Effects of dopamine and serotonin synthesis inhibitors on the ketamine-, d-amphetamine-, and cocaine-induced locomotor activity of preweanling and adolescent rats: sex differences.

The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker, it appears to stimulate the locomotor activity of both male and female rats via a monoaminergic mechanism. To more precisely determine the neural mechanisms underlying ketamine's actions, male and female preweanling and adolescent rats were pretreated with vehicle, the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), or the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA). After completion of the pretreatment regimen, the locomotor activating effects of saline, ketamine, d-amphetamine, and cocaine were assessed during a 2 h test session. In addition, the ability of AMPT and PCPA to reduce dorsal striatal DA and 5-HT content was measured in male and female preweanling, adolescent, and adult rats. Results showed that AMPT and PCPA reduced, but did not fully attenuate, the ketamine-induced locomotor activity of preweanling rats and female adolescent rats. Ketamine (20 and 40 mg/kg) caused a minimal amount of locomotor activity in male adolescent rats, and this effect was not significantly modified by AMPT or PCPA pretreatment. When compared to ketamine, d-amphetamine and cocaine produced different patterns of locomotor activity across ontogeny; moreover, AMPT and PCPA pretreatment affected psychostimulant- and ketamine-induced locomotion differently. When these results are considered together, it appears that both dopaminergic and serotonergic mechanisms mediate the ketamine-induced locomotor activity of preweanling and female adolescent rats. The dichotomous actions of ketamine relative to the psychostimulants in vehicle-, AMPT-, and PCPA-treated rats, suggests that ketamine modulates DA and 5-HT neurotransmission through an indirect mechanism.

Correlation between urinary fractionated metanephrines in 24-hour and spot urine samples for evaluating the therapeutic effect of metyrosine: a subanalysis of a multicenter, open-label phase I/II study.

We recently conducted an open-label phase I/II study to evaluate the efficacy and safety of preoperative and chronic treatment with metyrosine (an inhibitor of catecholamine synthesis) in pheochromocytoma/paraganglioma (PPGL) in Japan. We compared creatinine-corrected metanephrine fractions in spot urine and 24-hour urine samples (the current standard for the screening and diagnosis of PPGLs) from 16 patients to assess the therapeutic effect of metyrosine. Percent changes from baseline in urinary metanephrine (uMN) or normetanephrine (uNMN) were compared between spot and 24-hour urine samples. Mean percent changes in uMN or uNMN in spot and 24-hour urine were -26.36% and -29.27%, respectively. The difference in the percent change from baseline between uMN or uNMN in spot and 24-hour urine was small (-2.90%). The correlation coefficient was 0.87 for percent changes from baseline between uMN or uNMN measured in spot and 24-hour urine. The area under the receiver operator characteristic (ROC) curve of uMN or uNMN measured in spot urine vs. 24-hour urine (reference standard) to assess the efficacy of metyrosine treatment was 0.93. Correlations and ROCs between 24-hour urinary vanillylmandelic acid, adrenaline, and noradrenaline and 24-hour uMN or uNMN were similar to those between spot uMN or uNMN and 24-hour uMN or uNMN. No large difference was observed between spot and 24-hour urine for the assessment of metyrosine treatment by quantifying uMN or uNMN in Japanese patients with PPGLs. These results suggest that spot urine samples may be useful in assessing the therapeutic effect of metyrosine.

Prognostic value of metabolic tumor volume of pretreatment 18F-FAMT PET/CT in non-small cell lung Cancer.

