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Frontiers in Behavioral Neuroscience 2022Activity of the alpha-adrenergic receptor (α-AR) in the ventral tegmental area (VTA) modulates dopaminergic activity, implying its modulatory role in the behavioral...
Activity of the alpha-adrenergic receptor (α-AR) in the ventral tegmental area (VTA) modulates dopaminergic activity, implying its modulatory role in the behavioral functions of the dopamine (DA) system. Indeed, intra-VTA α-AR blockade attenuates conditioned stimulus dependent behaviors such as drug seeking responses signifying a role of the noradrenergic signaling in the VTA in conditioned behaviors. Importantly, the role of the VTA α-AR activity in Pavlovian associative learning with positive outcomes remains unknown. Here, we aimed to examine how intra-VTA α-AR blockade affects acquisition of cocaine-induced Pavlovian associative learning in the conditioned place preference (CPP) paradigm. The impact of α-AR blockade on cocaine-reinforced operant responding and cocaine-evoked ultrasonic vocalizations (USVs) was also studied. In addition, both α-AR immunoreactivity in the VTA and its role in phasic DA release in the nucleus accumbens (NAc) were assessed. We demonstrated cellular localization of α-AR expression in the VTA, providing a neuroanatomical substrate for the α-AR mechanism. We showed that prazosin (α-AR selective antagonist; 1 μg/0.5 μl) microinfusion attenuated electrically evoked DA transients in the NAc and dose-dependently (0.1-1 μg/0.5 μl) prevented the acquisition of cocaine CPP but did not affect cocaine-reinforced operant responding nor cocaine-induced positive affective state (measured as USVs). We propose that the VTA α-AR signaling is necessary for the acquisition of Pavlovian associative learning but does not encode hedonic value. Thus, α-AR signaling in the VTA might underlie salience encoding of environmental stimuli and reflect an ability of alerting/orienting functions, originating from bottom-up information processing to guide behaviors.
PubMed: 35990723
DOI: 10.3389/fnbeh.2022.969104 -
Case Reports in Psychiatry 2022Posttraumatic stress disorder (PTSD) is a debilitating stress disorder occurring in the context of a traumatic event and is characterized by intrusive and avoidance...
Posttraumatic stress disorder (PTSD) is a debilitating stress disorder occurring in the context of a traumatic event and is characterized by intrusive and avoidance symptoms, negative alterations in cognition and mood, and arousal and reactivity changes. Despite its representation throughout literature, the pathophysiology of PTSD remains incompletely understood, thus contributing to broad, variable, and at times, experimental treatment options. The authors present the first documented case of the rapid and successful management of PTSD using valproic acid and twice daily dosing of prazosin aimed at targeting symptoms of hyperarousal and both daily and nightly intrusive symptoms of flashbacks and nightmares, respectively. The authors also discuss postulations of the underlying mechanisms of action responsible for such symptom alleviation. Further investigation is needed to expand upon our knowledge of the use of such agents in the treatment of PTSD to improve upon existing clinical guidelines, especially in the acute setting, thus providing better overall prognosis.
PubMed: 35966042
DOI: 10.1155/2022/1223292 -
EBioMedicine Sep 2022Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.
METHODS
Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.
FINDINGS
We have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43, terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.
INTERPRETATION
Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.
FUNDING
This work was supported by project grant funding from MND Scotland, the My Name'5 Doddie Foundation, Medical Research Council Doctoral Student Training Fellowship [Ref: BST0010Z] and Academy of Medical Sciences grant [SGL023\1100].
Topics: Amyotrophic Lateral Sclerosis; Animals; DNA-Binding Proteins; Humans; Mice; Motor Neurons; Phenotype; Phosphoglycerate Kinase; Prazosin; Zebrafish
PubMed: 35963713
DOI: 10.1016/j.ebiom.2022.104202 -
Journal of Clinical Sleep Medicine :... Dec 2022Trauma associated sleep disorder is a proposed parasomnia that develops after trauma with clinical features of trauma related nightmares, disruptive nocturnal behaviors,...
