Milnacipran affects mouse impulsive, aggressive, and depressive-like behaviors in a distinct dose-dependent manner

Serotonin/noradrenaline reuptake inhibitors (SNRIs) are widely used for the treatment for major depressive disorder, but these drugs induce several side effects including increased aggression and impulsivity, which are risk factors for substance abuse, criminal involvement, and suicide. To address this issue, milnacipran (0, 3, 10, or 30 mg/kg), an SNRI and antidepressant, was intraperitoneally administered to mice prior to the 3-choice serial reaction time task, residente-intruder test, and forced swimming test to measure impulsive, aggressive, and depressive-like behaviors, respectively. A milnacipran dose of 10 mg/kg suppressed all behaviors, which was accompanied by increased dopamine and serotonin levels in the medial prefrontal cortex (mPFC) but not in the nucleus accumbens (NAc). Although the most effective dose for depressive-like behavior was 30 mg/kg, the highest dose increased aggressive behavior and unaffected impulsive behavior. Increased dopamine levels in the NAc could be responsible for the effects. In addition, the mice basal impulsivity was negatively correlated with the latency to the first agonistic behavior. Thus, the optimal dose range of milnacipran is narrower than previously thought. Finding drugs that increase serotonin and dopamine levels in the mPFC without affecting dopamine levels in the NAc is a potential strategy for developing novel antidepressants

Effect of clonidine on the release of serotonin from the rat hippocampus as measured by microdialysis

The purpose of the present study is to clarify the effect of clonidine on the release of serotonin from the rat hippocampus in vivo. For this purpose, endogenous serotonin release was measured by brain microdialysis. Potassium-evoked serotonin release from the hippocampus of freely moving rats was significantly inhibited when clonidine (10-5 M) was added to the perfusion solution, while the 5-hydroxyindoleacetic acid output remained unchanged. In catecholaminergically denervated rats, clonidine (10-5 M) also inhibited the potassium-evoked serotonin release from the hippocampus and the 5-hydroxyindoleacetic acid output was unaffected by clonidine. These results suggest that the inhibitory effect of clonidine on serotonin release from the hippocampus might reflect the activation of [alpha]2-adrenoceptors which are localized on the serotonergic nerve terminals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30049/1/0000417.pd

Opioid receptor regulation of 5-hydroxytryptamine release from the rat hippocampus measured by in vivo microdialysis

The modulation of serotonin (5-HT) release by opioid receptors in the hippocampus of the awake, unrestrained rat was evaluated by use of in vivo microdialysis. The hippocampus was perfused with Ringer's solution (2 [mu]l/min), and extracellular levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were estimated by assaying their concentration in the dialysate by HPLC-ECD. Addition of potassium (K+, 60 and 120 mM) to the perfusate evoked a concentration-dependent release of 5-HT, but did not alter extracellular 5-HIAA levels. Co-perfusion of morphine (0.1 to 10 [mu]M) with K+ (120 mM) produced a concentration-dependent reduction of 5-HT release. Naltrexone (0.03 to 3 mg/kg, i.p.), a relatively selective [mu]-opioid receptor antagonist, blocked in a dose-dependent manner the morphine (10 [mu]M)-induced inhibition of 5-HT release. Naltrexone alone did not alter significantly either extracellular 5-HT levels or the release of 5-HT evoked by K+. Neither co-perfusion with [-Pen2, -Pen5]-enkephalin (DPDPE, 1 to 10 [mu]M), an agonist selective for [delta]-opioid receptors, nor with U-69593 (10 [mu]M), an agonist selective for [kappa]-opioid receptors, modified the K+ (120 mM)-evoked release of 5-HT. These findings indicate that [mu]-opioid receptors modulate the physiological release of 5-HT from serotonergic neurons in the rat hippocampus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30746/1/0000396.pd

