Effect of haloperidol withdrawal on somatostatin level and binding in rat brain

1990 ◽  
Vol 10 (1) ◽  
pp. 15-22 ◽  
Author(s):  
E. Perez-Oso ◽  
M. P. Lopez-Ruiz ◽  
E. Arilla
Keyword(s):  
Side Effects ◽  
Rat Brain ◽  
Specific Binding ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Chronic Administration ◽  
Brain Areas ◽  
Frontoparietal Cortex ◽  
Receptor Number ◽  
Haloperidol Treatment

The effects of withdrawal on the level and specific binding of somatostatin in the frontoparietal cortex and hippocampus of the rat after chronic haloperidol treatment were examined using125I-Tyr11 somatostatin as tracer. One week after haloperiodol withdrawal the number of specific somatostatin receptors in both brain areas returned to control values, after having decreased as the result of chronic administration. Neither administration of haloperidol nor withdrawal of it affected the levels of somatostatin-like immunoreactivity (SLI) in the two brain areas studied. The return of the somatostatin receptor number to control values after haloperidol withdrawal may be related to the motor side-effects that are clinically observed when the haloperidol treatment is terminated.

Effects of Acute and Chronic Ethanol Administration and its Withdrawal on the Level and Binding of Somatostatin in Rat Brain

1990 ◽  
Vol 79 (5) ◽  
pp. 451-456 ◽  
Author(s):  
V. Barrios ◽  
M. N. Rodríguez-Sánchez ◽  
E. Arilla
Keyword(s):  
Nervous System ◽  
Specific Binding ◽  
Somatostatin Receptors ◽  
Chronic Administration ◽  
Ethanol Administration ◽  
Actual Number ◽  
Brain Areas ◽  
Frontoparietal Cortex ◽  
Acute Ethanol ◽  
Chronic Ethanol Administration

1. Acute ethanol administration resulted in an increase in the total number of specific somatostatin receptors in rat frontoparietal cortex and hippocampus, and a decrease in the level of somatostatin-like immuno-reactivity in the hippocampus but not in the frontoparietal cortex. 2. Chronic administration of ethanol caused a decrease in the number of somatostatin receptors in the frontoparietal cortex but not in the hippocampus, although the level of somatostatin-like immunoreactivity was unchanged in both brain areas. 3. A week after suppressing ethanol the value for specific binding of tracer to somatostatin receptors in the frontoparietal cortex was not significantly different from that of the control rats, although the actual number of receptors was slightly lower. 4. These results suggest a possible role for somatostatin in the nervous system during alcoholism and the post-withdrawal reaction.

scholarly journals Somatostatin analogues in the therapy of neuroendocrine tumors: Indications, contraindications, side-effects

2020 ◽  
Vol 74 ◽  
pp. 272-282
Author(s):  
Beata Polowczyk ◽  
Marcin Kałużny ◽  
Marek Bolanowski
Keyword(s):  
Side Effects ◽  
Neuroendocrine Tumors ◽  
Anterior Pituitary ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogues ◽  
In Vivo Studies ◽  
Symptomatic Therapy ◽  
Important Place ◽  
Somatostatin Receptor Ligands

The presence of somatostatin receptors (SSTRs) is crucial in planning the therapy of patients with neuroendocrine tumors. This applies especially to patients in whom surgery has proven unsuccessful or there are contraindications for it. Increased SSTR expression has been observed in many cancers originating in the neuroendocrine system. Among them we distinguish anterior pituitary adenomas producing GH in excess and leading to the development of acromegaly, adenocorticotropic adenomas that autonomously synthesize ACTH, which leads to the development of ACTH-dependent Cushing’s syndrome (Cushing’s disease), as well as adenomas of the anterior pituitary from thyrotropic cells. Rich expression of these receptors has been confirmed in epithelial tumors of neuroendocrine origin in the gastrointestinal tract, pancreas and lungs. Somatostatin analogues, also called somatostatin receptor ligands, are effective in symptomatic therapy; they enable disease control, exhibit anti-proliferative effects and allow hormonal balance, which reduces mortality among patients and improves their quality of life. The antitumor effect of somatostatin analogues has been proven in in vitro and in vivo studies. In therapy they are usually well tolerated and safe. For many years, somatostatin analogues have maintained an important place in the treatment of neuroendocrine tumors and are still the subject of many studies. The aim of the study is to analyze, based on available literature, therapeutic indications for the use of somatostatin analogues, taking into account contraindications for therapy and its possible side effects.

scholarly journals Fates of endocytosed somatostatin sst2 receptors and associated agonists

1998 ◽  
Vol 336 (2) ◽  
pp. 291-298 ◽  
Author(s):  
Jennifer A. KOENIG ◽  
Rejbinder KAUR ◽  
Iain DODGEON ◽  
J. Michael EDWARDSON ◽  
Patrick P. A. HUMPHREY
Keyword(s):  
Cell Surface ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Receptor Recycling ◽  
Extracellular Medium ◽  
Main Pathway ◽  
Surface Receptor ◽  
Receptor Number ◽  
Agonist Ligands ◽  
Somatostatin 14

