MHPG excretion in endogenous depression: Relationship to clinical state and the effects of ECT

In a group of 70 patients with endogenous depression entering a controlled trial of real versus sham ECT, urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion was significantly reduced by comparison with previously studied groups of control subjects, of acute and chronic schizophrenic patients and of anxious patients. However, urinary MHPG was unrelated to severity of depression, or to the presence of delusions, retardation or agitation. MHPG excretion did not predict clinical outcome, or the response to ECT. Urinary MHPG content at trial entry was unrelated to past tricyclic antidepressant or benzodiazepine medication, although an influence of the latter on the findings cannot be excluded, since all patients received benzodiazepine (nitrazepam) night sedation during the trial.During the 4-week trial MHPG excretion remained low and did not increase in relation to change in clinical state, although there was a small but significant increase in patients who received real ECT. The findings confirm that urinary MHPG excretion is reduced in depression, but establish that such reductions are not state dependent. Since the increase in MHPG excretion with ECT is not related to changes in clinical state, the former presumably does not reflect the mechanism of action of ECT.     

Pharmacokinetics of besulpamide in rats and dogs

The pharmacokinetics of besulpamide were studied in rats and its urinary excretion in rats and dogs. Kinetic characteristics were the same for both male and female rats according to a two-compartment open model. Biological half-life was 1-4 hr, absorption half-life was approximately 10 min and absolute bioavailability was nearly complete (F = 86.4%). In rats, urinary excretion of unchanged besulpamide was 30% after i.v. administration and 7% after oral administration, whereas in dogs after oral administration it was 54%. Values of the area under the plasma concentration-time curve in rats and percent of urinary excretion in dogs show that the kinetics of besulpamide are not dose-related when the drug is administered at doses of 10-50 mg/kg.     

The effect of dl-propranolol,d-propranolol and practolol on the hyperactivity induced in rats by prolonged isolation

Exploratory behaviour in an open field situation was found to be greatly increased in rats, isolated for 6–8 weeks, when compared with grouphoused controls. Propanolol, dl- and d- and practolol, 0.2–0.5 mg/kg reduced hypermotility, sniffing and rearing in isolated rats without affecting behaviour of group-housed rats. 20 mg/kg dl-propanolol was needed to reduce exploratory behaviour of group housed rats. Chlorpromazine reduced activity of isolated rats at a dose of 0.1 mg/kg, and group housed rats at 0.5–1 mg/kg. The action of propranolol does not appear to result from central receptor blockade because of the almost equal activity of d- and dl-propranolol. Since practolol was also active in this test, the effect of these drugs also does not appear to result from general C.N.S. depression. It is suggested that these compounds may reduce hyperactivity by diminishing an excessive release of central catecholamines.This work forms part of a Ph.D. Thesis by Z. Speiser to be submitted to Tel-Aviv University.     

Blockade of dopamine D₃ but not D₂ receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment

Dopamine D? receptors are densely expressed in mesolimbic projection areas, and selective antagonists enhance cognition, consistent with their potential therapeutic use in the treatment of schizophrenia. This study examines the effect of dopamine D? vs. D? receptor antagonists on the cognitive impairment and hyperactivity produced by social isolation of rat pups, in a neurodevelopmental model of certain deficits of schizophrenia. Three separate groups of male Lister hooded rats were group-housed or isolation-reared from weaning. Six weeks later rats received either vehicle or the dopamine D? selective antagonist, S33084 (0.04 and 0.16 mg/kg), the preferential D? antagonist, S33138 (0.16 and 0.63 mg/kg) or the preferential D? antagonist, L-741,626 (0.63 mg/kg) s.c. 30 min prior to recording; horizontal locomotor activity in a novel arena for 60 min and, the following day, novel object discrimination using a 2-h inter-trial interval. Isolation rearing induced locomotor hyperactivity in a novel arena and impaired novel object discrimination compared to that in group-housed littermates. Both S33084 and S33138 restored novel object discrimination deficits in isolation-reared rats without affecting discrimination in group-housed controls. By contrast, L-741,626 impaired novel object discrimination in group-housed rats, without affecting impairment in isolates. S33084 (0.16 mg/kg), S33138 and, less markedly, L741,626 reduced the locomotor hyperactivity in isolates without attenuating activity in group-housed controls. Selective blockade of dopamine D? receptors reverses the visual recognition memory deficit and hyperactivity produced by isolation rearing. These data support further investigation of the potential use of dopamine D? receptor antagonists to treat schizophrenia.     