EFFECTS OF 5-HT₃ RAS ON CDDP-INDUCED AKI

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice

VALPROIC ACID PROTECTS KIDNEYS FROM CISPLATIN

Cisplatin treatment is effective against several types of carcinomas. However, it frequently leads to kidney injury, which warrants effective prevention methods. Sodium valproic acid is a prophylactic drug candidate with a high potential for clinical application against cisplatin-induced kidney injury. Therefore, in this study, we aimed to elucidate the mechanism underlying the prophylactic effect of valproic acid on cisplatin-induced kidney injury in a mouse model and HK2 and PODO cells with cisplatin-induced toxicity. In the mouse model of cisplatin-induced kidney injury, various renal function parameters and tubular damage scores were worsened by cisplatin, but they were significantly improved upon combination with valproic acid. No difference was observed in cisplatin accumulation between the cisplatin-treated and valproic acid-treated groups in whole blood and the kidneys. The mRNA expression levels of proximal tubular damage markers, apoptosis markers, and inflammatory cytokines significantly increased in the cisplatin group 72 h after cisplatin administration but significantly decreased upon combination with valproic acid. In HK2 cells, a human proximal tubular cell line, the cisplatin-induced decrease in cell viability was significantly suppressed by co-treatment with valproic acid. Valproic acid may inhibit cisplatin-induced kidney injury by suppressing apoptosis, inflammatory responses, and glomerular damage throughout the kidneys by suppressing proximal tubular cell damage. However, prospective controlled trials need to evaluate these findings before their practical application

Inhibitory effects of clonidine on serotonergic neuronal activity as measured by cerebrospinal fluid serotonin and its metabolite in anesthetized rats

Clonidine-induced changes in the serotonergic neuronal activity of the central nervous system were estimated by measuring the concentrations of serotonin (5-HT) and its major metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), in the cerebrospinal fluid (CSF) of anesthetized rats. Clonidine (30 and 300 [mu]g/kg, i.v.) led to 74% and 60% reductions in the concentration of 5-HT in the CSF 60 min after administration. CSF 5-HIAA concentrations were also decreased to 77% and 66%, respectively. Clonidine-induced (30 [mu]g/kg, i.v.) decreases in CSF 5-HT and 5-HIAA concentrations were attenuated by pretreatment with idazoxan (5 mg/kg, i.p.). Idazoxan by itself did not alter the CSF 5-HT and 5-HIAA concentrations. Decreased CSF 5-HT and 5-HIAA concentrations after i.v. administration of clonidine (30 [mu]g/kg) were abolished by noradrenergic denervation after pretreatment with 6-hydroxydopamine (200 [mu]g/rat, i.c.v.). These results suggest the possibility that clonidine acts to inhibit the serotonergic neuronal activity, which is mediated via the [alpha]2-adrenoceptors. It indicates, moreover, that noradrenergic nervous systems are involved in the clonidine-induced inhibition of serotonergic neuronal activity. Therefore, noradrenergic neurons play a significant role in mediating the actions of clonidine on serotonergic neuronal activity in the rat brain.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31094/1/0000771.pd

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paperwe show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing

The Gender–Age–Physiology system as a prognostic model in patients with idiopathic pulmonary fibrosis treated with nintedanib: a longitudinal cohort study

Introduction: The Gender-Age-Physiology (GAP) system is a tool for predicting prognosis in patients with idiopathic pulmonary fibrosis (IPF). Yet, to date, the GAP system has not been evaluated in patients with IPF who received nintedanib. Material and methods: This single-center retrospective study included 89 patients with IPF who received Nintedanib for at least 3 months. All-cause mortality was set as the end point. Clinical parameters, including the GAP stage, were statistically analyzed for risk factors leading to mortality using the Cox proportional hazard model.Results: The median follow-up was 16.4 months (range 3.7–37.4 months), during which 23 patients died. Univariate analysis revealed that the GAP stage (hazard ratio [HR] 3.00, 95% confidence interval [CI] 1.52–5.92, p = 0.0014) and PaO2 (HR 0.95, 95% CI 0.92–0.98, p = 0.0063) were significant prognostic factors. Multivariate analysis revealed that the GAP stage was a significant prognostic factor (HR 2.26, 95% CI 1.07–4.78, p = 0.031). Log-rank analysis revealed that there were no significant differences in “Gender” (p = 0.47) and “Age” (p = 0.18) factors. However, there were significant differences in “Physiology” factors (% of forced vital capacity, p = 0.018; % of diffusing capacity of lung carbon monoxide, p < 0.001). The cumulative incidences of mortality at 1 and 2 years were as follows: GAP I: 5.1% and 6.8%; GAP II: 9.5% and 29.3%; and GAP III: 18.9% and 84.2%.Conclusions: The GAP system is useful as a prognostic tool in patients with IPF who have been treated with nintedanib