Anxiolytic-like effects of somatostatin isoforms SST 14 and SST 28 in two animal models (Rattus norvegicus) after intra-amygdalar and intra-septal microinfusions

Yeung, Michelle; Engin, Elif; Treit, Dallas

doi:10.1007/s00213-011-2248-x

Cited by 29 publications

(25 citation statements)

References 52 publications

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“…Growing evidence suggest that SST in the amygdala powerfully reduces anxiety (1, 2, 4–6), indicating that SST represents a potential pharmacological target against depression and anxiety (100, 101). Animal models show anxiolytic, and possibly antidepressant, effects of SST in the amygdala, and suggest a role in fear learning and expression (102, 103).…”

Section: Discussionmentioning

confidence: 99%

“…Growing evidence indicates expression of somatostatin (SST) and neuropeptide-Y (NPY) in amygdala neurons plays key roles in fear and stress responses, and in modulation of anxiety (1–6). Intraventricular, and intra-amygdala infusions of SST in rodents result in anxiolytic and antidepressant effects (1, 7).…”

Section: Introductionmentioning

confidence: 99%

“…Intraventricular, and intra-amygdala infusions of SST in rodents result in anxiolytic and antidepressant effects (1, 7). Mice lacking SST display increased anxiety-like behaviors (2), and neuroendocrine and molecular abnormalities reported in subjects with anxiety and depression (8).…”

Section: Introductionmentioning

confidence: 99%

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Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms

Pantazopoulos

Wiseman

Markota

et al. 2017

Biological Psychiatry

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Background Growing evidence points to a key role for somatostatin (SST) in schizophrenia (SZ) and bipolar disorder (BD). In the amygdala, neurons expressing SST play an important role in the regulation of anxiety, often comorbid in these disorders. We tested the hypothesis that SST-immunoreactive (IR) neurons are decreased in the amygdala of subjects with SZ and BD. Evidence for circadian SST expression in the amygdala and disrupted circadian rhythms and rhythmic peaks of anxiety in BD suggest a disruption of rhythmic expression of SST in this disorder. Methods Amygdala sections from 12 SZ, 15 BD, and 15 control subjects were processed for immunocytochemistry for SST and neuropeptide Y (NPY), a neuropeptide partially co-expressed in SST-IR neurons. Total numbers (Nt) of IR neurons were measured. Time of death (TOD) was used to test associations with circadian rhythms. Results SST-IR neurons were decreased in the lateral amygdala nucleus in BD (Nt, p= 0.003) and SZ (Nt, p=0.02). In normal controls, Nt of SST-IR neurons varied according to TOD. This pattern was altered in BD, characterized by decreases of SST-IR neurons selectively in subjects with TOD corresponding to the day (06:00–17:59). Numbers of NPY-IR neurons were not affected. Conclusions Decreased SST-IR neurons in the amygdala of SZ and BD, interpreted here as decreased SST expression, may disrupt responses to fear and anxiety regulation in these subjects. In BD, our findings raise the possibility that morning peaks of anxiety depend on a disruption of circadian regulation of SST expression in the amygdala.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms

Pantazopoulos

Wiseman

Markota

et al. 2017

Biological Psychiatry

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“…Intra-ventricular administration of somatostatin in rats produces anxiolytic- and antidepressant-like behaviors in the elevated plus-maze and forced swim tests, and a neurophysiological signature of anxiolytic drugs (e.g., reduction of theta frequency and theta frequency curve slope; Engin et al, 2008). Mice with intra-amygdalar and intra-septal microinfusions of somatostatin-14 and somatostatin-28 display reduced anxiety-like behavior in the elevated plus-maze and shock-probe tests (Yeung et al, 2011). Moreover, anxiolytic effects in the elevated plus-maze test are described after intra-cerebroventricular infusions of a selective Sst 2 receptor agonist, but not after infusions of the other four receptor agonists; antidepressant-like effects in the forced swim test are observed following infusions of either Sst 2 or Sst 3 agonists (Engin and Treit, 2009).…”

