behavior in rodents. The orexigenic response involves downstream orexin-1, neuropeptide Y1 and μ receptor signaling while the dipsogenic effect is mediated through the activation of the brain angiotensin 1 receptor. Brain sst2 activation is part of mechanisms underlying the stimulation of feeding and more prominently water intake in the dark phase and is able to counteract the anorexic response to visceral stressors.

Keywords: body weight, brain-gut axis, food intake, hypothalamus, satiation, satiety, somatostatin receptor, stress, water intake

Introduction

The 14 amino acid peptide, somatostatin was isolated in 1973 from 490,000 ovine hypothalami by Guillemin and colleagues as a potent inhibitor of growth hormone (GH) secretion from the pituitary in vitro and in vivo that led to its naming (Brazeau et al., 1973). Seven years later, Pradayrol et al. identified the N-terminally extended form, somatostatin-28, from porcine intestine (Pradayrol et al., 1980). In mammals, both somatostatin-14 and 28 originate from the prohormone, pro-somatostatin, which is generated after removal of a 24 amino acid signal sequence from the 116 amino acids precursor, pre-pro-somatostatin (Benoit et al., 1990). Somatostatin-14 and 28 bind with similar affinity to five distinct somatostatin receptor subtypes, sst1 to sst5 (Bruns et al., 1996; Patel, 1999). These receptors belong to the G-protein coupled seven transmembrane domain receptor family (Olias et al., 2004) and are related to the urotensin II receptors (Tostivint et al., 2014). In addition, spliced variants have been described for the sst2 including the full length sst2a and the C-terminally truncated form sst2b in rodents (Cole and Schindler, 2000). Both, sst2a and sst2b splice variants bind somatostatin and display similar potency and desensitization rates (Cole and Schindler, 2000). In addition, several functionally active truncated forms of the sst5 have been identified in humans and rodents (Cordoba-Chacon et al., 2010; Duran-Prado et al., 2009). These sst5 splice variants display a differential subcellular localization (Cordoba-Chacon et al., 2010) and a reduced [Ca2+]i response compared to somatostatin (Duran-Prado et al., 2009).

Soon after the initially described inhibitory action of somatostatin on GH secretion, several extra-pituitary effects were identified in line with the widespread brain distribution of the peptide (Finley et al., 1981; Viollet et al., 2008). In rodents, somatostatin acts in the brain to increase body temperature and influence visceral functions (e.g. increase blood pressure through vasopressin-dependent mechanisms, decrease heart rate, prevent sympathetically mediated hyperglycemia and stimulate gastric acid secretion) (Brown and Taché, 1981;Brown, 1981; Brown, 1988; Hajdu et al., 2000). Somatostatin was also found to induce behavioral alterations of food consumption – either increase or decrease as discussed below – (Feifel and Vaccarino, 1994), increased grooming (Van Wimersma Greidanus et al., 1987) and locomotor activity (Vecsei and Widerlov, 1990). Other early studies also pointed to the central action of somatostatin-28 to counteract the activation of the hypothalamic pituitary adrenal (HPA axis) and sympathetic nervous system induced by acute stressors (Brown et al., 1984).

The review will focus on recent advances that unraveled mechanisms involved in the alterations of food intake induced by pharmacological activation of brain somatostatin signaling pathways. We will also address new evidence that somatostatin in the brain induces a potent dipsogenic response through distinct mechanisms independent from the stimulation of food intake. The role of endogenous brain somatostatin signaling will be reviewed in the context of its relevance in regulation of nocturnal feeding and drinking behavior in rodents and stress-related alterations of food intake (Sominsky and Spencer, 2014). Progress in the characterization of somatostatin receptors involved in these behavioral changes was greatly facilitated by the use of stable and selective peptide somatostatin agonists and the development of selective somatostatin receptor antagonists (Table 1) (Erchegyi et al., 2008).

Table 1.

Amino acid sequence and receptor binding affinity of somatostatin and sst ligands listed in the order of appearance in this review.

PeptideReference Structure Receptor binding affinity (IC50, nM)a
sst1 sst2 sst3 sst4 sst5
somatostatin-14 (SST-14) (Viollet et al., 1995) Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cy s]-OH 0.1 – 1.5 1.7 1.7 1.0 – 1.6 0.2 – 2.2
somatostatin-28 (SST-28) (Viollet et al., 1995) Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]-OH 0.1 – 4.7 0.4 – 5.2 0.2 0.3 – 1.1 0.05 – 0.19
ODT8-SST (Erchegyi et al., 2008) des-AA1,2,4,5,12,13-(DTrp8)-SST 27.0 ± 3.4 41.0 ± 8.7 13.0 ±3.2 1.8 ± 0.7 46.0 ± 27.0
octreotide (Grace et al., 2008) H-(D)-Phe2-c[Cys3-Phe7-DTrp8-Lys9-Thr10-Cys14]-Thr15(ol) > 1K 1.9 ± 0.3 39 ± 14 > 1K 5.1 ± 1.1
sst2 agonist (compound 2, S-346-011) (Grace et al., 2006) des-AA1,4-6,11-13-[DPhe2,Aph7(Cbm),DTrp8]-Cbm-SST-Thr-NH2 > 1K 7.5 - 20 942 -1094 872 -957 109 -260
sst1 agonist (compound 25, S-406-062) (Erchegyi et al., 2009) des-AA1,4-6,10,12,13-[DTyr2,D-Agl(NMe,2naphtoyl)8,IAmp9]-SST-Thr-NH2 0.19 ± 0.04 > 1K 158.0 ± 14.0 27.0 ± 7.5 > 1K
sst4 agonist (compound 15, S-315-297) (Erchegyi et al., 2003) des-AA1,2,4,5,12,13-[Aph7]-Cbm-SST 650 ± 115 > 1K 780 ± 62 1.5 ± 0.07 > 1K
sst2 antagonist (compound 4, S-406-028) (Cescato et al., 2008) des-AA1,4-6,11-13-[pNO2-Phe2,DCys3,Tyr7,DAph(Cbm)8]-SST-2Nal-NH2 > 1K 2.6 ± 0.7 384.0 ± 97.0 > 1K > 1K
Open in a new tab

Affinities are derived from competitive radioligand displacement assays in cells stably expressing the cloned human receptor using 125I-[Leu8DTrp22Tyr25]SRIF-28 (Cescato et al., 2008; Erchegyi et al., 2003; Erchegyi et al., 2008; Erchegyi et al., 2009; Grace et al., 2006; Grace et al., 2008) except for somatostatin-14 (Viollet et al., 1995) and somatostatin-28 (Viollet et al., 1995).

Brain somatostatin signaling and the regulation of feeding behavior

Neuroanatomical support

Somatostatin (not distinguishing between 14 and 28) immunoreactivity was shown to be widely distributed in cell bodies and fibers of distinct nuclei throughout the rodent brain (Finley et al., 1981). In particular, dense somatostatin immunoreactivity is present in the hypothalamus, namely in the arcuate (Arc), ventromedial, periventricular and paraventricular (PVN) nuclei, and at the level of brainstem in the nucleus of the solitary tract (NTS) (Finley et al., 1981; Johansson et al., 1984; Moga and Gray, 1985; Viollet et al., 2008). These brain sites are well established to regulate food intake and energy balance (Schneeberger et al., 2014).

Consistent with the broad distribution of the ligand, the sst1-5 are also widely expressed throughout the brain and – although overlap exists – the sst subtypes show a distinct expression pattern (Olias et al., 2004). With regards to feeding regulatory centers, a dense expression of sst receptors has been detected in the dorsomedial hypothalamic nucleus (sst1 = sst3), ventromedial hypothalamic nucleus (sst1 > sst3 > sst2), PVN (sst2a = sst3) and Arc of the hypothalamus (sst1 = sst2a = sst3 > sst4), the NTS (sst1 = sst2 > sst3) and the dorsal motor nucleus of the vagus nerve (sst2a/b = sst4 > sst5) (Fehlmann et al., 2000; Hannon et al., 2002; Schindler et al., 1999; Schulz et al., 2000; Spary et al., 2008). Therefore, in feeding regulatory nuclei such as the Arc, PVN and NTS, both ligands and receptors are expressed. Interestingly, only the sst2 and sst3 are expressed in all three nuclei.