BACKGROUND: This study aimed to determine the prognostic value of positron emission tomography (PET) metabolic parameters-namely metabolic tumor volume (MTV), total lesion glycolysis (TLG), and total lesion retention (TLR)-on fluorine-18 (18F) fluorodeoxyglucose (FDG) and L- [3-18F]-α-methyltyrosine (18F-FAMT) PET/CT in patients with non-small-cell lung cancer (NSCLC). METHODS: The study group comprised 112 NSCLC patients who underwent 18F-FDG and 18F-FAMT PET/CT prior to any therapy. The MTV, TLG, TLR, and maximum standardized uptake value (SUVmax) of the primary tumors were determined. Automatic MTV measurement was performed using PET volume computer assisted reading software. (GE Healthcare). Cox proportional hazards models were built to assess the prognostic value of MTV, TLG (for 18F-FDG), TLR (for 18F-FAMT), SUVmax, T stage, N stage, M stage, clinical stage, age, sex, tumor histological subtype, and treatment method (surgery or other therapy) on overall survival (OS). RESULTS: Higher TNM, higher clinical stage, inoperable status, and higher values for all PET parameters (both 18F-FAMT and 18F-FDG PET) were significantly associated (P < 0.05) with shorter OS. Multivariate analysis revealed that a higher MTV of 18F-FAMT (hazard ratio [HR]: 2.88, CI: 1.63-5.09, P < 0.01) and advanced clinical stage (HR: 5.36, CI: 1.88-15.34, P < 0.01) were significant predictors of shorter OS. CONCLUSIONS: MTV of 18F-FAMT is of prognostic value for OS in NSCLC cases and can help guide decision-making during patient management.

The effect of metyrosine on oxidative gastric damage induced by ischemia/reperfusion in rats. Biochemical and histopathological evaluation.

PURPOSE: To investigate the effect of metyrosine against I/R induced gastric damage in rats. METHODS: Eighteen albino Wistar male rats were divided into groups; gastric I/R (GIR), 50 mg/kg metyrosine+gastric I/R (MGIR), and sham (SG) groups. 50 mg/kg metyrosine was given to the MGIR group, and distilled water was given to the GIR and SG groups by the oral gavage. After 30 minutes, 25 mg/kg thiopental sodium was injected intraperitoneally. Ischemia was achieved for 1 hour by clamping the celiac artery of the MGIR and GIR groups, then reperfusion was achieved for 3 hours. After that, animals were killed with 50 mg/kg thiopental. Biochemical and histopathological examinations performed on the gastric tissues. RESULTS: Metyrosine decreased the MDA and MPO and the increased the tGSH and SOD. In addition, it reduced inflammation by suppressing the decrease of COX-1 and the increase of COX-2. Histopathologically, metyrosine decreased symptoms caused by I/R such as mucosal necrosis, hemorrhage, edema, PMNL infiltration, and dilated congested blood vessels. CONCLUSIONS: Metyrosine prevented the I/R induced oxidative stress in the gastric tissue. Metyrosine may be beneficial for gastric I/R injury.

The effect of metyrosine on oxidative gastric damage induced by ischemia/reperfusion in rats. Biochemical and histopathological evaluation

Abstract Purpose: To investigate the effect of metyrosine against I/R induced gastric damage in rats. Methods: Eighteen albino Wistar male rats were divided into groups; gastric I/R (GIR), 50 mg/kg metyrosine+gastric I/R (MGIR), and sham (SG) groups. 50 mg/kg metyrosine was given to the MGIR group, and distilled water was given to the GIR and SG groups by the oral gavage. After 30 minutes, 25 mg/kg thiopental sodium was injected intraperitoneally. Ischemia was achieved for 1 hour by clamping the celiac artery of the MGIR and GIR groups, then reperfusion was achieved for 3 hours. After that, animals were killed with 50 mg/kg thiopental. Biochemical and histopathological examinations performed on the gastric tissues. Results: Metyrosine decreased the MDA and MPO and the increased the tGSH and SOD. In addition, it reduced inflammation by suppressing the decrease of COX-1 and the increase of COX-2. Histopathologically, metyrosine decreased symptoms caused by I/R such as mucosal necrosis, hemorrhage, edema, PMNL infiltration, and dilated congested blood vessels. Conclusions: Metyrosine prevented the I/R induced oxidative stress in the gastric tissue. Metyrosine may be beneficial for gastric I/R injury.

Perioperative hemodynamics and outcomes of patients on metyrosine undergoing resection of pheochromocytoma or paraganglioma.

