Browsing by Subject "Somatostatin"

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    Elucidating mechanisms that lead to persistent anxiety-like behavior in rats following repeated activation of corticotropin-releasing factor receptors in the basolateral amygdala
    (2012-03-16) Gaskins, Denise; Shekhar, Anantha, 1957-; Harris, Robert A. (Robert Allison), 1939-; Hingtgen, Cynthia M., 1966-; Truitt, William A.
    Anxiety disorders are estimated to impact 1 in 4 individuals within their lifetime. For some individuals, repeated episodes of the stress response leads to pathological anxiety and depression. The stress response is linked to increased levels of corticotropin-releasing factor (CRF) in the basolateral nucleus of the amygdala (BLA), a putative site for regulating anxiety and associative processes related to aversive emotional memories, and activation of CRF receptors in the BLA of rats produces anxiety-like behavior. Mimicking repeated episodes of the stress response, sub-anxiogenic doses of urocortin 1 (Ucn1), a CRF receptor agonist, are microinjected into the BLA of rats for five consecutive days, a procedure called priming. This results in 1) behavioral sensitization, such that a previously non-efficacious dose of Ucn1 will elicit anxiety-like response after the 3rd injection and 2) the development of a persistent anxiety-like phenotype that lasts at least five weeks after the last injection without any further treatment. Therefore, the purpose of this thesis was to identify mechanisms involved in the Ucn1-priming-induced anxiogenesis. The first a set of experiments revealed that the anxiety-like behavior was not due to aversive conditioning to the context or partner cues of the testing environment. Next, Ucn1-priming-induced gene expression changes in the BLA were identified: mRNA expression for Sst2, Sst4, Chrna4, Chrma4, and Gabrr1 was significantly reduced in Ucn1-primed compared to Vehicle-primed rats. Of these, Sst2 emerged as the primary receptor of interest. Subsequent studies found that antagonizing the Sstr2 resulted in anxiety-like behavior and activation of Sstr2 blocked acute Ucn1-induced anxiety-like responses. Furthermore, pretreatment with a Sstr2 agonist delayed the behavioral sensitization observed in Ucn1-induced priming but did not stop the development of persistent anxiety-like behavior or the Ucn1-priming-induced decrease in the Sstr2 mRNA. These results suggest that the decrease in Sstr2 mRNA is associated with the expression of persistent anxiety-like behavior but dissociated from the mechanisms causing the behavioral sensitization. Pharmacological studies confirmed that a reduced Sstr2 mediated effect in the BLA is likely to play a role in persistent anxiety and should be investigated further.
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    Sphingosine-1-phosphate receptor 1 agonist SEW2871 alters membrane properties of late-firing somatostatin expressing neurons in the central lateral amygdala
    (Elsevier, 2022) Mork, Briana E.; Lamerand, Sydney R.; Zhou, Shudi; Taylor, Bradley K.; Sheets, Patrick L.; Pharmacology and Toxicology, School of Medicine
    Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide spectrum of biological processes including apoptosis, immune response and inflammation. Here, we sought to understand how S1P signaling affects neuronal excitability in the central amygdala (CeA), which is a brain region associated with fear learning, aversive memory, and the affective dimension of pain. Because the G-protein coupled S1P receptor 1 (S1PR1) has been shown to be the primary mediator of S1P signaling, we utilized S1PR1 agonist SEW2871 and S1PR1 antagonist NIBR to determine a potential role of S1PR1 in altering the cellular physiology of neurons in the lateral division of the CeA (CeL) that share the neuronal lineage marker somatostatin (Sst). CeL-Sst neurons play a critical role in expression of conditioned fear and pain modulation. Here we used transgenic breeding strategies to identify fluorescently labeled CeL-Sst neurons for electrophysiological recordings. Using principal component analysis, we identified two primary subtypes of Sst neurons within the CeL in both male and female mice. We denoted the two types regular-firing (type A) and late-firing (type B) CeL-Sst neurons. In response to SEW2871 application, Type A neurons exhibited increased input resistance, while type B neurons displayed a depolarized resting membrane potential and voltage threshold, increased current threshold, and decreased voltage height. NIBR application had no effect on CeL Sst neurons, indicating the absence of tonic S1P-induced S1PR1. Our findings reveal subtypes of Sst neurons within the CeL that are uniquely affected by S1PR1 activation, which may have implications for how S1P alters supraspinal circuits.
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    Studies on the regulation of rat renal gluconeogensis: mechanism of action of somatostatin
    (1984) Alkhawajah, Abdulaziz Mansour
    Liver is considered the main glucostatic organ in the mammals. However, under a variety of physiological and pathological conditions the kidney plays a significant role in controlling glucose homeostasis. Regulation of renal gluconeogenesis by peptide hormones has not been extensively studied. Somatostatin, the growth hormone release inhibiting factor, has been shown to stimulate renal gluconeogenesis. In this study the detail mechanism of somatostatinstimulated renal glucose production is investigated. Prior treatment of the animals with reserpine to deplete tissues catecholamine stores did not abolish the stimulatory effact of soma tost a tin indicating that catecholamine rel ease may not mediate the enhanced gluconeogenic activity. Somatostatin effect was blocked by the alpha1-antagonist, prazocin, but not by the alpha2 antagonist, yohimbine, suggesting that alpha1 adrenergic receptors may be involved in somatostatin action. somatostatin decreased glucagonstimulated cyclic AMP accumulation and caused small but significant increase in renal cyclic AMP levels. It is proposed that somatostatin may act as a partial agonist to stimulate cyclic AMP production in rat renal tissues. Somatostatin-stimulated renal glucose synthesis is calcium dependent, since in a calcium-free system, somatostatin had no effect. Furthermore, somatostatin increased 45cCa++_ influx into renal tissues. The key rate limiting gluconeogenie reactions is stimulated by somatostatin in the renal cells as demonstrated by the increase in incorporation of [14c] from [14c]-pyruvate and [14c]-bicarbonate into glucose. In addition, somatostatin infusion increased the activities of the key enzymes, phosphoenol pyruvate carboxykinase and pyruvate carboxylase with no effect on fructose 1,6-bisphosphatase nor glucose-6-phosphatase. Somatostatin is shown to bind to one class of recognition sites in the rat renal plasma membranes which showed high Na-K ATPase and adenylate cylase (positive marker enzymes) activites and low activities for succinic dehydrogenase, glucose-6-phosphatase and beta-glucuronidase (negative marker enzymes). The dissociation constant (Kd) for the binding was 0.91 ± 0.06 nM and the binding capacity (Bmax) was 37.59 ± 1.04 fmole/mg protein. Somatostatin and Tyr1-somatostatin displaced [125I]-Tyr1-somatostatin binding with inhibition constant (Kr) values of 31.5 and 100 pM, respectively. This indicates the presence of specific receptors for somatostatin on rat renal cells.