Orexigenic response to central injection of stable somatostatin agonists

Early on, studies reported that injection of somatostatin-14 or the stable sst2,3,5 agonist octreotide (Table 1) into the brain stimulates food intake in rats (Table 2). Somatostatin or octreotide injected intracerebroventricularly (icv), into the dorsal hippocampus or anterior piriform cortex increased food intake in rats (Beranek et al., 1999; Danguir, 1988; Feifel and Vaccarino, 1990; Feifel et al., 1993; Rezek et al., 1976). More recent studies established that the stable pan-somatostatin agonist, ODT8-SST or octreotide injected icv at low doses (0.3 and 1 nmol/animal) induces a robust increase of food intake in ad libitum fed rats or mice under basal conditions during the light phase or already stimulated conditions during the dark photoperiod (when rodents usually eat) (Karasawa et al., 2014a; Karasawa et al., 2014b; Stengel et al., 2010a). The orexigenic response to icv injection of the stable somatostatin agonist, octreotide in rats is rapid in onset (within 10 min) (Beranek et al., 1999), reaches a peak response at the first hour post icv injection of the pan-somatostatin agonist, ODT8-SST and is long lasting (4 h) resulting in an enhanced cumulative food intake over a period of 9 h (Stengel et al., 2010a). A rapid orexigenic response to icv somatostatin (0.5 nmol) was also reported in non-mammalian species such as chicks under fasted or ad libitum feeding conditions (Tachibana et al., 2009).

Table 2.

Studies investigating the central effect of somatostatin and its analogues on food intake.

Somatostatin ligand Dose Route of injection Species Feeding status Photo-period Effect on food intake Duration of action Reference
Somatostatin-14 0.6 nmol dorsal hippocampal infusions rat not specified not specified voracious and prolonged eating not specified (Rezek et al., 1976)
Somatostatin-14 0.5 and 2 nmol icv injection chick ad libitum fed or 3-h fasted continuous light increase 1 h (Tachibana et al., 2009)
Octreotide 4.9 nmol/d icv infusion rat ad libitum fed light/dark increase 24 h (Danguir, 1988)
Octreotide 0.1 nmol icv injection rat ad libitum fed light increase 40 min (Beranek et al., 1999)
Octreotide 0.3 and 1 nmol icv injection mouse ad libitum fed light increase 4 h (Stengel et al., 2010b)
Somatostatin-14 0.4 – 40 pmol icv injection rat ad libitum fed light/dark increase of light phase food intake, no effect during the dark phase 1 h (Feifel and Vaccarino, 1990)
Somatostatin (length not specified) 1 pmol microinjection into anterior piriform cortex rat ad libitum fed dark increase 3 h (Cummings et al., 1998)
ODT8-SST 0.3 – 1 nmol icv injection rat ad libitum fed light/dark increase of light and dark phase food intake 4 h (Stengel et al., 2010a)
Somatostatin-14 9.8 nmol icv infusion rat rats with restricted feeding schedule (2 h/day) dark increase of food intake followed by decrease 1 h (Aponte et al., 1984)
Somatostatin-14 3 nmol third ventricle injection rat overnight fasted light decrease 1 h (Vijayan and McCann, 1977)
Somatostatin (length not specified) 0.3 – 0.9 nmol lateral hypothalamus infusion rat ad libitum fed light/dark decrease 24 h (Lin et al., 1987)
Somatostatin-14 3 nmol icv injection rat ad libitum fed light decrease 1 h (Feifel and Vaccarino, 1990)
Somatostatin (length not specified) 2 nmol microinjection into anterior piriform cortex rat ad libitum fed dark decrease 12 h (Cummings et al., 1998)
Somatostatin (length not specified) 0.5 – 1 nmol icv injection mouse ad libitum fed light/dark decrease of 24-h food intake 24 h (Nakahara et al., 2012)
Open in a new tab

Abbreviations: icv, intracerebroventricular

However, at higher doses (1 – 3 nmol/rat, or 1 nmol/mouse, icv), somatostatin decreased food intake in rats and mice (Cummings et al., 1998; Feifel and Vaccarino, 1990; Lin et al., 1987; Nakahara et al., 2012; Vijayan and McCann, 1977) (Table 2). The anorexigenic effect at higher doses may be related to the confounding effects due to the occurrence of other competing behavioral changes such as barrel rotation (Vecsei et al., 1989) and leakage into the peripheral circulation (Tannenbaum and Patel, 1986) – where the peptide largely exerts inhibitory effects (Bray, 1995). Taken together, activation of brain somatostatin signaling by icv injection of stable somatostatin agonists at low doses robustly increases food intake in rodents and non-mammalian species.

Role of brain somatostatin 2 receptor in the orexigenic effect

Further studies using selective sst receptor subtype agonists and antagonists (Table 1) delineated the primary involvement of the brain sst2 receptor in the orexigenic response to icv injection of somatostatin agonists. This is supported by the demonstration that the sst2 > sst5 > sst3 agonist, octreotide injected icv stimulates light phase food intake in ad libitum fed rats (Beranek et al., 1999; Danguir, 1988) and mice (Stengel et al., 2010b). This response is reproduced by the selective sst2 agonist, S-346-011 injected icv (0.09 – 0.9 nmol/rat and 0.9 nmol/mouse, respectively), while the sst1 (S-406-062) or sst4 agonists (S-315-297, Table 1) injected at ∼0.25 or 0.8 nmol have no effect (Stengel et al., 2010b; Stengel et al., 2010c). Moreover, the action of the pan-somatostatin agonist, ODT8-SST was blocked by icv injection of the selective peptide sst2 antagonist, S-406-028 (Table 1) in rats (Stengel et al., 2010a). Subsequent characterization of the sst2-mediated meal pattern associated with the orexigenic response in mice showed that during the 0 – 4 h period post icv injection of the sst2 agonist, S-346-011, there was an increase in the number of meals occurring after shorter intermeal intervals, whereas meal size was not altered compared to icv vehicle injected animals (Stengel et al., 2010b). These data indicate that the activation of sst2 signaling in the brain suppresses “satiety” (mechanisms causing delayed onset of the next meal after one completed meal), while not influencing “satiation” (mechanisms causing meal termination) (Fekete et al., 2007).

Brain orexigenic circuits recruited by intracerebroventricularly injected somatostatin agonists

Pharmacological approaches indicate that several orexigenic signaling pathways, namely neuropeptide Y (NPY), opioid and orexin (OX) – through activation of Y1, μ and OX1 receptors, respectively – are involved in mediating the icv pan-somatostatin agonist, ODT8-SST-induced stimulation of food intake in rats (Karasawa et al., 2014b; Stengel et al., 2010a). Peripheral injection of the μ-opioid receptor antagonist, naloxone (Bodnar, 2004) completely prevented the orexigenic effect of icv injected pan-somatostatin agonist, ODT8-SST in rats (Stengel et al., 2010a). Likewise, in chicks the opioid μ-receptor antagonist, β-funaltrexamine injected icv prevented the stimulation of food intake in response to icv somatostatin, while δ or κ opioid antagonists had no effect (Tachibana et al., 2009). The opioid dependence and the demonstration that the sst2 agonist, S-346-011 injected icv can further increase (1.4-times) already stimulated food intake induced by palatable high fat food in mice (Stengel et al., 2010b) suggest that sst2 signaling may be involved in reward-induced eating (Gosnell and Levine, 2009). The interaction of sst and opioid signaling is further corroborated at the cellular level since the sst2 has been shown to heterodimerize with the μ opioid receptor (Duran-Prado et al., 2008). However, whether this is linked with altered pharmacological and/or functional properties of sst2 within brain reward centers needs to be investigated.