INTRODUCTION: To describe outcomes of patients with metyrosine (MET) pretreatment for abdominal surgical resection of pheochromocytoma or paraganglioma (PCC/PGL) compared with patients who had phenoxybenzamine (PBZ) pretreatment. METHODS: Retrospective review of perioperative outcomes for PCC/PGL patients treated with MET and propensity-matched comparison of MET and PBZ (MET + PBZ) with PBZ alone. RESULTS: MET preparation was given in 63 cases (26 laparoscopic and 37 open, of which 55 also received PBZ). All patients had wide perioperative hemodynamic oscillations. Patients with open procedures required more intravenous fluids and blood transfusions; 35% required postoperative vasopressor infusions for hypotension and 38% developed acute kidney injury. One laparoscopic procedure required postoperative vasopressor infusion, and 12% of patients developed acute kidney injury. Forty-five MET + PBZ patients were propensity-matched with PBZ-only patients. Intraoperatively, MET + PBZ patients had lower minimum systolic and diastolic blood pressures than PBZ-only patients (median systolic, 74 vs 80 mm Hg, P = 0.01; median diastolic, 42 vs 46 mm Hg, P = 0.005) and larger intraoperative blood pressure oscillations (median systolic range, 112 vs 93 mm Hg, P = 0.06; median diastolic range, 58 vs 51 mm Hg, P = 0.02). Postoperative vasopressor infusion use was similar between MET + PBZ and PBZ only (16% vs 11%, P = 0.76). Major outcomes were not different between regimens. CONCLUSION: Large hemodynamic oscillations were present in our PCC/PGL patients treated with MET + PBZ. These patients had a wider range of intraoperative blood pressure variations than PBZ-only patients. No differences in postoperative comorbid outcomes were found between MET + PBZ and PBZ-only groups.

Reversible Pharmacological Induction of Motor Symptoms in MPTP-Treated Mice at the Presymptomatic Stage of Parkinsonism: Potential Use for Early Diagnosis of Parkinson's Disease.

A crucial event in the pathogenesis of Parkinson's disease is the death of dopaminergic neurons of the nigrostriatal system, which are responsible for the regulation of motor function. Motor symptoms first appear in patients 20-30 years after the onset of the neurodegeneration, when there has been a loss of an essential number of neurons and depletion of compensatory reserves of the brain, which explains the low efficiency of treatment. Therefore, the development of a technology for the diagnosing of Parkinson's disease at the preclinical stage is of a high priority in neurology. In this study, we have developed at an experimental model a fundamentally novel for neurology approach for diagnosis of Parkinson's disease at the preclinical stage. This methodology, widely used for the diagnosis of chronic diseases in the internal medicine, is based on the application of a challenge test that temporarily increases the latent failure of a specific functional system, thereby inducing the short-term appearance of clinical symptoms. The provocation test was developed by a systemic administration of α-methyl-p-tyrosine (αMpT), a reversible inhibitor of tyrosine hydroxylase to MPTP-treated mice at the presymptomatic stage of parkinsonism. For this, we first selected a minimum dose of αMpT, which caused a decrease of the dopamine level in the striatum of normal mice below the threshold at which motor dysfunctions appear. Then, we found the maximum dose of αMpT at which a loss of dopamine in the striatum of normal mice did not reach the threshold level, and motor behavior was not impaired. We showed that αMpT at this dose induced a decrease of the dopamine concentration in the striatum of MPTP-treated mice at the presymptomatic stage of parkinsonism below a threshold level that results in the impairment of motor behavior. Finally, we proved that αMpT exerts a temporal and reversible influence on the nigrostriatal dopaminergic system of MPTP-treated mice with no long-term side effects on other catecholaminergic systems. Thus, the above experimental data strongly suggest that αMpT-based challenge test might be considered as the provocation test for Parkinson's disease diagnosis at the preclinical stage in the future clinical trials.

Cardiac sympathetic activity in 22q11.2 deletion syndrome.

AIM: 22q11.2 deletion syndrome (22q11.2DS) affects catechol-O-methyl-transferase (COMT), which involves the degradation of norepinephrine (NE). Clinically, adults with 22q11.2DS are at increased risk for sudden unexpected death. Although the causes are likely multifactorial, increased cardiac sympathetic activity with subsequent fatal arrhythmia, due to increased levels of NE, should be considered as a possible mechanism predisposing to this premature death. The purpose of this study was to determine whether cardiac sympathetic activity is increased in 22q11.2DS, both at baseline and following an acute NE depletion with alpha-methyl-para-tyrosine (AMPT). METHODS: Five adults with 22q11.2DS and five age- and sex-matched healthy controls underwent 2 sessions with either AMPT or placebo administration before (123)I-mIBG scintigraphy. Heart-to-mediastinum ratios (H/M) were determined from the images 15min (early) and 4h (late) after administration of (123)I-mIBG and the washout (WO) was calculated as an indicator of adrenergic drive. RESULTS: At baseline there were no significant differences in both early and late H/M between 22q11.2DS and controls. However, there was a significant difference in WO between 22q11.2DS and controls (-4.92±2.8 and -10.44±7.2, respectively; p=0.027), but a "negative WO" does not support an increased sympathetic drive. In addition there was a trend towards a higher late H/M after AMPT administration compared to baseline which was more pronounced in 22q11.2DS. CONCLUSION: This study for the first time suggests normal cardiac sympathetic activity in adults with 22q11.2DS assessed by (123)I-mIBG scintigraphy. Although there is a small difference in adrenergic drive compared to healthy subjects, this most likely does not explain the increased unexpected death rate in the 22q11.2 DS population.

