Cerebromicrocirculatory defects in animal model of depression

In the tetrabenazine (TBZ) model of depression, the cerebromicrocirculation was discovered to respond abnormally to metabolic demand as mimicked by the administration of CO₂. Altered responsivity of cerebral blood flow and effective permeability of the blood — brain barrier to changes in PaCO₂ were found. These physiologic defects coincided temporally with TBZ-induced depletion of central norepinephrine and dopamine and with the development of the behavioral effects of TBZ (the end points used to test the antidepressant potential of experimental drugs). Pretreatment with amitriptyline (a standard antidepressant and amine reuptake inhibitor) prevented the development of these TBZ-induced abnormalities in the cerebromicrocirculation, just as it prevented the behavioral effects.     

The serotonin agonist, M-chlorophenylpiperazine, markedly increases levels of plasma catecholamines in the conscious rat

Intravenous administration of the serotonin agonist, m-chlorophenylpiperazine (m-CPP), produced large, dose-dependent increases in epinephrine, norepinephrine and dopamine in plasma in normal, conscious rats. Elevations in the levels of epinephrine, norepinephrine and dopamine (10-fold, 5-fold and 2-fold, respectively) were markedly reduced in pithed and splanchnic denervated rats, suggesting that CNS mechanisms are primarily responsible for the effect of m-CPP on catecholamines in plasma. The serotonin antagonist, metergoline (0.5 mg/kg), decreased the responses of epinephrine and dopamine to m-CPP by 60-80% and also tended to decrease the response of norepinephrine. These findings are consistent with other studies reporting that stimulation of serotonergic receptors increases centrally-mediated sympathetic outflow and leads to increases in the concentrations of norepinephrine, epinephrine and dopamine in plasma.     

Effect of neonatal catecholamine administration on later behaviour in rats

Summary Neonatal rats were chronically given (days 2–10) injections of 3 catecholamines (epinephrine, norepinephrine, and dopamine) and simultaneously exposed to a post-injection treatment of mechanical rotation or hypothermia. Later behavioral testing indicated a consistent deficit in learning scores for the amine subjects and differential effects for both the environmental treatments and the amines in terms of activity scores.This research was supported by Public Health Service Grant MH 08543 from the National Institute of Mental Health.     

A microdialysis profile of β-endorphin and catecholamines in the rat nucleus accumbens following alcohol administration

Rationale Alcohol stimulates the release of dopamine in the nucleus accumbens (NACB) of rats, mice and humans. There is evidence to suggest that the activation of beta-endorphin (β-EP) in the mesolimbic pathway by alcohol and other drugs of abuse may be associated with the rise in dopamine levels in the NACB. Objectives The present studies investigate whether the release of β-EP in the NACB is (1) dependent on the dose of alcohol that is administered, and (2) associated with changes in the extracellular concentrations of the catecholamines dopamine and norepinephrine, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the NACB. Methods Male Sprague-Dawley rats were implanted with a microdialysis probe positioned in the shell region of the NACB. Artificial cerebrospinal fluid was pumped at a rate of 2.3 μl/min in awake and freely moving animals and the dialysate was collected at 30-min intervals. After a baseline period, rats were injected intraperitoneally with either physiological saline or one of three doses of alcohol: 0.8, 1.6, or 2.4 g ethanol/kg body weight. The dialysates collected were analyzed with radioimmunoassay, to estimate the content of β-EP; and high performance liquid chromatography, to estimate the content of dopamine, norepinephrine, DOPAC and HVA. Results Alcohol induced a dose-dependent increase in the extracellular levels of β-EP and dopamine. However, elevations in the extracellular levels of norepinephrine, DOPAC and HVA did not reach significance. The largest increase in β-EP and dopamine was observed with the 2.4 g/kg dose. Conclusion The alcohol-induced release of β-EP and dopamine in the NACB is dose-dependent, where the highest dose resulted in more pronounced concentrations in the dialysate. Furthermore, the increase in the extracellular levels of dopamine appeared to occur at an earlier time point following alcohol administration, than for β-EP. These results suggest that alcohol stimulates dopamine and β-EP in the NACB, but probably does so via independent mechanisms.     

