scholarly journals Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 1007 ◽  
Author(s):  
Jessica C. Gaspar ◽  
Bright N. Okine ◽  
Alvaro Llorente-Berzal ◽  
Michelle Roche ◽  
David P. Finn
Keyword(s):  
Conditioned Fear ◽  
Intraperitoneal Administration ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Intraplantar Injection ◽  
Conditioned Analgesia ◽  
Sprague Dawley Rats ◽  
Pharmacological Blockade ◽  
Peroxisome Proliferator Activated Receptors ◽  
Nociceptive Behaviour

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPARα, PPARβ/δ, PPARγ) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPARα (GW6471), PPARβ/δ (GSK0660) or PPARγ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPARα and PPARβ/δ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPARγ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPARα and PPARβ/δ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPARγ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.

Serotonin depletion reduces both acquisition and expression of context-conditioned fear

2021 ◽  
pp. 1-8
Author(s):  
S. Melker Hagsäter ◽  
Robert Pettersson ◽  
Axel Holmäng ◽  
Elias Eriksson
Keyword(s):  
Unconditioned Stimulus ◽  
Memory Consolidation ◽  
Clinical Studies ◽  
Conditioned Fear ◽  
Sprague Dawley ◽  
Serotonin Synthesis ◽  
Synthesis Inhibitor ◽  
Serotonin Depletion ◽  
Sprague Dawley Rats ◽  
The Impact

Abstract Objective: Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear. Methods: Male Sprague–Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only. Results: The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear. Conclusion: Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.

scholarly journals Contrasting pharmacological ETB receptor blockade with genetic ETB deficiency in renal responses to big ET-1

2001 ◽  
Vol 6 (1) ◽  
pp. 39-43 ◽  
Author(s):  
DAVID M. POLLOCK
Keyword(s):  
Renal Plasma Flow ◽  
Urine Flow ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Clearance Studies ◽  
Etb Receptor ◽  
Pharmacological Blockade ◽  
Series Of Experiments ◽  
Renal Responses

Renal clearance studies were conducted to determine the role of ETB receptors in the renal response to big endothelin-1 (big ET-1). Two series of experiments were conducted on Inactin-anesthetized rats to contrast acute pharmacological blockade of ETB receptors vs. genetic ETB receptor deficiency. In the first series, Sprague-Dawley rats were given either ETB-selective antagonist, A-192621, or vehicle (0.9% NaCl) prior to infusion of big ET-1 (10 pmol·kg−1·min−1) for 60 min. A-192621 significantly increased baseline mean arterial pressure (MAP; 102 ± 4 vs. 141 ± 6 mmHg, P < 0.05) and urine flow rate (0.5 ± 0.1 vs. 1.3 ± 0.2 μl/min, P < 0.05) without any effect on glomerular filtration rate (GFR) or effective renal plasma flow (ERPF). Big ET-1 significantly increased MAP in both groups but to a higher level in rats given antagonist (120 ± 6 vs. 169 ± 6 mmHg, P < 0.05). Big ET-1 increased urine flow in control rats but decreased in rats given antagonist. GFR and ERPF were decreased in rats given big ET-1, an effect that was exaggerated by ETB blockade. Another series of experiments examined the response to big ET-1 in rats lacking functional renal ETB receptors, known as spotting lethal ( sl) rats. Surprisingly, rats heterozygous ( sl/+) for ETB receptor deficiency had a significantly higher baseline MAP compared with homozygous ( sl/ sl) rats (134 ± 6 vs. 112 ± 7 mmHg, P < 0.05), although other variables were similar. Big ET-1 produced no significant change in MAP in either group. Urine flow, GFR, and ERPF were significantly decreased in both groups, although these changes were much larger in sl/ sl rats. These experiments indicate that the ETB receptor plays an important role in limiting the renal hemodynamic response to big ET-1. Furthermore, the diuretic actions of big ET-1 require a functional ETB receptor.

scholarly journals WY-14643, a Potent Peroxisome Proliferator Activator Receptor-α PPAR-α Agonist Ameliorates the Inflammatory Process Associated to Experimental Periodontitis

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Enrico Briguglio ◽  
Rosanna Di Paola ◽  
Irene Paterniti ◽  
Emanuela Mazzon ◽  
Giacomo Oteri ◽  
...  
Keyword(s):  
Inflammatory Process ◽  
Inos Expression ◽  
Peroxisome Proliferator ◽  
Myeloperoxidase Activity ◽  
Sprague Dawley ◽  
Silk Thread ◽  
Tyrosine Residues ◽  
Markers Of Inflammation ◽  
Sprague Dawley Rats ◽  
Experimental Periodontitis

We have investigated the effects of WY14643, a potent peroxisome proliferator activator receptor-α(PPAR-α) agonist, in a rat model of ligature-induced periodontitis. Male Sprague-Dawley rats were lightly anaesthetized with pentobarbitone (35 mg/kg). Sterile, 2-0 black braided silk thread was placed around the cervix of the lower left first molar and knotted medially. Animals received WY14643 (1 mg/kg i.p, daily for eight days). Eighths days after placement of the ligature, we evaluated several markers of inflammation such us (1) myeloperoxidase activity, (2) a cytokines and adhesion molecules expression, (3) NF-κB expression, (4) iNOS expression, (5) the nitration of tyrosine residues, (6) activation of the nuclear enzyme poly(ADP-ribose) polymerase, (7) apoptosis, and (8) the degree of gingivomucosal tissues injury. Administration of WY14643 significantly decreased all of the parameters of inflammation as described above. These results demonstrate that WY14643 exerts an anti-inflammatory role during experimental periodontitis and is able to ameliorate the tissue damage.