Reduced insulin sensitivity is related to less endogenous dopamine at D2/3 receptors in the ventral striatum of healthy nonobese humans.

BACKGROUND: Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D2/3 receptor radiotracer [(11)C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity. METHODS: Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [(11)C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion. RESULTS: Endogenous dopamine at ventral striatum dopamine D2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36). CONCLUSION: In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities.

Dopamine depletion attenuates some behavioral abnormalities in a hyperdopaminergic mouse model of bipolar disorder.

BACKGROUND: Patients with BD suffer from multifaceted symptoms, including hyperactive and psychomotor agitated behaviors. Previously, we quantified hyperactivity, increased exploration, and straighter movements of patients with BD mania in the human Behavioral Pattern Monitor (BPM). A similar BPM profile is observed in mice that are hyperdopaminergic due to reduced dopamine transporter (DAT) functioning. We hypothesized that dopamine depletion through alpha-methyl-p-tyrosine (AMPT) administration would attenuate this mania-like profile. METHODS: Male and female DAT wild-type (WT; n=26) and knockdown (KD; n=28) mice on a C57BL/6 background were repeatedly tested in the BPM to assess profile robustness and stability. The optimal AMPT dose was identified by treating male C57BL/6 mice (n=39) with vehicle or AMPT (10, 30, or 100mg/kg) at 24, 20, and 4h prior to testing in the BPM. Then, male and female DAT WT (n=40) and KD (n=37) mice were tested in the BPM after vehicle or AMPT (30mg/kg) treatment. RESULTS: Compared to WT littermates, KD mice exhibited increased activity, exploration, straighter movement, and disorganized behavior. AMPT-treatment reduced hyperactivity and increased path organization, but potentiated specific exploration in KD mice without affecting WT mice. LIMITATIONS: AMPT is not specific to dopamine and also depletes norepinephrine. CONCLUSIONS: KD mice exhibit abnormal exploration in the BPM similar to patients with BD mania. AMPT-induced dopamine depletion attenuated some, but potentiated other, aspects of this mania-like profile in mice. Future studies should extend these findings into other aspects of mania to determine the suitability of AMPT as a treatment for BD mania.

The neuropeptide Y Y1 receptor knockdown modulates activator protein 1-involved feeding behavior in amphetamine-treated rats.

BACKGROUND: Hypothalamic neuropeptide Y (NPY) and two immediate early genes, c-fos and c-jun, have been found to be involved in regulating the appetite-suppressing effect of amphetamine (AMPH). The present study investigated whether cerebral catecholamine (CA) might regulate NPY and POMC expression and whether NPY Y1 receptor (Y1R) participated in activator protein-1 (AP-1)-mediated feeding. METHODS: Rats were given AMPH daily for 4 days. Changes in the expression of NPY, Y1R, c-Fos, c-Jun, and AP-1 were assessed and compared. RESULTS: Decreased CA could modulate NPY and melanocortin receptor 4 (MC4R) expressions. NPY and food intake decreased the most on Day 2, but Y1R, c-Fos, and c-Jun increased by approximately 350%, 280%, and 300%, respectively, on Day 2. Similarly, AP-1/DNA binding activity was increased by about 180% on Day 2. The expression patterns in Y1R, c-Fos, c-Jun, and AP-1/DNA binding were opposite to those in NPY during AMPH treatment. Y1R knockdown was found to modulate the opposite regulation between NPY and AP-1, revealing an involvement of Y1R in regulating NPY/AP-1-mediated feeding. CONCLUSIONS: These results point to a molecular mechanism of CA/NPY/Y1R/AP-1 signaling in the control of AMPH-mediated anorexia and may advance the medical research of anorectic and anti-obesity drugs.