Effects of debrisoquin on the excretion of catecholamine and octopamine metabolites in the rat and guinea pig

The effects of debrisoquin, administered daily for 4 days to rats (40 mg/kg, i.p.) and guinea pigs (4 mg/kg, i.p.), were determined for urinary excretion of several acidic and neutral amine metabolites, including the norepinephrine metabolites, 3-methoxy-4-hydroxyphenethylene glycol (MHPG) and vanillylmandelic acid (VMA), the dopamine metabolites, 3,4-dihydroxyphenethanol (DHPE), 3-methoxy-4-hydroxyphenethanol (MHPE), and homovanillic acid (HVA), and the octopamine metabolite, p-hydroxyphenylglycol (pHPG). The excretion of MHPG was reduced to 32% of control in rats and to 46% in guinea pigs, HVA was reduced to 64 and 80% in these two species, respectively, and MHPE was lowered to 59% of control in the rat but was not affected in the guinea pig. DHPE and pHPG were not altered significantly in either species. VMA was a minor metabolite in both species, being less than 6% of MHPG, and its formation was blocked only partially (rat) or not at all (guinea pig) by debrisoquin. The data refute the idea based on previous in vitro studies that VMA is a major metabolite of norepinephrine in the periphery of the guinea pig as it is in man.     

Excretion of 14C-labeled cyanide in rats exposed to chronic intake of potassium cyanide

The excretion of an acute dose of 14C-labeled cyanide in urine, feces, and expired air was studied in rats exposed to daily intake of unlabeled KCN in the diet for 6 weeks. Urinary excretion was the main route of elimination of cyanide carbon in these rats, accounting for 83% of the total excreted radioactivity in 12 hr and 89% of the total excreted radioactivity in 24 hr. The major excretion metabolite of cyanide in urine was thiocyanate, and this metabolite accounted for 71 and 79% of the total urinary activity in 12 hr and 24 hr, respectively. The mean total activity excreted in expired air after 12 hr was only 4%, and this value did not change after 24 hr. Of the total activity in expired air in 24 hr, 90% was present as carbon dioxide and 9% as cyanide. When these results were compared with those observed for control rats, it was clear that the mode of elimination of cyanide carbon in both urine and breath was not altered by the chronic intake of cyanide.     

Antihypertensive effect of non-diuretic doses of cicletanine on a stress-induced model in the rat

Cicletanine was tested at different doses (7.5, 10 and 30 mg/kg, p.o.) on young rats showing high blood pressure readings after social deprivation for 7 consecutive days. At all dose levels, the compound produced a statistically significant decrease in systolic blood pressure of isolated but not group-housed rats. In contrast, the drug did not affect the heart rate in any of the cases. Interestingly, cicletanine was only found to enhance urinary excretion at the highest dose assayed. The putative mechanism of the antihypertensive action of the drug at non-diuretic doses is discussed.     

Do urinary MHPG and plasma drug levels correlate with response to amitriptyline therapy?

Twenty-nine inpatients with primary affective disorder were treated with 150 mg amitriptyline (AT) daily for 28 days. Pretreatment urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured in two or three 24-h urine samples. Plasma levels of AT and nortriptyline (NT) were determined after 14, 21, and 28 days of treatment. MHPG excretion was significantly correlated with clinical response to treatment. Responders defined by two different methods showed higher pretreatment MHPG excretion than nonresponders. Correspondingly, high MHPG excretors (median split) showed significantly more improvement than low excretors. These relationships were even more apparent when possibly incomplete urine samples (creatinine excretion below 1000 mg/24 h) were excluded. The high and low MHPG subgroups did not significantly differ from each other in their plasma levels of AT, NT, or AT plus NT. A significant rank correlation between clinical response and plasma levels of AT and/or NT did not exist, but there was a trend towards lower levels in responders.Dedicated to Prof. Heimann on the occassion of his 60th birthday     