STUDY OBJECTIVES
Trauma associated sleep disorder is a proposed parasomnia that develops after trauma with clinical features of trauma related nightmares, disruptive nocturnal behaviors, and autonomic disturbances. The purpose of this case series is to better characterize the clinical and video-polysomnographic features of patients meeting clinical criteria for this proposed parasomnia.
METHODS
Semistructured clinical interview and detailed video-polysomnography review of 40 patients. Movements and vocalizations in rapid eye movement sleep were quantified according to the rapid eye movement sleep behavior disorder severity scale.
RESULTS
Patients (n = 40, 32 males) were service members and veterans with a median age of 38.9 years (range 24-57 years) who reported trauma related nightmares and disruptive nocturnal behaviors at home. On video-polysomnography, 28 (71.8%) patients had disruptive nocturnal behaviors in rapid eye movement sleep consisting of limb, head, and axial movements; vocalizations were present in 8 (20%). On the rapid eye movement sleep behavior disorder severity scale, most (n = 28, 71.8%) had a low rating but those with greater severity (n = 11, 28.2%) had a higher prevalence of posttraumatic stress disorder ( = .013) and markedly less N3 sleep ( = .002). The cohort had a high rate of insomnia (n = 35, 87.5%) and obstructive sleep apnea (n = 19, 47.5%). Most patients were treated with prazosin (n = 29, 72.5%) with concomitant behavioral health interventions (n = 25, 64.1%); 15 (51.7%) patients receiving prazosin reported improved symptomatology.
CONCLUSIONS
Disruptive nocturnal behaviors can be captured on video-polysomnography during rapid eye movement sleep, although they may be less pronounced than what patients report in their habitual sleeping environment. Clinical and video-polysomnographic correlations are invaluable in assessing patients with trauma associated sleep disorder to document objective abnormalities. This case series provides a further basis for establishing trauma associated sleep disorder as a unique parasomnia.
CITATION
Brock MS, Matsangas P, Creamer JL, et al. Clinical and polysomnographic features of trauma associated sleep disorder. . 2022;18(12):2775-2784.
Topics: Male; Humans; Young Adult; Adult; Middle Aged; REM Sleep Behavior Disorder; Dreams; Sleep Wake Disorders; Parasomnias; Prazosin
PubMed: 35962771
DOI: 10.5664/jcsm.10214 -
Neurochemical Research Nov 2022Phenylephrine (PE) is a canonical α-adrenoceptor-selective agonist. However, unexpected effects of PE have been observed in preclinical and clinical studies, that...
Phenylephrine (PE) is a canonical α-adrenoceptor-selective agonist. However, unexpected effects of PE have been observed in preclinical and clinical studies, that cannot be easily explained by its actions on α-adrenoceptors. The probability of the involvement of α- and β-adrenoceptors in the effect of PE has been raised. In addition, our earlier study observed that PE released noradrenaline (NA) in a [Ca]-independent manner. To elucidate this issue, we have investigated the effects of PE on [H]NA release and α-mediated smooth muscle contractions in the mouse vas deferens (MVD) as ex vivo preparation. The release experiments were designed to assess the effects of PE at the presynaptic terminal, whereas smooth muscle isometric contractions in response to electrical field stimulation were used to measure PE effect postsynaptically. Our results show that PE at concentrations between 0.3 and 30 µM significantly enhanced the resting release of [H]NA in a [Ca]-independent manner. In addition, prazosin did not affect the release of NA evoked by PE. On the contrary, PE-evoked smooth muscle contractions were inhibited by prazosin administration indicating the α-adrenoceptor-mediated effect. When the function of the NA transporter (NAT) was attenuated with nisoxetine, PE failed to release NA and the contractions were reduced by approximately 88%. The remaining part proved to be prazosin-sensitive. The present work supports the substantial indirect effect of PE which relays on the cytoplasmic release of NA, which might explain the reported side effects for PE.
Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Cytoplasm; Male; Mice; Norepinephrine; Phenylephrine; Prazosin; Receptors, Adrenergic, alpha-1
PubMed: 35945308
DOI: 10.1007/s11064-022-03681-2 -
Frontiers in Psychiatry 2022Psychological trauma in childhood can lead to post-traumatic disorder (PTSD) with protracted comorbid depression, which responds poorly to conventional antidepressants....