In addition to the μ receptor opioid antagonist, the Y1 receptor antagonist, BIBP-3226 (O'Shea et al., 1997) or the OX1 antagonist, SB-334867 (Smart et al., 2001) injected icv also completely blocked the orexigenic effect induced by icv injection of the pan-somatostatin agonist, ODT8-SST (Karasawa et al., 2014b; Stengel et al., 2010a). The demonstration that the sst2 antagonist, S-406-028 did not alter the orexigenic response to icv orexin-A in rats indicates that the orexin-OX1 pathway is downstream to the sst2 activation (Karasawa et al., 2014b). Other studies have established that the NPY-NPY1 signaling in the Arc is involved in the downstream mediation of orexin A's orexigenic effect (Yamanaka et al., 2000). Therefore, the signaling cascade targeted by icv injection of the stable pan-somatostatin agonist, ODT8-SST may involve the activation of the sst2➔orexin-A-OX1➔NPY-NPY1 circuitry (Fig. 1). This assumption is supported by convergent neuroanatomical and electrophysiological studies showing that orexin-expressing neurons in the lateral hypothalamic area project to NPY-immunopositive neurons in the Arc (Horvath et al., 1999) and activate these neurons (Muroya et al., 2004; van den Top et al., 2004). Moreover, the food intake stimulation by icv orexin-A is blunted by icv injection of an NPY1 antagonist (Jain et al., 2000). However, it cannot be ruled out that in addition, the pan-somatostatin agonist ODT8-SST acts by directly stimulating NPY signaling in the Arc as sst2 receptors are localized on 50% of NPY expressing neurons in the Arc (Lanneau et al., 2000). The exact anatomical circuits by which somatostatin-sst2 signaling stimulates OX1 bearing neurons are still to be identified. Activation of sst2 by icv injection of the pan-somatostatin agonist, ODT8-SST or a selective sst2 agonist (S-346-011) induces Fos expression in the supraoptic nucleus and PVN, unlike in orexin-expressing neurons of the lateral hypothalamic area (Goebel et al., 2010) supporting an indirect action. GABAergic neurons are inhibited by somatostatin-sst2 signaling in the brain (Chigr et al., 2001; Meyer et al., 1989) and may thereby reduce the inhibitory tone on orexin neurons, a hypothesis that warrants further investigation. Whether cannabinoid signaling is also involved in somatostatin's orexigenic effect as recently suggested based on the co-localization of CB1 and somatostatin in the PVN (Zou et al., 2015) will be subject to further studies.

Figure 1.

Figure 1

Open in a new tab

Suggested downstream hypothalamic circuitries involved in the somatostatin-sst2 signaling-induced orexigenic response.

The stable pan-somatostatin agonist, ODT8-SST increases food intake via activation of sst2 receptors, an action that involves a downstream stimulation of orexin OX1 ➔ NPY Y1 signaling and also μ opioid receptors, indicating an involvement of the rewarding aspect of food. A dimerization of sst2 and μ opioid receptors might be involved, although the functional relevance of this phenomenon remains to be further characterized. On the other hand, an inhibition of leptin as well as GABA signaling is also likely to contribute to somatostatin's orexigenic effect. Abbreviations: ↓ decrease; ↑ increase; - inhibition; + stimulation; ARC, arcuate nucleus; GABA, gamma-aminobutyric acid; icv, intracerebroventricular; PVN, paraventricular nucleus of the hypothalamus; SON; supraoptic nucleus; sst2, somatostatin receptor 2; STAT3, signal transducer and activator of transcription 3.

Additional mechanisms modulating the somatostatin orexigenic response may involve the interplay with leptin, an adipose tissue-derived anorexigenic hormone that contributes to the long term regulation of body weight (Friedman, 1997). Somatostatin dampened leptin signaling as shown by the reduction in STAT3-phosphorylation level and nuclear STAT3 translocation in various hypothalamic nuclei, an effect mediated by several sst receptors (sst3 > sst1 > sst2) (Stepanyan et al., 2007). This could contribute to a reduction of leptin's anorexigenic action. Conversely, leptin injected icv reduced sst2 protein expression in the rat hippocampus (Perianes-Cachero et al., 2012) followed by a delayed increase of sst2 protein expression (Perianes-Cachero et al., 2013) which may be a counter-regulatory mechanism to balance leptin's action in the rat brain. In an in vitro preparation of rat fetal hypothalamic neurons, leptin also decreases somatostatin mRNA expression and somatostatin secretion under basal as well as NPY stimulated conditions (Quintela et al., 1997) further underlining the antagonistic interplay between these two hormones. Taken together, somatostatin's action in the brain is likely to be exerted via sst2 signaling stimulating orexigenic pathways: sst2➔orexin-A-OX1➔NPY-NPY1 and may also involve inhibiting the leptin anorexigenic pathway (Fig. 1).

Central action of somatostatin on energy metabolism

The robust increase in food intake observed after acute icv injection of the pan-somatostatin agonist, ODT8-SST (1 nmol/rat) in rats was accompanied by an increase in energy expenditure as assessed by indirect calorimetry (Stengel et al., 2010a). The peptide also increases body temperature and grooming under these conditions (Stengel et al., 2010a). These functional alterations may – at least in part – contribute to the observed decrease in body weight at 24 h after the icv injection (Stengel et al., 2010a).

Dipsogenic response to central injection of somatostatin agonists

Two earlier studies reported that the icv injection of low doses of the stable somatostatin agonist, octreotide (0.01 – 0.4 nmol) increased water consumption when assessed without food for a 10-min period post injection (Hajdu et al., 2000; Hajdu et al., 2003). In the presence of food, the somatostatin peptide agonist stimulates first drinking behavior within 1 min followed by eating after 10 min (Beranek et al., 1999). These reports were the first observations indicative of a dipsogenic effect, independent of food intake, induced by injection of the somatostatin agonist. Recent studies demonstrated that the activation of brain sst receptors by icv injection of endogenous ligands, somatostatin-14 or cortistatin, a structurally related peptide (de Lecea, 2008) which activates sst1-sst5 with binding affinities comparable to those of somatostatin-14 (Siehler et al., 2008) or the pan-somatostatin agonist, ODT8-SST (0.6 nmol/rat), stimulates water consumption in rats deprived of food (Karasawa et al., 2014a). The dipsogenic response was observed only during the first 10 min after icv injection of somatostatin or cortistatin and maintained for 60 min after icv injection of ODT8-SST (Karasawa et al., 2014a).

Interestingly, when food intake was assessed without water or water intake without food for 1-h, the pan-somatostatin agonist, ODT8-SST stimulated both food and water intake, while somatostatin-14 and cortistatin rapidly (within 10 min) stimulated water but not food intake in rats (Karasawa et al., 2014a). This may be related to the short half-life of somatostatin-14 and cortistatin compared to the stable pan-agonist, ODT8-SST not allowing these endogenous peptides to reach feeding-regulatory centers, while those regulating thirst are affected (Karasawa et al., 2014a). The demonstration that in rats with access only to either food or water or both concomitantly, icv ODT8-SST induces a dipsogenic response of similar magnitude, further supports the independence of water intake from that of food consumption (Karasawa et al., 2014a).

Role of somatostatin 2 receptor

Convergent pharmacological evidence established that the dipsogenic response to icv injection of the pan-somatostatin agonist, ODT8-SST and cortistatin in rats is primarily mediated by the sst2 receptor. Reports showed that the selective sst2 agonist (S-346-011, 0.8 nmol, icv) stimulates water intake with a similar magnitude to that of icv ODT8-SST or cortistatin in rats deprived of food during the test (Karasawa et al., 2014a). By contrast, the sst1 agonist (S-406-062) or sst4 agonist (S-315-297, Table 1) under the same conditions had no significant effect (Karasawa et al., 2014a). Moreover, icv injection of the sst2 antagonist (S-406-028) completely prevented the dipsogenic response to icv ODT8-SST and cortistatin (Karasawa et al., 2014a).

Mechanism of action

The activation of the brain sst2 receptor-induced dipsogenic response involves downstream angiotensin II-angiotensin-1 (AT1) receptors well established to regulate thirst and fluid maintenance (Fitzsimons, 1998). Saralasin, an AT1 and AT2 receptor antagonist or the AT1 antagonist, losartan injected icv in rats without access to food completely blocked the stimulation of water intake induced by icv injection of the stable somatostatin agonists, octreotide and ODT8-SST or cortistatin (Hajdu et al., 2000; Karasawa et al., 2014a). Moreover, icv octreotide induced the release of angiotensin I in the rat hypothalamus within 10 min (Gardi et al., 2001). By contrast, the angiotensin II-induced increase of water consumption in rats was not altered by a selective sst2 antagonist further supporting the action of angiotensin II signaling downstream of the somatostatin-sst2 receptor pathway (Karasawa et al., 2014a).