Effects of intraventricular injections of 6-hydroxydopamine on amine metabolites in rat brain and urine

The effects in rats of intraventricular injections of 6-hydroxydopamine (6-OHDA) on the urinary excretion 1-3 weeks later of 3-methoxy-4-hydroxyphenethylene glycol (MHPG), 3,4-dihydroxyphenethanol (DHPE), 3-methoxy-4-hydroxyphenethanol (MHPE), p-hydroxyphenylglycol (pHPG), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined. The excretion of MHPG was decreased to 63 and 71% of control on days 7 and 14, respectively, but had returned to control levels by day 23, even though the brain levels were decreased by 87%. Free and total HVA excretion was reduced on both days 7 and 23, but free and total DOPAC was reduced only on day 7. Based on these data, it can be estimated that about 39% of the free and 46% of the total HVA in urine originates in the CNS. The excretion of conjugated HVA was decreased by 70-80%, but this decrease does not support the notion that the conjugated form of HVA is derived principally from the brain and thus serves as a better marker of brain dopamine metabolism, since the level of this metabolite in the brain was not correspondingly decreased but was instead increased. Urinary DOPAC levels were generally more variable and derived to a greater extent from the periphery; therefore, DOPAC appears to be less suitable than HVA as a marker of brain dopamine. The results also indicate that as much as 35% of the urinary MHPG may originate in the CNS, although compensatory changes in catecholamine metabolism in either the brain or in the periphery may have somewhat influenced this estimate. The results also suggest that at least as much pHPG as MHPG in urine derives from the CNS. The data are consistent with the idea that the neutral dopamine metabolites largely derive from the brain, but the relatively small depletion in their brain levels produced by 6-OHDA prevented the exact proportion being determined accurately.     

Influence of adrenergic blockers and antilipemic agents on pharmacodynamic actions of morphine in carbon tetrachloride-treated rats

The analgesic activity of morphine was markedly prolonged in rats by 24 hr pretreatment with carbon tetrachloride. The urinary excretion of morphine was drastically reduced in these rats indicating impairment in morphine metabolism. However, pretreatment with alpha and beta adrenergic blockers or 20-hr post treatment with antilipemic agents greatly diminished the CCl₄ induced prolongation of analgesic activity. These agents also increased the urinary morphine excretion that was reduced by CCl₄ treatment. All the adrenergic blockers except propranolol and both antilipemic agents caused a significant reduction in the lipid content of the liver. Since the liver fat plays a significant role in hemodynamic resistance induced by CCl₄ treatment, the protection afforded by adrenergic blockers and antilipemic agents to the drug metabolizing enzyme system could be related to their lipid-lowering activity.     

The formation and release of metaraminol during exposure to warm or cold environments

1. Rats were injected intraperitoneally with alpha-methyl-m-tyrosine (400 mg/kg) and placed at either 27 degrees C or 4 degrees C. The levels of alpha-methyl-m-tyramine, metaraminol and noradrenaline were determined in heart tissue after 1, 4 and 12 hr of treatment. The excretion of metaraminol, alpha-methyl-m-tyramine, noradrenaline, adrenaline and 3-methoxy-4-hydroxyphenylglycol (MHPG) was also estimated in both treated and control rats.2. Cold exposure increased both the formation and excretion of metaraminol. Hearts removed from the cold-stressed rats 4 hr after injection contained significantly more metaraminol than hearts taken from animals maintained in the warm environment. Twelve hours after treatment, no metaraminol remained in the hearts of cold-exposed rats, whereas significant quantities of the amine still remained in the hearts of rats kept at 27 degrees C. These results support the false transmitter concept advanced for metaraminol as they demonstrate that in vivo sympathetic stimulation can increase both the formation and release of metaraminol.3. Alpha-methyl-m-tyrosine produced a greater fall in cardiac noradrenaline in the rats kept at 27 degrees C. Whereas an approximate mole-for-mole replacement of metaraminol for noradrenaline existed at 27 degrees C, no such relationships existed at 4 degrees C. Twelve hours after treatment the hearts of cold-stressed rats contained no metaraminol and only 40% of control noradrenaline levels. These results do not support the necessity for a mole-for-mole replacement of noradrenaline with metaraminol to produce a catecholamine loss.4. Alpha-methyl-m-tyrosine depressed the noradrenaline excretion for at least 24 hr in the cold-stressed rats. Excretion of 3-methoxy-4-hydroxyphenylglycol was also lower in the treated rats between 0 and 12 hr in the cold but rose abruptly between 12 and 24 hr to exceed the quantity excreted by the control animals. This increase suggests an increase in noradrenaline synthesis, which may be related to the depletion of metaraminol from the body.5. The results of this paper support the postulate that metaraminol may function as a false transmitter. They do not agree with the concept that the loss of noradrenaline from tissue sites is dependent upon a mole-for-mole replacement with metaraminol.     