Changes of acetylcholine, catecholamines and amino acid in mice brain following treatment with Nuvacron and Furadan

The effects of multiple intraperitoneal doses of Nuvacron (0.8 mg/kg) or Furadan (0.25 mg/kg) on the concentrations of brain neurotransmitters in mice were studied. The following were measured: acetylcholine, acetylcholinesterase, gamma-aminobutyric acid, epinephrine, norepinephrine, dopamine and 5-hydroxytryptamine. These pesticides caused a significant decrease in acetylcholinesterase activity and a significant increase in acetylcholine, gamma-amino-butyric acid, epinephrine, norepinephrine, dopamine and 5-hydroxy tryptamine concentrations. The increased concentrations of the neurotransmitters in mouse brain might be associated with CNS depressant action induced by the insecticides.     

The effect of indomethacin and dexamethasone on the excretion of epinephrine, levarterenol and dopamine in the urine of rats with adjuvant arthritis

The repeated application of indometacine or dexamethasone on rats with adjuvant arthritis results in a most cases significant inhibition of the arthritis in the primary and secondary phase as well as in a normalisation of the increased urinary excretion of epinephrine and norepinephrine of untreated arthritis rats. The dopamine excretion of adjuvant arthritis rats was also higher then the prepared rats. We suppose, that the results show the regulative endogenous excretion of epinephrine and norepinephrine in inflammatory processes. Consequently these drugs have essentially antiinflammatory activities. The inhibition of the inflammation is than connected with the normalisation of the excretion of catecholamines.     

Sympathetic nervous system response in acute cardiovascular toxicity induced by amitriptyline in conscious rabbits

The response of the sympathetic nervous system in the acute cardiovascular toxicity induced by amitriptyline, a tricyclic antidepressant drug, has been evaluated in the conscious rabbit. The ip injection of amitriptyline at increasing doses (12.5, 25, 37.5, and 50 mg/kg) resulted in drug concentrations in plasma and tissue which correlated with the administered doses. A fall in arterial pressure (at least 25% compared to controls) and characteristic ECG abnormalities were induced during the first 10 min. Acute renal insufficiency without hyperkalemia was detected 3 hr postdosage in all treated rabbits. Assessment of the adrenergic activity made by monitoring plasma catecholamines revealed early elevation of plasma epinephrine concentrations associated with a marked rise in plasma norepinephrine concentrations. In control rabbits receiving ip physiological saline and subjected to the same procedures, ECG, blood pressure, and plasma catecholamines concentrations remained unaltered during the entire monitoring period. The hyperactivity of the adrenergic nervous system, as assessed by the measurement of plasma catecholamines, in the amitriptyline-intoxicated conscious rabbit seems to be established. The origin of these catecholamines remains to be investigated.     

去甲肾上腺素、肾上腺素及去甲肾上腺素—多巴酚丁胺对感染性休克病人全身及胃粘膜氧代谢的影响

目的:比较多巴胺、去甲肾上腺素、肾上腺素及去甲肾上腺素-多巴酚丁胺对感染性休克患者全身及胃 粘膜氧代谢的影响.方法:首先用多巴胺,然后随机应用肾上腺素、去甲肾上腺素,或去甲肾上腺素-多巴酚丁胺,调整剂量维持平均动脉压>9.31 kPa.药物注射后 120 min,记录血流动力学、氧代谢及胃粘膜pH参数.结果:与其它三组比较,肾上腺素使心率明显增加(P<0.05),心排指数明显高于去甲肾上腺素组或去甲肾上腺素-多巴酚丁胺组(P<0.05),氧摄取率明显低于其它三组(P<0.05).与多巴胺、肾上腺素比较,去甲肾上腺素-多巴酚丁胺合用时动脉血乳酸值明显降低(P<0.05).与肾上腺素比较,去甲肾上腺素-多巴酚丁胺合用时胃粘膜pH值明显增加(7.25±0.09 vs 7.14±0.07,P<0.05).结论:多巴胺、去甲肾上腺素、肾上腺素及去甲肾上腺素-多巴酚丁胺均能升高血压.但是肾上腺素和多巴胺使氧代谢恶化,而去甲肾上腺素与小剂量多巴酚丁胺合用可改善胃粘膜灌注和组织氧利用.     