Although the exact neuroanatomical substrate(s) through which sst2 receptor activation recruits the brain angiotensin-AT1 system (McKinley et al., 2003) remains to be determined, indirect evidence supports the PVN as a site of action. The pan-somatostatin agonist, ODT8-SST or the sst2 agonist injected icv did not activate the subfornical organ (SFO) or median preoptic nucleus while activating magnocellular neurons in the PVN and supraoptic nucleus (Goebel et al., 2010; Karasawa et al., 2014a). These hypothalamic nuclei are part of the angiotensinergic system descending from the SFO and organum vasculosum's lamina terminalis (Fitzsimons, 1998; Miselis, 1981). Other evidence shows that icv injection of angiotensin II induces c-Fos/c-Jun prominently in neurons of the PVN and SON co-expressing the AT1 receptor (Moellenhoff et al., 2001). Moreover, the PVN and surrounding areas are sites of action for the somatostatin agonist, octreotide to induce a drinking response in rats (Hajdu et al., 2003). There is also a dense expression of sst2 receptors in the PVN with neuronal localization supporting both pre- and post-synaptic actions (Csaba et al., 2003; Dournaud et al., 1996). Moreover, the inhibitory action of somatostatin on GABA transmission is well documented (Kumar and Grant, 2010). Therefore, it may be speculated that the activation of sst2 pathways may reduce the tonic GABAergic inhibitory influence on the angiotensin system that drives drinking (Tanaka et al., 2003).

A recent study demonstrated that the dipsogenic response to icv injection of the pan-somatostatin agonist, ODT8-SST is also blocked by the icv OX1 antagonist, SB-334867 in rats with access to food post injection (Karasawa et al., 2014b). Orexin A can exert dipsogenesis in the absence of food upon icv injection (Kunii et al., 1999). However, as the orexin pathway is also part of the orexigenic circuitry of brain sst2 activation, the role of OX1 signaling in the stimulation of drinking induced by activation of sst2 receptors still needs to be ascertained in the absence of food. In summary, brain somatostatin/cortistatin exerts a rapid in onset dipsogenic response via the activation of an sst2-AT1 signaling pathway most likely taking place within the PVN.

Role of brain somatostatin 2 receptor signaling in nocturnal feeding and drinking

One recent study indicates the physiological relevance of sst2 signaling in the diurnal regulation of food intake in rats, namely in the nocturnal feeding behavior, when rodents show their maximal food consumption. The sst2 antagonist, S-406-028 injected icv reduced the cumulative dark phase food intake at 5 h and 14 h post injection by 27% and 29%, respectively in rats, while having no effect during the light phase (Stengel et al., 2010c). However, under other conditions of stimulated food intake by acute tail pinch in the light phase, the sst2 antagonist injected icv did not alter the robust feeding response in rats (Goebel-Stengel et al., 2014).

Importantly, the activation of brain sst2 contributes to the early nocturnal water intake. There is indeed a nocturnal pattern of water ingestion in rats that is well established to be independent of food intake (Karasawa et al., 2014a; Oatley, 1971). First evidence shows that somatostatin and cortistatin-14 injected at low doses devoid of orexigenic effects stimulate water intake resulting in a consumption similar to that occurring spontaneously during the first hours of the dark phase (Karasawa et al., 2014a). Furthermore, the sst2 antagonist, S-406-028 injected icv inhibited the stimulated water intake observed during the dark phase by >50 %, an effect that lasted over a period of three hours (Karasawa et al., 2014a). Lastly, consistent reports showed that hypothalamic somatostatin content and release are subject to a circadian rhythm with a peak of peptide release at the beginning of the dark phase while lowest levels are observed in the early light phase (Gardi et al., 1999; Ishikawa et al., 1997; Shinohara et al., 1991). In summary, brain somatostatin signaling is likely to be primarily involved in the physiological regulation of nocturnal water intake and to contribute partly to dark phase feeding in rats.

Modulation of stress-related decrease in food intake by somatostatin agonists

Various conditions of acute stress, such as exposure to nociceptive stimuli, immobilization, handling or low doses of endotoxin lead to an increase of hypothalamic somatostatin mRNA expression and peptide release in the median eminence in rats (Arancibia et al., 1984; Arancibia et al., 2000; Priego et al., 2005). The enhanced somatostatin release under conditions of acute stress is further supported by the finding of reduced peptide content in the supraoptic nucleus and the PVN, the locus coeruleus and nucleus of the solitary tract in the rat brainstem (Arancibia et al., 2000; Negro-Vilar and Saavedra, 1980). Likewise, in lambs the stress of maternal separation enhanced somatostatin concentration in nerve terminals of the median eminence (Polkowska and Wankowska, 2010). Other studies also showed that rats exposed to an elevated plus maze displayed activation of somatostatin neurons in the basolateral amygdala (Butler et al., 2012). Lastly, predator stress up-regulates the expression of sst2 mRNA in the anterior cingulate cortex and the amygdala (Nanda et al., 2008).

In rodents, most stressors including psychological (e.g. acute restraint or emotional stress), somatic (e.g. abdominal surgery) or immunological (e.g. injection of the endotoxin lipopolysaccharide) reduce food intake during the post stress-period through – at least in part – the activation of brain corticotropin releasing factor (CRF) receptors in rats (Hotta et al., 1999; Krahn et al., 1986; Sekino et al., 2004; Shibasaki et al., 1988b; Stengel and Taché, 2014a). Convergent pharmacological reports indicate that the activation of brain sst2 signaling can prevent the stress-related suppression of food intake. Indeed, earlier studies showed that icv injection of somatostatin-14, somatostatin-28 or octreotide blunted the reduction of food intake induced by restraint (Somiya and Tonoue, 1984) and suppressed the anorexigenic action of CRF (Shibasaki et al., 1988a). Furthermore, the pan-somatostatin agonist, ODT8-SST or a selective sst2 agonist injected icv completely abolished the inhibition of food intake observed at 2, 4 and 9 h after abdominal surgery in rats, resulting in a normalization of food consumption through a sst2 mediated action (Stengel et al., 2011). Although ghrelin, a major stimulator of food intake, is reduced by abdominal surgery and restored by icv injection of the stable somatostatin agonist, ODT8-SST (Stengel and Taché, 2012), the additional blockade of the ghrelin receptor under these conditions did not alter the orexigenic effect of the pan-somatostatin agonist, ODT8-SST after abdominal surgery (Stengel et al., 2011). Collectively, stress-related activation of brain somatostatin expression and release along with pharmacological evidence that the activation of somatostatin receptors counteracts the anorexic response to acute stressors support a modulatory role of brain sst2 signaling in the stress response (Stengel et al., 2013). Further studies are required to assess whether brain somatostatin-sst2 signaling plays a physiological role in modulating the response to stress through CRF, the hallmark transmitter of the stress response (Stengel and Taché, 2014a).

Summary

Somatostatin and its five receptors are widely expressed in the brain with specific expression patterns indicating the involvement in various homeostatic processes. Early on, a central action of somatostatin administered at low doses to stimulate food intake has been reported. The development of selective sst agonists and antagonists recently allowed the characterization of receptors involved, highlighting a prominent role of the sst2 for the orexigenic action of brain somatostatin in rodents. Activation of sst2 signaling recruits a series of orexigenic pathways involving μ-opioid, OX1, and NPY1 receptors (Fig. 1) and the inhibition of leptin signaling. Recent studies also point towards a rapid and robust dipsogenic response following the activation of brain sst2. The stimulation of drinking behavior occurs independently of the orexigenic action and involves angiotensin II-AT1 signaling. The brain somatostatin-sst2 signaling contributes in part to nocturnal eating and more importantly to the water consumption. Pharmacological activation of brain sst2 also prevents visceral stress-related inhibition of food intake, e.g. during postoperative gastric ileus known to involve CRF (Stengel and Taché, 2014b) adding to existing evidence that brain somatostatin counteracts several functional responses to acute stressors by interacting with CRF (Stengel et al., 2013).

Highlights.