Somatostatin agonists are rapidly and efficiently internalized with the somatostatin sst2 receptor. The fate of internalized agonists and receptors is of critical importance because the rate of ligand recycling back to the cell surface can limit the amount of radioligand accumulated inside the cells, whereas receptor recycling might be of vital importance in providing the cell surface with dephosphorylated, resensitized receptors. Furthermore the accumulation of radioisotope-conjugated somatostatin agonists inside cancer cells resulting from receptor-mediated internalization has been used as a treatment for cancers that overexpress somatostatin receptors. In the present study, radio-iodinated agonists at the sst2 somatostatin receptor were employed to allow quantitative analysis of the fate of endocytosed agonist. After endocytosis, recycling back to the cell surface was the main pathway for both 125I-labelled somatostatin-14 (SRIF-14) and the more stable agonist 125I-labelled cyclo(N-Me-Ala-Tyr-d-Trp-Lys-Abu-Phe) (BIM-23027; Abu stands for aminobutyric acid), accounting for 75–85% of internalized ligand when re-endocytosis of radioligand was prevented. We have shown that there is a dynamic cycling of both somatostatin agonist ligands and receptors between the cell surface and internal compartments both during agonist treatment and after surface-bound agonist has been removed, unless steps are taken to prevent the re-activation of receptors by recycled agonist. Internalization leads to increased degradation of 125I-labelled SRIF-14 but not 125I-labelled BIM-23027. The concentration of recycled agonist accumulating in the extracellular medium was sufficient to re-activate the receptor, as measured both by the inhibition of forskolin-stimulated adenylate cyclase and the recovery of surface receptor number after internalization.

scholarly journals Plasticity in Ligand Recognition at Somatostatin Receptors

2021 ◽  
Author(s):  
Michael J. Robertson ◽  
Justin G. Meyerowitz ◽  
Ouliana Panova ◽  
Kenneth Borrelli ◽  
Georgios Skiniotis
Keyword(s):  
Conformational Changes ◽  
Drug Targets ◽  
Specific Binding ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Sequence Divergence ◽  
Receptor Activation ◽  
Ligand Recognition ◽  
Neuroendocrine Neoplasms ◽  
Subtype Selectivity

Somatostatin is a signaling peptide that plays a pivotal and wide-ranging role in physiologic processes relating to metabolism and growth through its actions at somatostatin receptors (SSTRs). Somatostatin receptors, particularly somatostatin receptor 2, are key drug targets for neuroendocrine neoplasms, with several synthetic peptide agonists currently in use. Here, we present the cryogenic electron microscopy structures of SSTR2 in the active G-protein complex with either the endogenous ligand SST14 or the FDA-approved drug octreotide. Complemented by biochemical assays and molecular dynamics simulations, these structures reveal key details of ligand recognition, receptor activation, and subtype-selectivity at somatostatin receptors. We find that SSTR ligand recognition is highly diverse, as demonstrated by ligand-induced conformational changes in ECL2, substantial sequence divergence across subtypes in extracellular regions, and loss of ligand binding upon several structurally homologous substitutions between subtypes. Despite this complexity, were are able to rationalize several discrete sources of SSTR subtype selectivity and identify an additional key interaction for SSTR2/3/5 specific binding. These results shed light on the basis of ligand recognition by somatostatin receptors and provide valuable insights for structure-based drug discovery at these important targets.

scholarly journals Chronic administration of bifemelane hydrochoride increases somatostatin receptor binding in aged rat brain.

1991 ◽  
Vol 28 (1) ◽  
pp. 18-23 ◽  
Author(s):  
Hirohiko Sato ◽  
Kimunao Mizukawa ◽  
Norio Ogawa ◽  
Masato Asanuma ◽  
Haruhiko Takayama ◽  
...  
Keyword(s):  
Rat Brain ◽  
Receptor Binding ◽  
Somatostatin Receptor ◽  
Chronic Administration ◽  
Aged Rat

scholarly journals Molecular characterization of the solubilized receptor of somatostatin from rat pancreatic acinar membranes

1988 ◽  
Vol 254 (3) ◽  
pp. 641-647 ◽  
Author(s):  
S Knuhtsen ◽  
J P Esteve ◽  
B Bernadet ◽  
N Vaysse ◽  
C Susini
Keyword(s):  
Specific Binding ◽  
Somatostatin Receptor ◽  
Regulatory Protein ◽  
Somatostatin Receptors ◽  
Broad Band ◽  
Gel Filtration ◽  
Cross Linking ◽  
Guanine Nucleotide Binding ◽  
Binding Subunit