Section: Somatostatin: Genes Neurons and Pharmacologymentioning

confidence: 99%

Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

2013

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Our knowledge of the pathophysiology of affect dysregulation has progressively increased, but the pharmacological treatments remain inadequate. Here, we summarize the current literature on deficits in somatostatin, an inhibitory modulatory neuropeptide, in major depression and other neurological disorders that also include mood disturbances. We focus on direct evidence in the human postmortem brain, and review rodent genetic and pharmacological studies probing the role of the somatostatin system in relation to mood. We also briefly go over pharmacological developments targeting the somatostatin system in peripheral organs and discuss the challenges of targeting the brain somatostatin system. Finally, the fact that somatostatin deficits are frequently observed across neurological disorders suggests a selective cellular vulnerability of somatostatin-expressing neurons. Potential cell intrinsic factors mediating those changes are discussed, including nitric oxide induced oxidative stress, mitochondrial dysfunction, high inflammatory response, high demand for neurotrophic environment, and overall aging processes. Together, based on the co-localization of somatostatin with gamma-aminobutyric acid (GABA), its presence in dendritic-targeting GABA neuron subtypes, and its temporal-specific function, we discuss the possibility that deficits in somatostatin play a central role in cortical local inhibitory circuit deficits leading to abnormal corticolimbic network activity and clinical mood symptoms across neurological disorders.

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“…36 Microinjections of SST into the amygdala or ventricles exert anxiolytic effects in the elevated plus maze test. 37,38 Reducing SST neuronal function acutely and chronically in the frontal cortex yields opposite effects on behavioral emotionality, suggesting that mood regulation may depend on complex network adaptations including multiple regions and on the timeframe. 39 In addition, it is not known whether HPA axis dysregulation of Sst KO mice contributes to these behavioral changes.…”

Section: Introductionmentioning

confidence: 99%

Somatostatin, neuronal vulnerability and behavioral emotionality

2015

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Somatostatin (SST) deficits are common pathological features in depression and other neurological disorders with mood disturbances, but little is known about the contribution of SST deficits to mood symptoms or causes of these deficits. Here we show that mice lacking Sst (SstKO) exhibit elevated behavioral emotionality, high basal plasma corticosterone and reduced gene expression of Bdnf, Cortistatin, and Gad67, together recapitulating behavioral, neuroendocrine and molecular features of human depression. Studies in SstKO and heterozygous (SstHZ) mice show that elevated corticosterone is not sufficient to reproduce the behavioral phenotype, suggesting a putative role for Sst cell-specific molecular changes. Using laser-capture microdissection, we show that cortical SST-positive interneurons display significantly greater transcriptome deregulations after chronic stress compared to pyramidal neurons. Protein translation through eukaryotic initiation factor 2 (EIF2) signaling, a pathway previously implicated in neurodegenerative diseases, was most affected and suppressed in stress-exposed SST neurons. We then show that activating EIF2 signaling through EIF2 kinase inhibition mitigated stress-induced behavioral emotionality in mice. Together, our data suggest that (1) low SST plays a causal role in mood-related phenotypes, (2) deregulated EIF2-mediated protein translation may represent a mechanism for vulnerability of SST neurons, and (3) that global EIF2 signaling has antidepressant/anxiolytic potential.

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Anxiolytic-like effects of somatostatin isoforms SST 14 and SST 28 in two animal models (Rattus norvegicus) after intra-amygdalar and intra-septal microinfusions

Cited by 29 publications

References 52 publications

Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms

Decreased Numbers of Somatostatin-Expressing Neurons in the Amygdala of Subjects With Bipolar Disorder or Schizophrenia: Relationship to Circadian Rhythms

Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

Somatostatin, neuronal vulnerability and behavioral emotionality

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