  • Besides regulation of growth hormone, somatostatin affects several homeostatic systems

  • Somatostatin interacts with five somatostatin receptors (sst1-5)

  • Brain somatostatin exerts a robust orexigenic effect

  • Independent from its orexigenic actions, brain somatostatin also exerts a dipsogenic effect

  • Somatostatin counterbalances the response to stress

Acknowledgments

This work was supported by NIH Center Grant DK-41301 (Animal Core), VA Research Career Scientist (Y.T.), German Research Foundation STE 1765/3-1 (A.S.) and Charité University Funding UFF 88-226-168 (A.S.).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  1. Aponte G, Leung P, Gross D, Yamada T. Effects of somatostatin on food intake in rats. Life Sci. 1984;35:741–6. doi: 10.1016/0024-3205(84)90342-4. [DOI] [PubMed] [Google Scholar]
  2. Arancibia S, Epelbaum J, Boyer R, Assenmacher I. In vivo release of somatostatin from rat median eminence after local K+ infusion or delivery of nociceptive stress. Neurosci Lett. 1984;50:97–102. doi: 10.1016/0304-3940(84)90469-5. [DOI] [PubMed] [Google Scholar]
  3. Arancibia S, Rage F, Grauges P, Gomez F, Tapia-Arancibia L, Armario A. Rapid modifications of somatostatin neuron activity in the periventricular nucleus after acute stress. Exp Brain Res. 2000;134:261–7. doi: 10.1007/s002210000462. [DOI] [PubMed] [Google Scholar]
  4. Benoit R, Esch F, Bennett HP, Ling N, Ravazzola M, Orci L, Mufson EJ. Processing of prosomatostatin. Metabolism. 1990;39:22–5. doi: 10.1016/0026-0495(90)90202-n. [DOI] [PubMed] [Google Scholar]
  5. Beranek L, Hajdu I, Gardi J, Taishi P, Obal F, Jr, Krueger JM. Central administration of the somatostatin analog octreotide induces captopril-insensitive sleep responses. Am J Physiol. 1999;277:R1297–304. doi: 10.1152/ajpregu.1999.277.5.R1297. [DOI] [PubMed] [Google Scholar]
  6. Bodnar RJ. Endogenous opioids and feeding behavior: a 30-year historical perspective. Peptides. 2004;25:697–725. doi: 10.1016/j.peptides.2004.01.006. [DOI] [PubMed] [Google Scholar]
  7. Bray GA. Nutrient intake is modulated by peripheral peptide administration. Obes Res. 1995;3(Suppl 4):569S–572S. doi: 10.1002/j.1550-8528.1995.tb00229.x. [DOI] [PubMed] [Google Scholar]
  8. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. 1973;179:77–9. doi: 10.1126/science.179.4068.77. [DOI] [PubMed] [Google Scholar]
  9. Brown M, Taché Y. Hypothalamic peptides: central nervous system control of visceral functions. Fed Proc. 1981;40:2565–9. [PubMed] [Google Scholar]
  10. Brown M, Taché Y, Rivier J, Pittman Q. Peptides and regulation of body temperature. In: Martin JB, Reichlin S, Bick KL, editors. Neurosecretion and Brain Peptides. Raven Press; New York: 1981. pp. 397–407. Vol. [PubMed] [Google Scholar]
  11. Brown MR, Rivier C, Vale W. Central nervous system regulation of adrenocorticotropin secretion: role of somatostatins. Endocrinology. 1984;114:1546–9. doi: 10.1210/endo-114-5-1546. [DOI] [PubMed] [Google Scholar]
  12. Brown MR. Somatostatin-28 effects on central nervous system regulation of vasopressin secretion and blood pressure. Neuroendocrinology. 1988;47:556–62. doi: 10.1159/000124975. [DOI] [PubMed] [Google Scholar]
  13. Bruns C, Raulf F, Hoyer D, Schloos J, Lubbert H, Weckbecker G. Binding properties of somatostatin receptor subtypes. Metabolism. 1996;45:17–20. doi: 10.1016/s0026-0495(96)90072-4. [DOI] [PubMed] [Google Scholar]
  14. Butler RK, White LC, Frederick-Duus D, Kaigler KF, Fadel JR, Wilson MA. Comparison of the activation of somatostatin- and neuropeptide Y-containing neuronal populations of the rat amygdala following two different anxiogenic stressors. Exp Neurol. 2012;238:52–63. doi: 10.1016/j.expneurol.2012.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cescato R, Erchegyi J, Waser B, Piccand V, Maecke HR, Rivier JE, Reubi JC. Design and in vitro characterization of highly sst2-selective somatostatin antagonists suitable for radiotargeting. J Med Chem. 2008;51:4030–7. doi: 10.1021/jm701618q. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Chigr F, M'Hamed SB, Najimi M. Allosteric modulation of GABAA receptor by somatostatin is altered under stress in rat brainstem. Folia Biol (Praha) 2001;47:196–9. [PubMed] [Google Scholar]
  17. Cole SL, Schindler M. Characterisation of somatostatin sst2 receptor splice variants. J Physiol Paris. 2000;94:217–37. doi: 10.1016/s0928-4257(00)00207-2. [DOI] [PubMed] [Google Scholar]
  18. Cordoba-Chacon J, Gahete MD, Duran-Prado M, Pozo-Salas AI, Malagon MM, Gracia-Navarro F, Kineman RD, Luque RM, Castano JP. Identification and characterization of new functional truncated variants of somatostatin receptor subtype 5 in rodents. Cell Mol Life Sci. 2010;67:1147–63. doi: 10.1007/s00018-009-0240-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Csaba Z, Simon A, Helboe L, Epelbaum J, Dournaud P. Targeting sst2A receptor-expressing cells in the rat hypothalamus through in vivo agonist stimulation: neuroanatomical evidence for a major role of this subtype in mediating somatostatin functions. Endocrinology. 2003;144:1564–73. doi: 10.1210/en.2002-221090. [DOI] [PubMed] [Google Scholar]
  20. Cummings SL, Truong BG, Gietzen DW. Neuropeptide Y and somatostatin in the anterior piriform cortex alter intake of amino acid-deficient diets. Peptides. 1998;19:527–35. doi: 10.1016/s0196-9781(97)00468-3. [DOI] [PubMed] [Google Scholar]
  21. Danguir J. Food intake in rats is increased by intracerebroventricular infusion of the somatostatin analogue SMS 201-995 and is decreased by somatostatin antiserum. Peptides. 1988;9:211–3. doi: 10.1016/0196-9781(88)90030-7. [DOI] [PubMed] [Google Scholar]
  22. de Lecea L. Cortistatin--functions in the central nervous system. Mol Cell Endocrinol. 2008;286:88–95. doi: 10.1016/j.mce.2007.12.014. [DOI] [PubMed] [Google Scholar]
  23. Dournaud P, Gu YZ, Schonbrunn A, Mazella J, Tannenbaum GS, Beaudet A. Localization of the somatostatin receptor SST2A in rat brain using a specific anti-peptide antibody. J Neurosci. 1996;16:4468–78. doi: 10.1523/JNEUROSCI.16-14-04468.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Duran-Prado M, Malagon MM, Gracia-Navarro F, Castano JP. Dimerization of G protein-coupled receptors: new avenues for somatostatin receptor signalling, control and functioning. Mol Cell Endocrinol. 2008;286:63–8. doi: 10.1016/j.mce.2007.12.006. [DOI] [PubMed] [Google Scholar]
  25. Duran-Prado M, Gahete MD, Martinez-Fuentes AJ, Luque RM, Quintero A, Webb SM, Benito-Lopez P, Leal A, Schulz S, Gracia-Navarro F, Malagon MM, Castano JP. Identification and characterization of two novel truncated but functional isoforms of the somatostatin receptor subtype 5 differentially present in pituitary tumors. J Clin Endocrinol Metab. 2009;94:2634–43. doi: 10.1210/jc.2008-2564. [DOI] [PubMed] [Google Scholar]
  26. Erchegyi J, Waser B, Schaer JC, Cescato R, Brazeau JF, Rivier J, Reubi JC. Novel sst(4)-selective somatostatin (SRIF) agonists. 3. Analogues amenable to radiolabeling. J Med Chem. 2003;46:5597–605. doi: 10.1021/jm030245x. [DOI] [PubMed] [Google Scholar]