Psychological trauma in childhood can lead to post-traumatic disorder (PTSD) with protracted comorbid depression, which responds poorly to conventional antidepressants. Previous studies have shown that prazosin, an α1-adrenergic receptor antagonist, can help eliminate nightmares and improve sleep quality and suicidal ideation in PTSD patients. This case report presents that prazosin had a rapid antidepressant effect in a female adolescent PTSD patient with treatment-resistant depression (TRD). Prazosin improved not only depression symptoms but also sleep quality, suicidal ideation, and cognitive function. Prazosin was well tolerated without obvious adverse effects. Our preliminary study suggests that further clinical trials are needed to determine the efficacy and safety of prazosin in treating PTSD patients with comorbid TRD.
PubMed: 35935442
DOI: 10.3389/fpsyt.2022.803220 -
Andrology Nov 2022Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such...
BACKGROUND
Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the α -adrenergic receptors such as doxazosin, tamsulosin, and prazosin.
OBJECTIVES
To investigate the liberation of 6-ND by human epididymal vas deferens (HEVDs) and its pharmacological actions.
METHODS
The in vitro liberation of 6-ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC-MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric-field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L-NAME and the release of catecholamines and the contractile response to EFS were assessed.
RESULTS
6-ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6-ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L-NAME reduced both the 6-ND release and the contractions induced by EFS.
DISCUSSION AND CONCLUSION
6-ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and α -adrenergic receptor antagonists.
Topics: Adrenergic Antagonists; Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Carbamazepine; Chromatography, Liquid; Desipramine; Dopamine; Doxazosin; Epinephrine; Humans; Male; Muscle Contraction; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Prazosin; Rats; Receptors, Adrenergic; Tamsulosin; Tandem Mass Spectrometry; Vas Deferens
PubMed: 35934935
DOI: 10.1111/andr.13263 -
Journal of Obstetrics and Gynaecology... Aug 2022Pheochromocytoma during pregnancy is a rare cause of secondary hypertension with lethal consequences to both mother and fetus. As patients are young, the possibility of...
INTRODUCTION
Pheochromocytoma during pregnancy is a rare cause of secondary hypertension with lethal consequences to both mother and fetus. As patients are young, the possibility of syndromic associations like MEN-2, VHL, NF-1, etc., needs to be considered.
METHODOLOGY
Three primigravida were diagnosed before the 20th week of gestation when they presented with classical triad of pheochromocytoma.
RESULTS
Diagnosis of pheochromocytoma was confirmed by 24 h urinary metanephrine/normetanephrine or epinephrine/norepinephrine levels. Non-contrast MRI abdomen could localize the tumor. One patient had medullary thyroid carcinoma with hyperparathyroidism, indicative of MEN-2A. Another patient had brain stem hemangioblastoma, pancreatic cysts and family history of spinal hemangioblastoma, so diagnosed to have Von Hippel-Lindau (VHL) syndrome. Whereas, the third patient had sporadic pheochromocytoma. Preoperatively, they required antihypertensive medications including prazosin and metoprolol. They underwent laparoscopic/open adrenalectomy between 19th and 21st week of gestation without complication. Histopathology in all the three patients revealed low-grade pheochromocytoma by pheochromocytoma of the adrenal gland scaled score. None required antihypertensive medications after surgery. All the three newborns were small for gestational age, while one neonate expired due to intra-cardiac rhabdomyoma. So, the timely evaluation and surgical intervention for pheochromocytoma avoid lethal consequences.
CONCLUSIONS
Pregnancy leads to unmasking of pheochromocytoma as it is physiological stress. The syndromic association is more frequent as the population is younger. A poor fetal outcome like IUGR can be explained by endovascular changes in uterine vessel or due to the associated manifestations of MEN-2A, VHL syndromes. Family members should be screened for associated syndromic feature.
PubMed: 35928058
DOI: 10.1007/s13224-021-01532-8 -
Pharmacology Research & Perspectives Aug 2022The relationship between cardiovascular diseases and iron disorders has gained increasing attention; however, the effects of hypotensive drugs on iron metabolic...