Co-dergocrine mesylate inhibits the increase in plasma catecholamines caused by nifedipine in essential hypertension

Summary Co-dergocrine mesylate (Cod), which inhibits norepinephrine secretion by stimulating presynaptic dopamine receptors, and has no known metabolic side effect, has an additive antihypertensive effect to that of Nifedipine (Nif). Plasma norepinephrine, epinephrine, renin activity and aldosterone have been measured after acute administration of Nif and Cod alone and in combination to 18 patients with a diastolic blood pressure > 105 mm Hg in a cross-over, randomized, double-blind study. Every patient received 4 mg Cod then 20 mg Nif, placebo then 20 mg Nif and 4 mg Cod then placebo. The second treatment was always given 1 h after the first medication. Blood pressure was measured before and every 15 min during the study period. Blood for measurement of catecholamines, aldosterone and renin activity was collected before medication, 1 h after the first dose and 90 min after the second treatment.Blood pressure was significantly lower (P < 0.05) where Cod preceded Nif. Cod caused a significant decrease in plasma norepinephrine from 293 to 202 pg · ml^–1 and in epinephrine from 67 to 55 pg · ml^–1. The Nif-induced increase in norepinephrine from a pre-treatment value of 293 pg · ml^–1 with preceding Cod to 331 pg · ml^–1 was much less than the increase with placebo as premedication, from 284 to 440 pg · ml^–1. Nif caused an increase in renin activity but no increase in aldosterone.Nif-related side effects, such as flushing and headache, occurred in 6 patients of whom 5 had no received Cod as premedication. Due to the stabilizing action of Cod on catecholamines and on the side effects of Nif, Cod may be preferable to other antihypertensives in augmenting the antihypertensive action of Nif.     

Studies on the mechanism by which tyrosine raises urinary catecholamines

The source of urinary catecholamines and the mechanisms by which tyrosine administration raises these compounds were investigated in rats. Adrenalectomy blocked the tyrosine-induced rise in urinary epinephrine but not dopamine or norepinephrine. Following chemical sympathectomy with 6-hydroxydopamine (6-OHDA), the tyrosine-induced increased in urinary norepiphine was diminished, but epinephrine and dopamine responses were unaffected. Cardiac norepinephrine, which is normally unchanged following tyrosine administration, became significantly elevated in 6-OHDA-pretreated animals. At the doses used in this study, tyrosine had no effect on the uptake or metabolic clearance of circulating catecholamines. We conclude that tyrosine augments the synthesis of the three catecholamines in sympathoadrenal cells by increasing the extent to which tyrosine hydroxylase is saturated with its amino acid substrate. Moreover, the effects of tyrosine on peripheral catecholamine synthesis may be enhanced under conditions of increased sympathetic activity.     