Effects of voluntary ethanol consumption on emotional state and stress responsiveness in socially isolated rats

Social isolation of rats immediately after weaning is thought to represent an animal model of anxiety-like disorders. This mildly stressful condition reduces the cerebrocortical and plasma concentrations of 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) as well as increases the sensitivity of rats to the effects of acute ethanol administration on the concentrations of this neuroactive steroid. We further investigated the effects of voluntary consumption of ethanol at concentrations increasing from 2.5 to 10% over 4 weeks of isolation. Isolated rats showed a reduced ethanol preference compared with group-housed animals. Ethanol consumption did not affect the isolation-induced down-regulation of BDNF or Arc, but it attenuated the increase in the cerebrocortical concentration of 3α,5α-TH PROG induced by foot-shock stress in both isolated and group-housed animals as well as increased the percentage of number of entries made by socially isolated rats into the open arms in the elevated plus-maze test. Ethanol consumption did not affect expression of the α₄ subunit of the GABA_A receptor in the hippocampus of group-housed or isolated rats, whereas it up-regulated the δ subunit throughout the hippocampus under both conditions. The results suggest that low consumption of ethanol may ameliorate some negative effects of social isolation on stress sensitivity and behavior.     

The relationship between hepatic microsomal biphenyl 2-hydroxylase, 4-hydroxylase and urinary glucaric acid excretion in the rat

Treatment of rats with phenobarbital (PB) caused an increase in microsomal biphenyl 4-hydroxylase activity and urinary glucaric acid excretion. Hepatic microsomal biphenyl 4-hydroxylase activity was correlative with urinary glucaric excretion in PB-treated rats. Hepatic microsomal biphenyl 2-hydroxylase activity was not correlated with urinary glucaric excretion in PB, 3-methylcholanthrene (3-MC)- and beta-naphthoflavone (beta-NF)-treated rats. Pretreatment of rats with carbon tetrachloride caused decreases in urinary glucaric acid excretion and biphenyl 2- and 4-hydroxylase activities. On the other hand, pretreatment with cobalt chloride caused decreases of these enzyme activities, but not of urinary glucaric acid excretion. These findings suggest that the urinary glucaric acid level would not always provide an index for assessment of hepatic drug metabolizing enzyme activity. These findings suggest that the urinary glucaric acid level would not always provide an index for assessment of hepatic drug metabolizing enzyme activity.     

Effects of noradrenaline depletion in the brain on response to novelty in isolation-reared rats

RATIONALE: Social isolation from weaning in the rat produces a variety of neurochemical and behavioural effects in the adult that in part parallel changes seen in human schizophrenia. OBJECTIVES: The study investigated the effects of central noradrenaline (NA) depletion by the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), on the behaviour of isolation-reared rats. METHODS: Male Lister hooded rats were reared singly or in groups after weaning. During week 2, the rats were tested in photocell activity cages and were then injected with DSP-4 (25 mg/kg, IP). During week 4, rats were tested in the open field under the following conditions: open field alone, with two novel stimuli (T1), and with a familiar and a novel object (T2), and in the activity cages. RESULTS: DSP-4 significantly reduced cortical and hippocampal NA levels with no effect on the hypothalamus. Isolation-reared rats exhibited locomotor hyperactivity and reduced habituation to the testing arena, although their exploration of the novel objects in T1 was not significantly different from group-reared rats. DSP-4 treatment in group-reared rats increased inner zone activity in the open field but did not significantly affect the exploration of novel objects. DSP-4 treatment in isolates reduced exploration of objects at T2 while increasing exploration of the general environment. CONCLUSIONS: Isolation rearing influences the behavioural effects of central NA depletion. The results suggest isolation-induced changes in the central noradrenergic system in the isolated rat, supporting the view that early environmental factors can have long-term effects on central noradrenergic function as well as other neurotransmitter systems.     