  27. Erchegyi J, Grace CR, Samant M, Cescato R, Piccand V, Riek R, Reubi JC, Rivier JE. Ring size of somatostatin analogues (ODT-8) modulates receptor selectivity and binding affinity. J Med Chem. 2008;51:2668–75. doi: 10.1021/jm701444y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Erchegyi J, Cescato R, Grace CR, Waser B, Piccand V, Hoyer D, Riek R, Rivier JE, Reubi JC. Novel, potent, and radio-iodinatable somatostatin receptor 1 (sst1) selective analogues. J Med Chem. 2009;52:2733–46. doi: 10.1021/jm801314f. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Fehlmann D, Langenegger D, Schuepbach E, Siehler S, Feuerbach D, Hoyer D. Distribution and characterisation of somatostatin receptor mRNA and binding sites in the brain and periphery. J Physiol Paris. 2000;94:265–81. doi: 10.1016/s0928-4257(00)00208-4. [DOI] [PubMed] [Google Scholar]
  30. Feifel D, Vaccarino FJ. Central somatostatin: a re-examination of its effects on feeding. Brain Res. 1990;535:189–94. doi: 10.1016/0006-8993(90)91600-l. [DOI] [PubMed] [Google Scholar]
  31. Feifel D, Vaccarino FJ, Rivier J, Vale WW. Evidence for a common neural mechanism mediating growth hormone-releasing factor-induced and somatostatin-induced feeding. Neuroendocrinology. 1993;57:299–305. doi: 10.1159/000126372. [DOI] [PubMed] [Google Scholar]
  32. Feifel D, Vaccarino FJ. Growth hormone-regulatory peptides (GHRH and somatostatin) and feeding: a model for the integration of central and peripheral function. Neurosci Biobehav Rev. 1994;18:421–33. doi: 10.1016/0149-7634(94)90055-8. [DOI] [PubMed] [Google Scholar]
  33. Fekete EM, Inoue K, Zhao Y, Rivier JE, Vale WW, Szucs A, Koob GF, Zorrilla EP. Delayed satiety-like actions and altered feeding microstructure by a selective type 2 corticotropin-releasing factor agonist in rats: intra-hypothalamic urocortin 3 administration reduces food intake by prolonging the post-meal interval. Neuropsychopharmacology. 2007;32:1052–68. doi: 10.1038/sj.npp.1301214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Finley JC, Maderdrut JL, Roger LJ, Petrusz P. The immunocytochemical localization of somatostatin-containing neurons in the rat central nervous system. Neuroscience. 1981;6:2173–92. doi: 10.1016/0306-4522(81)90006-3. [DOI] [PubMed] [Google Scholar]
  35. Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev. 1998;78:583–686. doi: 10.1152/physrev.1998.78.3.583. [DOI] [PubMed] [Google Scholar]
  36. Friedman JM. Leptin, leptin receptors and the control of body weight. Eur J Med Res. 1997;2:7–13. [PubMed] [Google Scholar]
  37. Gardi J, Obal F, Jr, Fang J, Zhang J, Krueger JM. Diurnal variations and sleep deprivation-induced changes in rat hypothalamic GHRH and somatostatin contents. Am J Physiol. 1999;277:R1339–44. doi: 10.1152/ajpregu.1999.277.5.R1339. [DOI] [PubMed] [Google Scholar]
  38. Gardi J, Szentirmai E, Hajdu I, Obal F, Jr, Krueger JM. The somatostatin analog, octreotide, causes accumulation of growth hormone-releasing hormone and depletion of angiotensin in the rat hypothalamus. Neurosci Lett. 2001;315:37–40. doi: 10.1016/s0304-3940(01)02311-4. [DOI] [PubMed] [Google Scholar]
  39. Goebel-Stengel M, Stengel A, Wang L, Taché Y. Orexigenic response to tail pinch: role of brain NPY(1) and corticotropin releasing factor receptors. Am J Physiol Regul Integr Comp Physiol. 2014;306:R164–74. doi: 10.1152/ajpregu.00335.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Goebel M, Stengel A, Wang L, Coskun T, Alsina-Fernandez J, Rivier J, Taché Y. Pattern of Fos expression in the brain induced by selective activation of somatostatin receptor 2 in rats. Brain Res. 2010;1351:150–64. doi: 10.1016/j.brainres.2010.07.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Gosnell BA, Levine AS. Reward systems and food intake: role of opioids. Int J Obes (Lond) 2009;33(Suppl 2):S54–8. doi: 10.1038/ijo.2009.73. [DOI] [PubMed] [Google Scholar]
  42. Grace CR, Erchegyi J, Koerber SC, Reubi JC, Rivier J, Riek R. Novel sst2-selective somatostatin agonists. Three-dimensional consensus structure by NMR. J Med Chem. 2006;49:4487–96. doi: 10.1021/jm060363v. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Grace CR, Erchegyi J, Samant M, Cescato R, Piccand V, Riek R, Reubi JC, Rivier JE. Ring size in octreotide amide modulates differently agonist versus antagonist binding affinity and selectivity. J Med Chem. 2008;51:2676–81. doi: 10.1021/jm701445q. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Hajdu I, Obal F, Jr, Gardi J, Laczi F, Krueger JM. Octreotide-induced drinking, vasopressin, and pressure responses: role of central angiotensin and ACh. Am J Physiol Regul Integr Comp Physiol. 2000;279:R271–7. doi: 10.1152/ajpregu.2000.279.1.R271. [DOI] [PubMed] [Google Scholar]
  45. Hajdu I, Szentirmai E, Obal F, Jr, Krueger JM. Different brain structures mediate drinking and sleep suppression elicited by the somatostatin analog, octreotide, in rats. Brain Res. 2003;994:115–23. doi: 10.1016/j.brainres.2003.09.029. [DOI] [PubMed] [Google Scholar]
  46. Hannon JP, Petrucci C, Fehlmann D, Viollet C, Epelbaum J, Hoyer D. Somatostatin sst2 receptor knock-out mice: localisation of sst1-5 receptor mRNA and binding in mouse brain by semi-quantitative RT-PCR, in situ hybridisation histochemistry and receptor autoradiography. Neuropharmacology. 2002;42:396–413. doi: 10.1016/s0028-3908(01)00186-1. [DOI] [PubMed] [Google Scholar]
  47. Horvath TL, Diano S, van den Pol AN. Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations. J Neurosci. 1999;19:1072–87. doi: 10.1523/JNEUROSCI.19-03-01072.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Hotta M, Shibasaki T, Arai K, Demura H. Corticotropin-releasing factor receptor type 1 mediates emotional stress-induced inhibition of food intake and behavioral changes in rats. Brain Res. 1999;823:221–5. doi: 10.1016/s0006-8993(99)01177-4. [DOI] [PubMed] [Google Scholar]
  49. Ishikawa M, Mizobuchi M, Takahashi H, Bando H, Saito S. Somatostatin release as measured by in vivo microdialysis: circadian variation and effect of prolonged food deprivation. Brain Res. 1997;749:226–31. doi: 10.1016/S0006-8993(96)01163-8. [DOI] [PubMed] [Google Scholar]
  50. Jain MR, Horvath TL, Kalra PS, Kalra SP. Evidence that NPY Y1 receptors are involved in stimulation of feeding by orexins (hypocretins) in sated rats. Regul Pept. 2000;87:19–24. doi: 10.1016/s0167-0115(99)00102-0. [DOI] [PubMed] [Google Scholar]
  51. Johansson O, Hokfelt T, Elde RP. Immunohistochemical distribution of somatostatin-like immunoreactivity in the central nervous system of the adult rat. Neuroscience. 1984;13:265–339. doi: 10.1016/0306-4522(84)90233-1. [DOI] [PubMed] [Google Scholar]
  52. Karasawa H, Yakabi S, Wang L, Stengel A, Rivier J, Taché Y. Brain somatostatin receptor 2 mediates the dipsogenic effect of central somatostatin and cortistatin in rats: role in drinking behavior. Am J Physiol Regul Integr Comp Physiol. 2014a;307:R793–801. doi: 10.1152/ajpregu.00248.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Karasawa H, Yakabi S, Wang L, Taché Y. Orexin-1 receptor mediates the increased food and water intake induced by intracerebroventricular injection of the stable somatostatin pan-agonist, ODT8-SST in rats. Neurosci Lett. 2014b;576C:88–92. doi: 10.1016/j.neulet.2014.05.063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Krahn DD, Gosnell BA, Grace M, Levine AS. CRF antagonist partially reverses CRF- and stress-induced effects on feeding. Brain Res Bull. 1986;17:285–9. doi: 10.1016/0361-9230(86)90233-9. [DOI] [PubMed] [Google Scholar]
  55. Kumar U, Grant M. Somatostatin and somatostatin receptors. Results Probl Cell Differ. 2010;50:137–84. doi: 10.1007/400_2009_29. [DOI] [PubMed] [Google Scholar]