Effect of methylprednisolone on bone mineral density in rats with ovariectomy-induced bone loss and suppressed endogenous adrenaline levels by metyrosine.

OBJECTIVES: In this study, effect of methylprednisolone on bone mineral density (BMD) was investigated in rats with overiectomy induced bone lose and suppressed endogenous adrenalin levels, and compared to alendronate. MATERIALS AND METHODS: Severity of bone loss in the examined material (femur bones) was evaluated by BMD measurement. RESULTS: The group with the highest BMD value was metyrosinemetyrosine + methylprednisolone combination (0.151 g/cm(2)), while that with the lowest BMD was methylprednisolone (0.123 g/cm(2)). Alendronate was effective only when used alone in ovariectomized rats (0.144 g/cm(2)), but not when used in combination with methylprednisolone (0.124 g/cm(2)). In the ovariectomized rat group which received only metyrosine, BMD value was statistically indifferent from ovariectomized control group. CONCLUSIONS: Methylprednisolone protected bone loss in rats with suppressed adrenaline levels because of metyrosinemetyrosine.

Growth hormone response to catecholamine depletion in unmedicated, remitted subjects with major depressive disorder and healthy controls.

We investigated whether the human growth hormone (HGH) response to catecholamine depletion differs between fully remitted patients with major depressive disorder and healthy control subjects. Fourteen unmedicated subjects with remitted major depressive disorder (RMDD) and 11 healthy control subjects underwent catecholamine depletion with oral α-methylparatyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover study. The main outcome measure was the serum level of HGH. The diagnosis × drug interaction for HGH serum concentration was significant (F1,23 = 7.66, P < 0.02). This interaction was attributable to the HGH level increasing after AMPT administration in the RMDD subjects but not in the healthy subjects. In the RMDD sample, the AMPT-induced increase in HGH concentration correlated inversely with AMPT-induced anxiety symptoms as assessed using the Beck Anxiety Inventory (r = -0.63, P < 0.02). There was a trend toward an inverse correlation of the AMPT-induced HGH concentration changes with AMPT-induced depressive symptoms as measured by the BDI (r = -0.53, P = 0.05). Following catecholamine depletion, the RMDD subjects were differentiated from control subjects by their HGH responses. This finding, together with the negative correlation between HGH response and AMPT-induced anxiety symptoms in RMDD subjects, suggests that AMPT administration results in a deeper nadir in central catecholaminergic transmission, as reflected by a greater disinhibition of HGH secretion, in RMDD subjects versus control subjects.

The activation of α1-adrenoceptors is implicated in the antidepressant-like effect of creatine in the tail suspension test.

The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by our group. In this study we investigated the involvement of the noradrenergic system in the antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered by i.c.v. route (1 µg/site) decreased the immobility time in the TST, suggesting the central effect of this compound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), but not by yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist). Creatine (0.01 mg/kg, subeffective dose) in combination with subeffective doses of amitriptyline (1 mg/kg, p.o., tricyclic antidepressant), imipramine (0.1 mg/kg, p.o., tricyclic antidepressant), reboxetine (2 mg/kg, p.o., selective noradrenaline reuptake inhibitor) or phenylephrine (0.4 µg/site, i.c.v., α1-adrenoceptor agonist) reduced the immobility time in the TST as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of α1-adrenoceptor and that creatine produces synergistic effects in the TST with antidepressants that modulate noradrenaline transporter, suggesting that an improvement in the response to the antidepressant therapy may occur when creatine is combined with these antidepressants. Furthermore, the synergistic effect of creatine (0.01 mg/kg, p.o.) and reboxetine (2 mg/kg, p.o.) combination was abolished by the α1-adrenoceptor antagonist prazosin, indicating that the antidepressant-like effect of combined therapy is likely mediated by an activation of α1-adrenoceptor.

The protective effects of metyrosine, lacidipine, clonidine, and moxonidine on kidney damage induced by unilateral ureteral obstruction in rats.