The factors affecting plasma catecholamines concentration in rats and man

Rat and human plasma catecholamines were measured simultaneously by HPLC-THI, HPLC-ECD and REA, and the three methods were compared. An attempt was also made to determine the factors affecting the estimated value of plasma catecholamine concentration. Our study showed that: Sensitivity and reproducibility to norepinephrine and epinephrine were identical in all three methods. One advantage of the REA method is that comparatively smaller sample volumes are required to produce similar results. Plasma dopamine concentration in peripheral blood samples was determined by the HPLC-ECD rather than the HPLC-THI method. Withdrawal of 5 ml of blood produced a significant increase in norepinephrine, epinephrine and dopamine in rat plasma. The catecholamine concentration in these cases was determined by the REA method. Plasma norepinephrine concentration did not increase with age in Wistar Kyoto rats. However, plasma norepinephrine concentration increased significantly with age in stroke-prone spontaneously hypertensive rats (SHRSP). Plasma norepinephrine concentration in male SHRSP was greater than that in female SHRSP. SHRSP-plasma norepinephrine concentrations rose in parallel to increases in blood pressure. The plasma norepinephrine concentration in SHRSP with cerebral hemorrhage rose significantly as compared with the plasma norepinephrine levels in SHRSP without cerebral bleeding. Because each method of determination of plasma catecholamine concentration has both merits and demerits, selection should be determined by sample size and amount of catecholamines in the plasma samples. Factors affecting the estimated value of plasma catecholamine concentration should be taken into consideration.     

Effects of different monoamine oxidase inhibitors on the metabolism of L-dopa in the rat brain

The influence of monoamine oxidases A and B on the metabolism of dopamine or the expanded dopamine pool following L-dopa administration remains unclear. This study found that treatment of Sprague-Dawley rats with monoamine oxidase inhibitors strongly affected L-dopa metabolism in the brain, but the influence varied with each individual inhibitor. In animals pretreated with pargyline or clorgyline, L-dopa administration led to huge accumulations of dopamine and significantly raised central norepinephrine concentrations. In contrast, similar L-dopa injections in deprenyl-pretreated rats caused only a moderate rise in dopamine and no change in norepinephrine. There seems to be little relationship between the degree of monoamine oxidase inhibition and the accumulation of catecholamines and their metabolites in the rat brain. The effects of monoamine oxidase inhibitors on dopamine accumulation appeared to occur outside the catecholaminergic neurons since in the animals pretreated with 6-hydroxydopamine, which decreased significantly the content of brain catecholamines, dopamine accumulation following L-dopa administration still remained considerable. On the other hand, the influence of monoamine oxidase inhibitors on brain norepinephrine concentrations seemed to originate in the noradrenergic neurons because norepinephrine increase was greatly reduced in rats treated with 6-hydroxydopamine but was restored when the treatment with 6-hydroxydopamine was accompanied by desimipramine which specifically protects noradrenergic stores.     

Management of the cardiovascular complications of tricyclic antidepressant poisoning : role of sodium bicarbonate

Experimental studies suggest that both alkalinisation and sodium loading are effective in reducing cardiotoxicity independently. Species and experimental differences may explain why sodium bicarbonate appears to work by sodium loading in some studies and by a pH change in others. In the only case series, the administration of intravenous sodium bicarbonate to achieve a systemic pH of 7.5-7.55 reduced QRS prolongation, reversed hypotension (although colloid was also given) and improved mental status in patients with moderate to severe tricyclic antidepressant poisoning. This clinical study supports the use of sodium bicarbonate in the management of the cardiovascular complications of tricyclic antidepressant poisoning. However, the clinical indications and dosing recommendations remain to be clarified.Hypotension should be managed initially by administration of colloid or crystalloid solutions, guided by central venous pressure monitoring. Based on experimental and clinical studies, sodium bicarbonate should then be administered. If hypotension persists despite adequate filling pressure and sodium bicarbonate administration, inotropic support should be initiated. In a non-randomised controlled trial in rats, epinephrine resulted in a higher survival rate and was superior to norepinephrine both when the drugs were used alone or when epinephrine was used in combination with sodium bicarbonate. Sodium bicarbonate alone resulted in a modest increase in survival rate but this increased markedly when sodium bicarbonate was used with epinephrine or norepinephrine. Clinical studies suggest benefit from norepinephrine and dopamine; in an uncontrolled study the former appeared more effective. Glucagon has also been of benefit. Experimental studies suggest extracorporeal circulation membrane oxygenation is also of potential value.The immediate treatment of arrhythmias involves correcting hypoxia, electrolyte abnormalities, hypotension and acidosis. Administration of sodium bicarbonate may resolve arrhythmias even in the absence of acidosis and, only if this therapy fails, should conventional antiarrhythmic drugs be used. The class 1b agent phenytoin may reverse conduction defects and may be used for resistant ventricular tachycardia. There is also limited evidence for benefit from magnesium infusion. However, class 1a and 1c antiarrhythmic drugs should be avoided since they worsen sodium channel blockade, further slow conduction velocity and depress contractility. Class II agents (beta-blockers) may also precipitate hypotension and cardiac arrest.     