  56. Kunii K, Yamanaka A, Nambu T, Matsuzaki I, Goto K, Sakurai T. Orexins/hypocretins regulate drinking behaviour. Brain Res. 1999;842:256–61. doi: 10.1016/s0006-8993(99)01884-3. [DOI] [PubMed] [Google Scholar]
  57. Lanneau C, Peineau S, Petit F, Epelbaum J, Gardette R. Somatostatin modulation of excitatory synaptic transmission between periventricular and arcuate hypothalamic nuclei in vitro. J Neurophysiol. 2000;84:1464–74. doi: 10.1152/jn.2000.84.3.1464. [DOI] [PubMed] [Google Scholar]
  58. Lin MT, Chen JJ, Ho LT. Hypothalamic involvement in the hyperglycemia and satiety actions of somatostatin in rats. Neuroendocrinology. 1987;45:62–7. doi: 10.1159/000124704. [DOI] [PubMed] [Google Scholar]
  59. McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, Oldfield BJ, Mendelsohn FA, Chai SY. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol. 2003;35:901–18. doi: 10.1016/s1357-2725(02)00306-0. [DOI] [PubMed] [Google Scholar]
  60. Meyer DK, Conzelmann U, Schultheiss K. Effects of somatostatin-14 on the in vitro release of [3H]GABA from slices of rat caudatoputamen. Neuroscience. 1989;28:61–8. doi: 10.1016/0306-4522(89)90232-7. [DOI] [PubMed] [Google Scholar]
  61. Miselis RR. The efferent projections of the subfornical organ of the rat: a circumventricular organ within a neural network subserving water balance. Brain Res. 1981;230:1–23. doi: 10.1016/0006-8993(81)90388-7. [DOI] [PubMed] [Google Scholar]
  62. Moellenhoff E, Blume A, Culman J, Chatterjee B, Herdegen T, Lebrun CJ, Unger T. Effect of repetitive icv injections of ANG II on c-Fos and AT(1)-receptor expression in the rat brain. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1095–104. doi: 10.1152/ajpregu.2001.280.4.R1095. [DOI] [PubMed] [Google Scholar]
  63. Moga MM, Gray TS. Evidence for corticotropin-releasing factor, neurotensin, and somatostatin in the neural pathway from the central nucleus of the amygdala to the parabrachial nucleus. J Comp Neurol. 1985;241:275–84. doi: 10.1002/cne.902410304. [DOI] [PubMed] [Google Scholar]
  64. Muroya S, Funahashi H, Yamanaka A, Kohno D, Uramura K, Nambu T, Shibahara M, Kuramochi M, Takigawa M, Yanagisawa M, Sakurai T, Shioda S, Yada T. Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci. 2004;19:1524–34. doi: 10.1111/j.1460-9568.2004.03255.x. [DOI] [PubMed] [Google Scholar]
  65. Nakahara K, Takata S, Ishii A, Nagao K, Bannai M, Takahashi M, Murakami N. Somatostatin is involved in anorexia in mice fed a valine-deficient diet. Amino Acids. 2012;42:1397–404. doi: 10.1007/s00726-011-0836-z. [DOI] [PubMed] [Google Scholar]
  66. Nanda SA, Qi C, Roseboom PH, Kalin NH. Predator stress induces behavioral inhibition and amygdala somatostatin receptor 2 gene expression. Genes Brain Behav. 2008;7:639–48. doi: 10.1111/j.1601-183X.2008.00401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Negro-Vilar A, Saavedra JM. Changes in brain somatostatin and vasopressin levels after stress in spontaneously hypertensive and Wistar-Kyoto rats. Brain Res Bull. 1980;5:353–8. doi: 10.1016/s0361-9230(80)80004-9. [DOI] [PubMed] [Google Scholar]
  68. O'Shea D, Morgan DG, Meeran K, Edwards CM, Turton MD, Choi SJ, Heath MM, Gunn I, Taylor GM, Howard JK, Bloom CI, Small CJ, Haddo O, Ma JJ, Callinan W, Smith DM, Ghatei MA, Bloom SR. Neuropeptide Y induced feeding in the rat is mediated by a novel receptor. Endocrinology. 1997;138:196–202. doi: 10.1210/endo.138.1.4899. [DOI] [PubMed] [Google Scholar]
  69. Oatley K. Dissociation of the circadian drinking pattern from eating. Nature. 1971;229:494–6. doi: 10.1038/229494a0. [DOI] [PubMed] [Google Scholar]
  70. Olias G, Viollet C, Kusserow H, Epelbaum J, Meyerhof W. Regulation and function of somatostatin receptors. J Neurochem. 2004;89:1057–91. doi: 10.1111/j.1471-4159.2004.02402.x. [DOI] [PubMed] [Google Scholar]
  71. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. 1999;20:157–98. doi: 10.1006/frne.1999.0183. [DOI] [PubMed] [Google Scholar]
  72. Perianes-Cachero A, Burgos-Ramos E, Puebla-Jimenez L, Canelles S, Viveros MP, Mela V, Chowen JA, Argente J, Arilla-Ferreiro E, Barrios V. Leptin-induced downregulation of the rat hippocampal somatostatinergic system may potentiate its anorexigenic effects. Neurochem Int. 2012;61:1385–96. doi: 10.1016/j.neuint.2012.09.019. [DOI] [PubMed] [Google Scholar]
  73. Perianes-Cachero A, Burgos-Ramos E, Puebla-Jimenez L, Canelles S, Frago LM, Hervas-Aguilar A, de Frutos S, Toledo-Lobo MV, Mela V, Viveros MP, Argente J, Chowen JA, Arilla-Ferreiro E, Barrios V. Acute up-regulation of the rat brain somatostatin receptor-effector system by leptin is related to activation of insulin signaling and may counteract central leptin actions. Neuroscience. 2013;252:289–301. doi: 10.1016/j.neuroscience.2013.08.019. [DOI] [PubMed] [Google Scholar]
  74. Polkowska J, Wankowska M. Effects of maternal deprivation on the somatotrophic axis and neuropeptide Y in the hypothalamus and pituitary in female lambs. The histomorphometric study. Folia Histochem Cytobiol. 2010;48:299–305. doi: 10.2478/v10042-010-0024-0. [DOI] [PubMed] [Google Scholar]
  75. Pradayrol L, Jornvall H, Mutt V, Ribet A. N-terminally extended somatostatin: the primary structure of somatostatin-28. FEBS Lett. 1980;109:55–8. doi: 10.1016/0014-5793(80)81310-x. [DOI] [PubMed] [Google Scholar]
  76. Priego T, Ibanez de Caceres I, Martin AI, Villanua MA, Lopez-Calderon A. Endotoxin administration increases hypothalamic somatostatin mRNA through nitric oxide release. Regul Pept. 2005;124:113–8. doi: 10.1016/j.regpep.2004.07.001. [DOI] [PubMed] [Google Scholar]
  77. Quintela M, Senaris R, Heiman ML, Casanueva FF, Dieguez C. Leptin inhibits in vitro hypothalamic somatostatin secretion and somatostatin mRNA levels. Endocrinology. 1997;138:5641–4. doi: 10.1210/endo.138.12.5713. [DOI] [PubMed] [Google Scholar]
  78. Rezek M, Havlicek V, Hughes KR, Friesen H. Central site of action of somatostatin (SRIF): role of hippocampus. Neuropharmacology. 1976;15:499–504. doi: 10.1016/0028-3908(76)90062-9. [DOI] [PubMed] [Google Scholar]
  79. Schindler M, Humphrey PP, Lohrke S, Friauf E. Immunohistochemical localization of the somatostatin sst2(b) receptor splice variant in the rat central nervous system. Neuroscience. 1999;90:859–74. doi: 10.1016/s0306-4522(98)00483-7. [DOI] [PubMed] [Google Scholar]
  80. Schneeberger M, Gomis R, Claret M. Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J Endocrinol. 2014;220:T25–46. doi: 10.1530/JOE-13-0398. [DOI] [PubMed] [Google Scholar]
  81. Schulz S, Handel M, Schreff M, Schmidt H, Hollt V. Localization of five somatostatin receptors in the rat central nervous system using subtype-specific antibodies. J Physiol Paris. 2000;94:259–64. doi: 10.1016/s0928-4257(00)00212-6. [DOI] [PubMed] [Google Scholar]
  82. Sekino A, Ohata H, Mano-Otagiri A, Arai K, Shibasaki T. Both corticotropin-releasing factor receptor type 1 and type 2 are involved in stress-induced inhibition of food intake in rats. Psychopharmacology (Berl) 2004;176:30–8. doi: 10.1007/s00213-004-1863-1. [DOI] [PubMed] [Google Scholar]
  83. Shibasaki T, Kim YS, Yamauchi N, Masuda A, Imaki T, Hotta M, Demura H, Wakabayashi I, Ling N, Shizume K. Antagonistic effect of somatostatin on corticotropin-releasing factor-induced anorexia in the rat. Life Sci. 1988a;42:329–34. doi: 10.1016/0024-3205(88)90642-x. [DOI] [PubMed] [Google Scholar]