PURPOSE: To investigate the effects of metyrosine, lacidipine, clonidine, and moxonidine on the renal damage in rats with unilateral ureteral ligation by examining the histological evidence of parenchymal damage and tubular dilatation, as well as biochemical changes indicating cell membrane damage and DNA oxidation. METHODS: Thirty-six albino Wistar rats were randomly divided into six equal groups: a healthy (intact) group, a unilateral ureteral ligation (control) group, and four drug treatment groups given metyrosine (50 mg/kg), lacidipine (2 mg/kg), clonidine (0.075 mg/kg), or moxonidine (0.2 mg/kg), respectively, for 10 days. The latter five groups underwent ligation of the left ureter. Ten days after the operation, we removed both kidneys from each rat in the control and drug treatment groups for renal pathological and biochemical [malondialdehyde (MDA), total glutathione, 8-hydroxy-2-deoxyguanine (8-OH-Gua)] examinations. Spectrophotometric assays were used to detect the malondialdehyde and total glutathione levels of the renal tissue. High-performance liquid chromatography was used to measure the 8-hydroxy-2-deoxyguanine levels. RESULTS: When the drug treatment groups were compared with the control group, the drug treatment groups' total glutathione level was higher and their malondialdehyde level was lower than that of the control group (P < 0.05), especially in the clonidine group (P < 0.0001). The 8-hydroxy-2-deoxyguanine levels of the drug treatment groups, except the lacidipine group, were significantly lower than that of the control group (P < 0.0001). There was no significant difference between the contralateral kidneys of the treatment groups and control group, according to the biochemical results. As revealed via light microscopy, clonidine and moxonidine treatment significantly reduced the tubular and glomerular damage, as well as the tubular dilation. The interstitial inflammation of the kidneys in the lacidipine group was higher than that of the other treatment groups. However, the apoptotic cell count was at a high level in both the lacidipine and metyrosine groups. The increase in the collagen content was most pronounced in the lacidipine and metyrosine groups. An examination of the contralateral kidneys showed no marked pathological findings. CONCLUSIONS: The use of a direct or indirect α2-adrenergic receptor agonist for the temporary treatment of unilateral ureteral obstruction-induced renal damage may be important for preventing renal structural injury. A more advanced study is necessary to determine the mechanisms underlying the protective effects of these drugs with regard to renal damage in ureteral obstruction.

Effects of epinephrine and cortisol on the analgesic activity of metyrosine in rats.

Some endogenous hormones (epinephrine and cortisol) can change an individual's pain threshold. Propranolol is a non-selective ß adrenergic receptor blocker which antagonises the anti-inflammatory effect of non-steroidal anti-inflammatory drugs via the ß1 and ß2 adrenergic receptors. The roles of epinephrine and cortisol were investigated in the analgesic activity of metyrosine in rats with reduced epinephrine levels induced by metyrosine. Pain threshold measurement was performed using an analgesimeter with different doses and the single or combined usage of metyrosine, prednisolone, metyrapone and propranolol in rats. Epinephrine and corticosterone levels were measured by high-performance liquid chromatography in metyrosineadministered rats. Metyrosine reduces the epinephrine levels without affecting the corticosterone levels, thereby creating an analgesic effect. It was determined that prednisolone did not have an analgesic effect in rats with normal epinephrine levels, but its analgesic activity increased with a parallel decrease in the epinephrine levels. Similarly, the combined use of prednisolone and metyrosine provided a stronger analgesic effect than that rendered by metyrosine alone. The strongest analgesic effect, however, was observed in the group of rats with the lowest epinephrine level in whom the metyrosine + prednisolone combination was administered. The findings of this study may be useful in severe pain cases in which the available analgesics are unable to relieve the individual's pain.

Central injection of ketone body suppresses luteinizing hormone release via the catecholaminergic pathway in female rats.