Sex as a factor influencing the responsiveness of arterioles to catecholamines

The present in vivo experiments on rat mesenteric arterioles, using a high magnification (up to 4000 ×) image-splitting television microscope recording system, demonstrate that dose—response curves for the constrictor catecholamines epinephrine and norepinephrine in female rats are significantly shifted in a parallel manner to the left of those obtained in male rats. The maximal arteriolar contractile (i.e., lumen diameter narrowings) responses to the catecholamines were, however, not altered by the sex differences. Dose—response curves for constrictions induced by dopamine or phenylephrine were not affected by a difference in sex. The sex-linked differences, observed in the present study, thus appear to be specific for catecholamine molecules exhibiting not only a catechol nucleus but an hydroxyl group on the β-carbon of the side chain. These findings could be interpreted as support for a role of sex hormones in control of blood flow.     

Effect of acutely and chronically administered venlafaxine on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model

The influence of acute and chronic treatments with intraperitoneal venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor, on the anticonvulsant activity of selected antiepileptic drugs was studied in the maximal electroshock test in mice. Venlafaxine (12.5 and 25 mg/kg), given either acutely or chronically, significantly increased the electroconvulsive threshold. Moreover, both acute and chronic venlafaxine, applied at the highest subprotective dose of 6.25 mg/kg, enhanced the anticonvulsant effect of valproate, without affecting the protective action of carbamazepine, phenobarbital and phenytoin. The antidepressant did not affect brain concentration of valproate, indicating that the interaction between the two drugs seems pharmacodynamic in nature. Despite the lack of effect on the antielectroshock action of the remaining antiepileptics, acute venlafaxine increased the brain concentration of phenobarbital, while chronic venlafaxine reduced the brain level of phenytoin. In terms of adverse effects, acute/chronic venlafaxine and antiepileptic drugs alone, as well as their combinations, did not produce significant motor or long-term memory deficits in mice. Summing up, it seems that venlafaxine may be considered as a safe drug for the clinical use in patients with epilepsy and depressive disorders.     

Catecholamine levels in discrete brain nuclei of seven month old genetically obese rats.

Catecholamine levels were measured in microdissected nuclear groups of seven month old, obese and lean, male and female Zucker rats. By analysis of variance, obese rats showed significantly reduced levels of norepinephrine and epinephrine in the paraventricular nucleus and of epinephrine and dopamine in the dorsomedial hypothalamic nucleus. Norepinephrine levels were increased in the median forebrain bundle and caudate nucleus. When compared by sex and genotype (t-test), the female obese rats had significant decreases compared to the leans of norepinephrine and epinephrine levels in the paraventricular and dorsomedial hypothalamic nuclei, while norepinephrine was increased in the median forebrain bundle and caudate nucleus. Dopamine was decreased in the dorsomedial and increased in the C2 nuclei. Male obese Zucker rats showed changes only in the dorsomedial and C2 nuclei where dopamine levels were decreased. In general, female obese and lean rats tended to have lower levels of catecholamines in various brain areas than males of the same genotype. Comparisons of these data to previous studies in younger Zucker rats [9,10] suggested that changes also occurred in various nuclei with aging. It is postulated that catecholamine deficits in certain hypothalamic nuclei of the Zucker obese rat may be a contributing factor to the development and/or maintenance of obesity, possibly in association with abnormalities in thermal regulation.     

Catecholamine receptors on locus coeruleus neurons: pharmacological characterization.