Free and conjugated 3-methoxy-4-hydroxyphenylglycol in human urine: Peripheral origin of glucuronide

The aim of our study was to investigate the endogenous origin of the three forms of 3-methoxy-4-hydroxyphenylglycol (MHPG) present in human urine and to further examine the hypothesis of an independent (peripheral or central) origin of glucuronide and sulfate conjugates. The urinary levels of free, sulfate, and glucuronide MHPG were determined in control subjects under normal conditions in relation to age, sex, and diet and in two experimental situations known to alter sympathetic activity. The mean daily excretion of total MHPG in a group of 14 men and 14 women was 1780 +/- 122 micrograms, with the free, sulfate, and the glucuronide representing 8% +/- 0.5%, 40% +/- 1.5%, and 52% +/- 1.6%, respectively. No influence of sex, age, or diet was observed on any form. Strong physical activity and anticipatory stress increased norepinephrine excretion and selectively increased MHPG glucuronide levels without changing the free or the sulfate excretion. We conclude that the total amounts of free, sulfate, and glucuronide MHPG found in urine originate from endogenous body pools with no interference of dietary components. The sympathetic nervous system seems to be the main source of glucuronide and arguments are given supporting the central origin of sulfate.     

Role of ethanol metabolism in the alcohol-induced increase in urinary folate excretion in rats

Chronic ethanol use can lead to folic acid deficiency in humans. In rats, acute doses of ethanol produce a marked increase in the urinary excretion of folate which is followed by a decrease in plasma folate levels. To assess the respective roles of ethanol and its metabolism in these effects, five groups of male Sprague-Dawley rats were treated orally as follows: (1) ethanol in four doses of 1 g/kg each at 0, 1, 2 and 3 hr; (2) ethanol as above plus the alcohol dehydrogenase inhibitor 4-methylpyrazole (4-MP) at 50 mg/kg, i.p., 15 min prior to 0 hr; (3) glucose in four isocaloric doses; (4) glucose plus 4-MP as above; and (5) methanol in four doses of 1 g/kg. Total folate levels in the urine peaked in both ethanol- and methanol-treated rats at the same time as the urine alcohol levels (after 6-8 hr) and then declined over the same time course as the alcohol levels. Concurrent administration of 4-MP inhibited the metabolism of ethanol and maintained the increase in urinary folate excretion throughout 24 hr. Ethanol administration produced minor changes in the relative distribution of folate derivatives in the urine, and these changes were not prevented by 4-MP treatment. The urinary levels of formic acid, which is metabolized by folate-dependent processes, were increased by ethanol administration; this increase was prevented by 4-MP. These results suggest that ethanol is not unique among alcohols in increasing urinary folate excretion and that ethanol metabolism plays no role in the increased urinary folate excretion. However, ethanol metabolism contributes to a second effect of ethanol on the folate system, which leads to increased urinary levels of formic acid.     

Effect of probenecid on free 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and its sulphate in human cerebrospinal fluid

In a mixed group of 46 patients with affective disorder, or with various neurologic disorders, high doses of probenecid (100 mg/kg over 18 hr) produced a significant increase in lumbar cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the major metabolite of norepinephrine centrally. This increase (averaging 60%) is modest in comparison to probenecid induced increases in homovanillic acid (HVA) or 5-hydroxyindo-leacetic acid (5-HIAA). Analysis for free MHPG and its sulfate showed no significant differences for either compound after nine hours. After 18 hours of treatment significant increases in free MHPG and small but not significant increases of MHPG.SO₄ were found. These results suggest that a probenecid sensitive active transport mechanism for MHPG.SO₄ of the degree demon-strated for HVA and 5-HIAA in humans, and for MHPG.SO₄ in rats, does not occur in human CSF.     