scholarly journals Rosiglitazone Attenuated Endothelin-1-Induced Vasoconstriction of Pulmonary Arteries in the Rat Model of Pulmonary Arterial Hypertension via Differential Regulation of ET-1 Receptors

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Yahan Liu ◽  
Xiao Yu Tian ◽  
Yu Huang ◽  
Nanping Wang
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Progressive Increase ◽  
Differential Regulation ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. Activation of the endothelin (ET)-1 system has been demonstrated in plasma and lung tissue of PAH patients as well as in animal models of PAH. Recently, peroxisome proliferator-activated receptorγ(PPARγ) agonists have been shown to ameliorate PAH. The present study aimed to investigate the mechanism for the antivasoconstrictive effects of rosiglitazone in response to ET-1 in PAH. Sprague-Dawley rats were exposed to chronic hypoxia (10% oxygen) for 3 weeks. Pulmonary arteries from PAH rats showed an enhanced vasoconstriction in response to ET-1. Treatment with PPARγagonist rosiglitazone (20 mg/kg per day) with oral gavage for 3 days attenuated the vasocontractive effect of ET-1. The effect of rosiglitazone was lost in the presence ofL-NAME, indicating a nitric oxide-dependent mechanism. Western blotting revealed that rosiglitazone increasedETBRbut decreasedETARlevel in pulmonary arteries from PAH rats.ETBRantagonist A192621 diminished the effect of rosiglitazone on ET-1-induced contraction. These results demonstrated that rosiglitazone attenuated ET-1-induced pulmonary vasoconstriction in PAH through differential regulation of the subtypes of ET-1 receptors and, thus, provided a new mechanism for the therapeutic use of PPARγagonists in PAH.

scholarly journals Serum Natriuretic Peptides as Differential Biomarkers Allowing for the Distinction between Physiologic and Pathologic Left Ventricular Hypertrophy

2016 ◽  
Vol 45 (2) ◽  
pp. 344-352 ◽  
Author(s):  
Michael E. Dunn ◽  
Thomas G. Manfredi ◽  
Kevin Agostinucci ◽  
Steven K. Engle ◽  
Josh Powe ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Left Ventricular ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sprague Dawley Rats ◽  
Exercise Induced

Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups. While the relative heart weights from both the swimming and drug-induced cardiac hypertrophy groups were increased 15% after 28 days of dosing, the serum NT-proANP and NT-proBNP values were only increased in association with cardiac hypertrophy caused by compound administration. Serum natriuretic peptide concentrations did not change in response to adaptive physiologic cardiac hypertrophy induced by a 28-day swimming protocol. These data support the use of natriuretic peptides as fluid biomarkers for the distinction between physiological and drug-induced cardiac hypertrophy.

scholarly journals Parametric modulators of sex-biased conditioned fear responding

2021 ◽  
Author(s):  
Julia R Mitchell ◽  
Sean G Trettel ◽  
Anna J Li ◽  
Sierra Wasielewski ◽  
Kylie A Huckleberry ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Early Recognition ◽  
Conditioned Fear ◽  
Sprague Dawley ◽  
Multiple Dimensions ◽  
Sprague Dawley Rats ◽  
Experimental Parameters ◽  
Behavioral Paradigm ◽  
Data Files ◽  
Chamber Size

Pavlovian fear conditioning is a widely used behavioral paradigm for studying associative learning in rodents. Despite early recognition that subjects may engage in a variety of behaviors that reflect the experimental parameters of a given protocol, the last several decades have seen the field narrow its focus to measure freezing as the sole indicator of conditioned fear. Additionally, unconditioned responses such as shock-related activity are rarely considered. We previously reported that female Sprague Dawley rats are more likely than males to engage in darting, an escape-like conditioned response that is associated with heightened shock reactivity, but we did not establish whether darting was sensitive to manipulations of factors such as chamber size, shock intensity, or number of trials. Our goal here was to address these questions by defining parametric and phenotypic predictors of darting in both sexes. To better capture fear-related behavioral repertoires in our animals, we developed ScaredyRat, a custom Python tool that analyzes Noldus Ethovision-generated raw data files to identify Darters and quantify both conditioned and unconditioned responses. We find that like freezing, darting probability scales with experimental alterations in multiple dimensions. In most cases, the sex bias towards females persists, but males will transition to darting in extended, or overtraining fear conditioning protocols.

scholarly journals Changes of biochemical parameters in rat intestinal mucosa induced by methotrexate and effects of enteral administration of glutamine

2004 ◽  
Vol 12 (1) ◽  
pp. 35-38 ◽  
Author(s):  
Katica Bajin-Katic ◽  
Karmen Stankov ◽  
Zoran Kovacevic
Keyword(s):  
Intestinal Mucosa ◽  
Biochemical Parameters ◽  
Intraperitoneal Administration ◽  
Mucosal Damage ◽  
Control Group ◽  
Intestinal Damage ◽  
Sprague Dawley ◽  
Regeneration Time ◽  
Sprague Dawley Rats ◽  
Previously Treated

BACKGROUND: Rapidly proliferating crypt cells of the intestinal epithelium, the precursors of the mature enterocytes, are extremely sensitive to the effects of cytostatic agents. We investigated the effects of the methotrexate on rat intestinal mucosa in order to get the information on biochemical indicators of intestinal damage. METHODS: Biochemical parameters were investigated in isolated intestinal mucosa of Sprague-Dawley rats, previously treated with methotrexate by intraperitoneal administration. Glutamine was dissolved in water and administered orally. RESULTS: The activity of glutaminase and alkaline phosphatase showed the enzymatic response to different doses of methotrexate. The activity of both enzymes was significantly lower in the mucosa of treated animals, compared to control group. CONCLUSION: Minimal mucosal damage and regeneration time is dose dependent and influenced by the dosage schedule of antitumor therapy.

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