The somatostatin receptors on rat pancreatic acinar membranes were demonstrated by use of a radioiodinated (125I-) analogue of somatostatin (SMS 204-090 or [Tyr3]SMS). The tracer was found to bind to the receptor with a Kd of 58 pM. The number of sites detected by this tracer (4.7 pmol/mg of protein) was 5-10 times higher than the number of sites previously found with other tracers. Since the level of non-specific binding was also very low as compared with findings with other tracers, 125I-204-090 might be of interest in future attempts to characterize the somatostatin receptors in the pancreas. The prelabelled membranes were solubilized with 1% CHAPS, and the solubilized complexes were found to adsorb to wheat-germ-agglutinin-coupled agarose, from which they could be eluted with 4 mM-triacetylchitotriose. The complexes within this eluate were shown by gel filtration on Trisacryl GF-2000 to have an Mr of about 400,000. The dissociation of the complexes was augmented both within the membranes as well as in the solubilized state by incubation with the GTP analogue guanosine 5′-[gamma-thio]triphosphate, indicating that the complexes are probably functionally linked to a guanine-nucleotide-binding regulatory protein. After SDS/slab-gel electrophoresis and autoradiography of cross-linked complexes after treatment with the heterobifunctional reagent N-5-azido-2-nitrobenzoyloxysuccinimide, a broad band occurred at approximately Mr 90,000 both in the membranes and in the eluates of complexes after lectin-adsorption chromatography. We conclude that the augmentation of the number of detectable sites for binding of somatostatin, as well as the very low level of non-specific binding obtained by the use of 125I-[Tyr3]SMS as tracer, has made it possible for us to demonstrate the solubilization of the somatostatin receptor in conjunction with its ligand and a GTP-binding regulatory protein, and we have succeeded in cross-linking 125I-[Tyr3]SMS to a binding subunit of Mr 90,000 in the membranes and in demonstrating the presence of the same labelled binding subunit within complexes solubilized and chromatographed on a lectin column before cross-linking.

The Effect of a Single Dose of Quazepam (Sch-16134) on the Sleep of Chronic Insomniacs

1979 ◽  
Vol 7 (6) ◽  
pp. 583-587 ◽  
Author(s):  
Thomas Roth ◽  
Elizabeth I Tietz ◽  
Milton Kramer ◽  
Mark Kaffeman
Keyword(s):  
Single Dose ◽  
Side Effects ◽  
Chronic Administration ◽  
Sleep Efficiency ◽  
Objective Measures ◽  
Subjective Measures ◽  
Sleep Maintenance ◽  
Eeg Changes ◽  
Different Doses ◽  
Polysomnographic Recording

The present study evaluated the efficacy of 25 mg of quazepam, a new benzodiazepine hypnotic, in a population of chronic insomniacs. The results indicate that a single dose (25 mg) administered for one night was efficacious when measured both objectively by polysomnographic recording and subjectively by questionnaire with no reported side-effects. The change in the objective measures paralleled the direction of change in subjective measures. Sleep efficiency and sleep maintenance were improved without EEG changes in Stages 2, 3-4, and REM. Further study is needed to evaluate the effects of chronic administration of different doses of quazepam in chronic insomniacs.

scholarly journals Chemotherapy-Induced Upregulation of Somatostatin Receptor-2 Increases the Uptake and Efficacy of 177Lu-DOTA-Octreotate in Neuroendocrine Tumor Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 232
Author(s):  
Rashmi G. Shah ◽  
Marine A. Merlin ◽  
Samuel Adant ◽  
Fayçal Zine-Eddine ◽  
Jean-Mathieu Beauregard ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Objective Response ◽  
Peptide Receptor Radionuclide Therapy ◽  
Normal Cells ◽  
Radiation Delivery ◽  
Different Types ◽  
Pre Treatment ◽  
High Doses ◽  
Low Dose Chemotherapy

The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2. We report that an exposure to low or high doses of drugs, such as temozolomide for 24 h or 5 day results in upregulation of SSTR2 between 3–7 days, increased LuTate uptake and decreased rate of cell proliferation. This effect is at the level of SSTR2-mRNA and is more pronounced in low SSTR2 expressing BON-1 than in high SSTR2 expressing NCI-H727 or non-NET cancer or normal cells. Thus, a properly timed pre-treatment with low-dose chemotherapy could not only improve therapeutic efficacy of LuTate in NET patients who are presently eligible for PRRT, but also allow PRRT to be administered to patients with low SSTR-expressing NETs, who would otherwise not respond to this modality because of insufficient radiation delivery.

scholarly journals Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

2020 ◽  
Vol 14 (1) ◽  
pp. 19
Author(s):  
Melpomeni Fani ◽  
Viktoria Weingaertner ◽  
Petra Kolenc Peitl ◽  
Rosalba Mansi ◽  
Raghuvir H. Gaonkar ◽  
...  
Keyword(s):  
Protein Binding ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Preclinical Study ◽  
Clinical Translation ◽  
Hek293 Cells ◽  
Neuroendocrine Neoplasms ◽  
Receptor Subtype ◽  
Selection Of

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

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