The relationship between cardiovascular diseases and iron disorders has gained increasing attention; however, the effects of hypotensive drugs on iron metabolic alterations in hypertension are not well understood. The purpose of this study was to investigate iron metabolic changes after prazosin treatment of spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Our second objective was to examine the effects of hypertension and anti-hypertensive drugs on bone formation and resorption. SHRs and WKY rats were randomized into either prazosin-treated groups (WKY + PZ and SHR + PZ) or untreated groups (WKY and SHR). After 7 days of intragastric prazosin administration, the rats were sacrificed for analysis; blood samples and organs (the duodenum, liver, kidneys, spleen, and femur) were collected. Both WKY + PZ and SHR groups exhibited iron deficiency in the serum and liver. Prazosin increased the iron levels in the bone tissue of SHRs. Prazosin stimulated the expression of hepcidin mRNA in the liver of SHRs and inhibited the expression of this iron-regulatory hormone in WKY rats. FPN1 expression in the duodenum was increased significantly in SHRs, however markedly decreased after prazosin treatment. The expression of TLR4 and Ctsk was enhanced in the bone tissue of SHRs, whereas CLC-7 expression was inhibited. Both hypotension and hypertension can lead to iron deficiency. Treatment with prazosin restored iron homeostasis in SHRs. The inverse impacts of prazosin on hepatic hepcidin expression in SHRs versus WKY rats indicates differing iron regulatory mechanisms between hypertensive and normal animals. The osteoclast activity was found to be enhanced in SHRs. Further study is needed to address whether the changes in osteoblast and osteoclast activity in SHRs correlates with the effects on iron metabolism.
Topics: Animals; Hepcidins; Hypertension; Iron; Prazosin; Rats; Rats, Inbred SHR; Rats, Inbred WKY
PubMed: 35892277
DOI: 10.1002/prp2.991 -
Archives of Razi Institute Feb 2022The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first...
The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first experiment, the intracerebroventricular (ICV) injection of solutions was conducted which included 10 nmol of prazosin (an α-receptor antagonist), 300 nmol of histamine, co-injection of prazosin and histamine. Experiments two to five were conducted similarly the same as the first experiment, in which chickens were ICV injected with 13 nmol of yohimbine (an α-receptor antagonist), 24 nmol of metoprolol (a β adrenergic receptor antagonist), 5 nmol of ICI 118,551 (a β adrenergic receptor antagonist), and 20 nmol of SR 59230R (a β adrenergic receptor antagonist). The injected solutions in the sixth experiment included 300 nmol of noradrenaline, 250 nmol of α-FMH (an alpha fluoromethyl histidine), noradrenaline, and α-FMH. Seventh to ninth experiments were similar to the sixth experiment, except that the chickens were ICV injected with 300 nmol of chlorpheniramine (a histamine H receptors antagonist), 82 nmol of famotidine (a histamine H receptors antagonist), and 300 nmol of thioperamide (a histamine H receptors antagonist), rather than α-FMH. Afterward, the cumulative food intake was measured 120 min after injection. Based on the obtained results, both histamine ICV injection and noradrenaline injection reduced food intake (<0.05). Moreover, co-injection of histamine and ICI 118,551 (<0.05), and co-injection of noradrenaline and Chlorpheniramine reduced food intake (<0.05). In addition, noradrenaline and Thioperamide co-injection improved hypophagic effect of noradrenaline in neonatal chicken (<0.05). These findings suggested the effect of interconnection between adrenergic and histaminergic systems, which may be mediated by H and H histaminergic and β adrenergic receptors, on the regulation of food intake in the neonatal broiler chicken.
Topics: Adrenergic Agents; Adrenergic Antagonists; Animals; Animals, Newborn; Appetite; Chickens; Chlorpheniramine; Feeding Behavior; Histamine; Norepinephrine; Prazosin; Receptors, Adrenergic; Receptors, Histamine
PubMed: 35891757
DOI: 10.22092/ARI.2021.354450.1638