There is evidence that the noradrenergic neurons of the locus coeruleus (LC) possess α-adrenoreceptors in the vicinity of their cell bodies. To further characterize this receptor, we studied the responses of LC neurons to a series of catecholamine agonist and antagonist drugs using the techniques of single-unit recording and microiontophoresis. The spontaneous firing of LC neurons was inhibited by microiontophoretic application of norepinephrine, epinephrine, the α-adrenoreceptor agonist clonidine and the β-agonist isoproterenol. These inhibitions were blocked by the α-adrenergic antagonist piperoxane but not by the β-antagonist sotalol. In addition these cells were strongly inhibited by dopamine or α-methylnorepinephrine, but only weakly inhibited by phenylephrine or the dopamine agonist apomorphine. The dopamine antagonist trifluoperazine was ineffective in blocking the inhibitions of LC neurons by both dopamine and norepinephrine. The rank order of potencies of agonist drugs in inhibiting LC neurons was clonidine > > α-methylnorepinephrine ? epinephrine = norepinephrine > > phenylephrine. In this respect the LC α-receptor is similar to ‘presynaptic’ or ‘α₂’ receptors or peripheral sympathetic nerves and differs from the classical postsynaptic α-receptor. The noradrenergic neurons of the LC thus appear to possess catecholamine receptors on or near their cell bodies which have pharmacological characteristics of ‘presynaptic’ α-adrenergic receptors. The LC receptors are distinct from central dopamine receptors and from norepinephrine receptors areas of the brain receiving their noradrenergic iput fom the LC.     

Behavioral effects of intracerebrally administered catecholamines in mice and their modifications by some adrenergic blocking agents

Increasing doses of epinephrine (E), norepinephrine (NE) and dopamine (DA) were administered intracerebrally to mice.These drugs cause, at low doses (1–10 g/mouse) purely excitatory symptoms, while at high doses (30–100 g/mouse) they induce a biphasic syndrome, consisting of an initial period of excitation, followed by depression. In animals pretreated with -adrenolytics (yohimbine and phentolamine) the excitation caused by the low doses of the catecholamines was unaffected, while the running fits and the depression elicited by the high doses were attenuated or abolished.     

Effects of carbamazepine on serum antidepressant concentrations in psychiatric patients.

The combination of carbamazepine and an antidepressant (doxepin, amitriptyline, mianserin) was given to 22 psychiatric inpatients with 29 measurements of their serum antidepressant concentrations. For comparison, sex-, age-, and dose-matched inpatients, treated with the antidepressant but not with carbamazepine, were selected as controls (N = 29). All the patients were treated with their routine daily dose for at least 7 days before the gas-chromatographic measurement of serum predose concentrations of the antidepressants. In patients with carbamazepine, serum doxepin and doxepin + nordoxepin concentrations (N = 17) were decreased significantly (p less than 0.05), on average to 46% and 45%, respectively, as compared to that in subjects without carbamazepine. Also in carbamazepine + amitriptyline patients, serum nortriptyline and amitriptyline + nortriptyline concentrations (N = 8) were significantly lower than in those not receiving carbamazepine (p less than 0.05). The mean serum antidepressant levels were decreased to 42% and 40%, respectively. The serum mianserin concentration of carbamazepine patients (N = 4) was reduced to 30% of that in patients not treated with carbamazepine (p less than 0.01). The percentage fractions of demethylated metabolites (nordoxepin, nortriptyline) from the total antidepressant levels were not influenced by carbamazepine. In patients treated with carbamazepine, serum total antidepressant concentrations remained more often below the suggested therapeutic ranges than in those patients without carbamazepine. The results suggest that serum antidepressant concentrations are reduced by concurrent carbamazepine therapy, and that the concentrations should be carefully monitored when carbamazepine is added to the antidepressant regimen.     

Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study

Curcumin is the active ingredient of commonly used spice Curuma longa Linn. In the present study, the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice): Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20 mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7 (curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p < 0.05). The effect of curcumin (100 mg/kg) was similar to that of fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to drugs having mixed effects on serotonin and catecholamines levels in the brain.