Acute and chronic idazoxan in normal volunteers: biochemical, physiological and psychological effects

The acute and chronic effects of the selective a(2)-antagonist idazoxan were studied in 12 normal volunteers. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), blood pressure and psychological responses to oral challenge doses of idazoxan 40 mg were measured twice, on the first and 22nd day of treatment with idazoxan 40 mg t.d.s. Changes in nocturnal melatonin output were studied on six occasions, before, during and after idazoxan treatment. Although baseline MHPG levels were significantly reduced after chronic treatment with idazoxan, idazoxan challenge did not alter MHPG concentrations on either test day. A small rise in systolic blood pressure occurred after acute but not chronic idazoxan challenge tests. Systolic blood pressure values were significantly lower during the chronic compared with the acute test. Diastolic blood pressure and heart rate were not affected by acute or chronic treatment. Subjects reported increases in self- ratings of arousal and reductions in sedation and anxiety of similar magnitude after acute and chronic idazoxan. Nocturnal plasma melatonin secretion was not altered by drug administration or withdrawal, although urinary 6-sulphatoxymelatonin excretion was significantly reduced on acute withdrawal. The increase in systolic blood pressure and arousal self-ratings after acute idazoxan are in accordance with the reported effects of other a(2)-antagonists, although we did not find increased anxiety or elevated plasma MHPG levels. Chronic idazoxan appears to reduce or normalize activity of noradrenergic systems, indicated by reduced baseline systolic blood pressure and MHPG, and loss of the pressor response to idazoxan. Withdrawal of idazoxan leads to an abrupt fall in noradrenergic activity, as demonstrated by the fall in urinary 6-sulphatoxymelatonin.     

Brain catecholamine metabolites and behavior in morphine withdrawal

Morphine withdrawal behavior, brain and plasma catecholamine metabolites, and brain beta-noradrenergic receptor binding were examined after acute treatment with naloxone in rats treated with morphine pellets or a sham pelleting procedure. Increases in brain 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), a norepinephrine metabolite, occurred in parallel with rated withdrawal behavior. Withdrawal behavior correlated significantly with brain, and, more modestly, with plasma levels of MHPG but did not correlate with beta-receptor binding or HVA. The effectiveness of debrisoquin sulfate was variable, but the reductions in withdrawal signs and cerebral cortex MHPG were strongly correlated. These data support a direct relationship between presynaptic noradrenergic hyperactivity and opiate withdrawal behavior.     

Effects of chronic metaraminol treatment on the sympathetic activity of intact and adrenal demedullated rats kept in warm or cold environments

1. Rats were placed at 27 degrees C or 4 degrees C and given metaraminol ((10 mg/kg)/day) in their drinking water for 8 weeks. One experiment was run using adrenal demedullated rats. These animals were treated with metaraminol, as mentioned above, and kept at 4 degrees C for 4 weeks.2. Body temperature and metabolic rate were determined at selected intervals. Urine was collected on day 7 of each week and analysed for adrenaline, noradrenaline, metanephrine, normetanephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG). At the end of each study the rats were killed and the tissues removed and analysed for metaraminol, adrenaline and noradrenaline.3. All animals survived the metaraminol treatment and no change in metabolic rate or body temperature was seen. Metaraminol depressed the growth rate of the rats.4. Metaraminol caused a fall in tissue noradrenaline concentrations, with only negligible quantities being found in brain, heart, lung, liver, kidney and spleen. Only the adrenals contained significant quantities of catecholamines. All tissues contained large amounts of metaraminol.5. Despite the almost complete depletion of noradrenaline from sympathetic nerves, metaraminol did not depress the excretion of noradrenaline, normetanephrine and MHPG, in fact excretion of the latter two substances was higher in the treated animals. The failure of the drug to impair the normal cold-induced increase in noradrenaline secretion explains the survival of the rats at 4 degrees C.6. Adrenal demedullation did not prevent the metaraminol-treated rats from excreting large quantities of noradrenaline, normetanephrine and MHPG in the cold. It is apparent, therefore, that in the intact rats the noradrenaline emanated from the practically depleted nerves. The increase in MHPG excretion, seen during metaraminol treatment, suggests an increased rate of noradrenaline turnover.7. In conclusion, although metaraminol uptake is accompanied by a fall in tissue noradrenaline concentrations, the presence of metaraminol does not depress noradrenaline release. These results do not support the concept that metaraminol can replace noradrenaline and function as a false transmitter.