  84. Shibasaki T, Yamauchi N, Kato Y, Masuda A, Imaki T, Hotta M, Demura H, Oono H, Ling N, Shizume K. Involvement of corticotropin-releasing factor in restraint stress-induced anorexia and reversion of the anorexia by somatostatin in the rat. Life Sci. 1988b;43:1103–10. doi: 10.1016/0024-3205(88)90468-7. [DOI] [PubMed] [Google Scholar]
  85. Shinohara K, Isobe Y, Takeuchi J, Inouye ST. Circadian rhythms of somatostatin-immunoreactivity in the suprachiasmatic nucleus of the rat. Neurosci Lett. 1991;129:59–62. doi: 10.1016/0304-3940(91)90720-e. [DOI] [PubMed] [Google Scholar]
  86. Siehler S, Nunn C, Hannon J, Feuerbach D, Hoyer D. Pharmacological profile of somatostatin and cortistatin receptors. Mol Cell Endocrinol. 2008;286:26–34. doi: 10.1016/j.mce.2007.12.007. [DOI] [PubMed] [Google Scholar]
  87. Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, Jerman JC. SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol. 2001;132:1179–82. doi: 10.1038/sj.bjp.0703953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Sominsky L, Spencer SJ. Eating behavior and stress: a pathway to obesity. Front Psychol. 2014;5:434. doi: 10.3389/fpsyg.2014.00434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Somiya H, Tonoue T. Neuropeptides as central integrators of autonomic nerve activity: effects of TRH, SRIF, VIP and bombesin on gastric and adrenal nerves. Regul Pept. 1984;9:47–52. doi: 10.1016/0167-0115(84)90006-5. [DOI] [PubMed] [Google Scholar]
  90. Spary EJ, Maqbool A, Batten TF. Expression and localisation of somatostatin receptor subtypes sst1-sst5 in areas of the rat medulla oblongata involved in autonomic regulation. J Chem Neuroanat. 2008;35:49–66. doi: 10.1016/j.jchemneu.2007.06.002. [DOI] [PubMed] [Google Scholar]
  91. Stengel A, Coskun T, Goebel M, Wang L, Craft L, Alsina-Fernandez J, Rivier J, Taché Y. Central injection of the stable somatostatin analog ODT8-SST induces a somatostatin2 receptor-mediated orexigenic effect: role of neuropeptide Y and opioid signaling pathways in rats. Endocrinology. 2010a;151:4224–35. doi: 10.1210/en.2010-0195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Stengel A, Goebel M, Wang L, Rivier J, Kobelt P, Mönnikes H, Taché Y. Activation of brain somatostatin(2) receptors stimulates feeding in mice: Analysis of food intake microstructure. Physiol Behav. 2010b;101:614–22. doi: 10.1016/j.physbeh.2010.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Stengel A, Goebel M, Wang L, Rivier J, Kobelt P, Mönnikes H, Taché Y. Selective central activation of somatostatin2 receptor increases food intake, grooming behavior and rectal temperature in rats. J Physiol Pharmacol. 2010c;61:399–407. [PMC free article] [PubMed] [Google Scholar]
  94. Stengel A, Goebel-Stengel M, Wang L, Luckey A, Hu E, Rivier J, Taché Y. Central administration of pan-somatostatin agonist ODT8-SST prevents abdominal surgery-induced inhibition of circulating ghrelin, food intake and gastric emptying in rats. Neurogastroenterol Motil. 2011;23:e294–308. doi: 10.1111/j.1365-2982.2011.01721.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Stengel A, Taché Y. Yin and Yang - the Gastric X/A-like Cell as Possible Dual Regulator of Food Intake. J Neurogastroenterol Motil. 2012;18:138–49. doi: 10.5056/jnm.2012.18.2.138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Stengel A, Rivier J, Taché Y. Modulation of the adaptive response to stress by brain activation of selective somatostatin receptor subtypes. Peptides. 2013;42:70–7. doi: 10.1016/j.peptides.2012.12.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Stengel A, Taché Y. CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress. Front Neurosci. 2014a;8:52. doi: 10.3389/fnins.2014.00052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Stengel A, Taché Y. Brain peptides and the modulation of postoperative gastric ileus. Curr Opin Pharmacol. 2014b;19:31–7. doi: 10.1016/j.coph.2014.06.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Stepanyan Z, Kocharyan A, Behrens M, Koebnick C, Pyrski M, Meyerhof W. Somatostatin, a negative-regulator of central leptin action in the rat hypothalamus. J Neurochem. 2007;100:468–78. doi: 10.1111/j.1471-4159.2006.04219.x. [DOI] [PubMed] [Google Scholar]
  100. Tachibana T, Cline MA, Sugahara K, Ueda H, Hiramatsu K. Central administration of somatostatin stimulates feeding behavior in chicks. Gen Comp Endocrinol. 2009;161:354–9. doi: 10.1016/j.ygcen.2009.01.022. [DOI] [PubMed] [Google Scholar]
  101. Tanaka J, Fujisawa S, Nomura M. GABAergic modulation of the ANG II-induced drinking response in the rat medial preoptic nucleus. Pharmacol Biochem Behav. 2003;76:43–51. doi: 10.1016/s0091-3057(03)00195-3. [DOI] [PubMed] [Google Scholar]
  102. Tannenbaum GS, Patel YC. On the fate of centrally administered somatostatin in the rat: massive hypersomatostatinemia resulting from leakage into the peripheral circulation has effects on growth hormone secretion and glucoregulation. Endocrinology. 1986;118:2137–43. doi: 10.1210/endo-118-5-2137. [DOI] [PubMed] [Google Scholar]
  103. Tostivint H, Ocampo Daza D, Bergqvist CA, Quan FB, Bougerol M, Lihrmann I, Larhammar D. Molecular evolution of GPCRs: Somatostatin/urotensin II receptors. J Mol Endocrinol. 2014;52:T61–86. doi: 10.1530/JME-13-0274. [DOI] [PubMed] [Google Scholar]
  104. van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci. 2004;7:493–4. doi: 10.1038/nn1226. [DOI] [PubMed] [Google Scholar]
  105. Van Wimersma Greidanus TB, Maigret C, Krechting B. Excessive grooming induced by somatostatin or its analog SMS 201-995. Eur J Pharmacol. 1987;144:277–85. doi: 10.1016/0014-2999(87)90380-3. [DOI] [PubMed] [Google Scholar]
  106. Vecsei L, Pavo I, Zsigo J, Penke B, Widerlov E. Comparative studies of somatostatin-14 and some of its fragments on passive avoidance behavior, open field activity and on barrel rotation phenomenon in rats. Peptides. 1989;10:1153–7. doi: 10.1016/0196-9781(89)90007-7. [DOI] [PubMed] [Google Scholar]
  107. Vecsei L, Widerlov E. Effects of somatostatin-28 and some of its fragments and analogs on open-field behavior, barrel rotation, and shuttle box learning in rats. Psychoneuroendocrinology. 1990;15:139–45. doi: 10.1016/0306-4530(90)90022-2. [DOI] [PubMed] [Google Scholar]
  108. Vijayan E, McCann SM. Suppression of feeding and drinking activity in rats following intraventricular injection of thyrotropin releasing hormone (TRH) Endocrinology. 1977;100:1727–30. doi: 10.1210/endo-100-6-1727. [DOI] [PubMed] [Google Scholar]
  109. Viollet C, Prevost G, Maubert E, Faivre-Bauman A, Gardette R, Kordon C, Loudes C, Slama A, Epelbaum J. Molecular pharmacology of somatostatin receptors. Fundam Clin Pharmacol. 1995;9:107–13. doi: 10.1111/j.1472-8206.1995.tb00269.x. [DOI] [PubMed] [Google Scholar]
  110. Viollet C, Lepousez G, Loudes C, Videau C, Simon A, Epelbaum J. Somatostatinergic systems in brain: networks and functions. Mol Cell Endocrinol. 2008;286:75–87. doi: 10.1016/j.mce.2007.09.007. [DOI] [PubMed] [Google Scholar]
  111. Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I, Miwa Y, Goto K, Sakurai T. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res. 2000;859:404–9. doi: 10.1016/s0006-8993(00)02043-6. [DOI] [PubMed] [Google Scholar]
  112. Zou S, Somvanshi RK, Paik S, Kumar U. Colocalization of cannabinoid receptor 1 with somatostatin and neuronal nitric oxide synthase in rat brain hypothalamus. J Mol Neurosci. 2015;55:480–91. doi: 10.1007/s12031-014-0369-5. [DOI] [PubMed] [Google Scholar]

RESOURCES