Ketosis is found in various pathophysiological conditions, including diabetes and starvation, that are accompanied by suppression of gonadal activity. The aim of the present study was to determine the role of ketone body in the brain in regulating pulsatile luteinizing hormone (LH) secretion in female rats. Injection of 3-hydroxybutyrate (3HB), a ketone body, into the fourth cerebroventricle (4V) induced suppression of pulsatile LH secretion in a dose-dependent manner in ovariectomized (OVX) rats with an estradiol (E2) implant producing diestrus plasma E2 levels. Plasma glucose and corticosterone levels increased immediately after the 4V 3HB injection, suggesting that the treatment caused a hunger response. The 3HB-induced suppression of LH pulses might be mediated by noradrenergic inputs to the hypothalamic paraventricular nucleus (PVN) because a local injection of α-methyl- p-tyrosine, a catecholamine synthesis inhibitor, into the PVN blocked 3HB-induced suppression of LH pulses and PVN noradrenaline release was increased by 4V 3HB injection in E2-primed OVX rats. These results suggest that ketone body sensed by a central energy sensor in the hindbrain may suppress gonadotropin release via noradrenergic inputs to the PVN under ketosis.

Dopaminergic modulation of the human reward system: a placebo-controlled dopamine depletion fMRI study.

Reward related behaviour is linked to dopaminergic neurotransmission. Our aim was to gain insight into dopaminergic involvement in the human reward system. Combining functional magnetic resonance imaging with dopaminergic depletion by α-methylparatyrosine we measured dopamine-related brain activity in 10 healthy volunteers. In addition to blood-oxygen-level-dependent (BOLD) contrast we assessed the effect of dopaminergic depletion on prolactin response, peripheral markers for dopamine and norepinephrine. In the placebo condition we found increased activation in the left caudate and left cingulate gyrus during anticipation of reward. In the α-methylparatyrosine condition there was no significant brain activation during anticipation of reward or loss. In α-methylparatyrosine, anticipation of reward vs. loss increased activation in the right insula, left frontal, right parietal cortices and right cingulate gyrus. Comparing placebo versus α-methylparatyrosine showed increased activation in the left cingulate gyrus during anticipation of reward and the left medial frontal gyrus during anticipation of loss. α-methylparatyrosine reduced levels of dopamine in urine and homovanillic acid in plasma and increased prolactin. No significant effect of α-methylparatyrosine was found on norepinephrine markers. Our findings implicate distinct patterns of BOLD underlying reward processing following dopamine depletion, suggesting a role of dopaminergic neurotransmission for anticipation of monetary reward.

[Clinical course of patient with malignant pheochromocytoma who was treated with CVD chemotherapy and alpha-methyl-p-tyrosine].

A 31-years-old woman was diagnosed as pheocromocytoma by the various endocrine testings and 131I-MIBG scintigraphy. The CT scan and bone scintigraphy showed right adrenal tumor, along with liver metastasis, lymph nodes swelling around aorta and multiple bone metastases. She underwent chemotherapy consisting with Cyclophosphamide, Vincristine, Dacarbazine (CVD) and alpha-methyl-p-tyrosine (alphaMT), resulting in stable disease for 27 months. However, catecholamine levels increased gradually four weeks later. We would have planned 131I-MIBG therapy, but bone marrow suppression did not allow us to do it. She died of DIC.

Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular dopamine pool and the alpha-methyl-para-tyrosine-sensitive cytosolic dopamine pool. Given the similarities between dexamphetamine and SKF38393, we hypothesized that both types of pool also contribute to the striatally applied SKF38393-induced dopamine efflux. Using in vivo microdialysis technique, we analysed the contribution of these pools to the SKF38393-induced striatal dopamine efflux in freely moving rats. The increase of dopamine efflux induced by 1.5 microg SKF38393 was largely prevented by either reserpine (5mg/kg i.p., given 24h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2h earlier), showing that both the vesicular dopamine pool and the cytosolic dopamine pool contribute to the SKF38393-induced increase in striatal dopamine efflux. The sum of the amounts of dopamine that was sensitive to either reserpine or alpha-methyl-para-tyrosine, was greater than 100%, namely 137.6% of the basal dopamine level and 143.9% of the SKF38393-induced dopamine level, suggesting that striatally applied SKF38393 promotes the redistribution of dopamine from vesicles to the cytosol, and vice versa. The finding that the combined treatment of reserpine and alpha-methyl-para-tyrosine only inhibited the SKF38393-induced striatal dopamine efflux till 86.0% of the control, is ascribed to the notion that SKF38393 can also inhibit the re-uptake of dopamine. The latter conclusion has far-reaching consequences for studies in which the effects of SKF38393 are simply ascribed to its dopamine D1 receptor stimulation capacity.