MHPG Concentrations Research Articles

Differential responses to mental stress in high and low anxious normal humans assessed by frontal midline theta activity

The distinct EEG theta rhythm from the frontal midline area observed during performance of mental tasks has been called Fmθ. In the present study, plasma catecholamine responses to mental stress were investigated using male students with ( n = 12) and without ( n = 12) Fmθ. The subjects were requested to complete the trait anxiety scale of STAI, and control blood samples were obtained. 65 min later, their EEGs were recorded during performance of an arithmetic addition task for 5 min. The state anxiety scores of STAI were obtained twice before and after the EEG recording. Blood samples were drawn three times during the state anxiety test and the EEG recording. The Fmθ appearance group showed low trait anxiety and a decrease of state anxiety after the mental task; however, the Fmθ non-appearance group exhibited high trait anxiety and no changes of state anxiety before and after the mental task. The concentrations of DA, HVA, NA and MHPG in the Fmθ appearance group showed lower levels at all times compared to those in the non-appearance group. In the Fmθ appearance group, an increase of DA turnover was observed by the addition of mental task. On the other hand, the Fmθ non-appearance group showed an increase of NA turnover.

Treatment of drug-resistant chronic schizophrenics with an association of neuroleptics and the calcium antagonist nimodipine

SummaryNimodipine was administered at the daily dose of 90 mg po, for 30 days, to ten chronic undifferentiated schizophrenics, eight men and two women, aged 31-35 years, maintained on previously longlasting neuroleptic treatments. In five patients, a placebo period of 15 days preceded the administration of the drug. Monitoring of psychiatric symptomatology by the Brief Psychiatric Rating Scale (BPRS) revealed significant nimodipine-induced improvement. However, the Andreasen Rating Scale for Positive Symptoms (SAPS) showed favourable effects only in the five patients who had not received placebo, while in the others both SAPS and the Andreasen Rating Scale for Negative Symptoms (SANS) showed no significant effect of therapy. The Tardive Dyskinesia Scale revealed no improvements of neurological symptoms after either placebo or drug treatment. Measurement of plasma MHPG concentrations revealed no significant changes induced by either placebo or nimodipine, while HVA plasma levels showed a trend toward decrease, and prolactin a trend toward increase, after nimodipine.

Treatment of Tension‐type Headache With Tizanidine Hydrochloride: Its Efficacy and Relationship to the Plasma MHPG Concentration

Seventy-eight patients with tension-type headache (TH) were treated with tizanidine hydrochloride (tizanidine). Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and serum free fatty acids (FFA) levels in these patients were determined before the treatment with tizanidine. Eighteen healthy volunteers composed the control group. Four weeks after the treatment with tizanidine 24 (31%) of 78 patients showed excellent improvement (excellent group); 28 (35%) showed moderate improvement (moderate group); 18 (23%) showed mild improvement (mild group); 7 (10%) showed no improvement and one (1%) showed worsening of her headache (no change and worsened group). The plasma MHPG levels in the excellent group were significantly higher than in the other groups, including the control group. The serum FFA levels in the excellent group were significantly higher than in the controls. In this study, 66% of the patients reported improvement in their headaches. Some patients with TH had high plasma MHPG levels and these patients in particular showed excellent improvement after the administration of tizanidine. Though there may be a placebo response to some extent, the clinical usefulness of tizanidine for TH seems to be excellent. Further study is necessary concerning the pharmacological effect of tizanidine and plasma MHPG levels in patients with TH.

3-Methoxy-4-hydroxyphenylethyleneglycol concentrations in discrete hypothalamic nuclei reflect the activity of noradrenergic neurons

An analytical technique is described which permits the quantitation of picogram concentration of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in acid hydrolyzed extracts of microdissected regions of the rat brain, and this procedure is used to determine if alterations in the activity of noradrenergic neurons are reflected by changes in the concentrations of MHPG in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the rat hypothalamus. MHPG was not detected in non-hydrolyzed samples of either the PVN or SON, but following acid hydrolysis (heating of samples at 94°C for 5 min in 0.16 M perchloric acid) MHPG was detected in both of these regions. These results indicate that MHPG exists primarily as a conjugate in the PVN and SON. Neurotoxin-induced lesions of the ventral noradrenergic bundle decreased norepinephrine (NE) and MHPG concentrations in the PVN and SON, demonstrating that tissue levels of MHPG in these brain regions are dependent upon the presence of noradrenergic neurons. Electrical stimulation of the locus coeruleus increased MHPG concentrations in the PVN, but not in the SON, whereas electrical stimulation of the medial forebrain bundle increased MHPG concentrations in both of these regions. The α 2-adrenergic receptor antagonist idazoxan incrased, while the α 2-adrenergic receptor agonist clonidine decreased MHPG concentrations in both the PVN and SON, but neither idazoxan nor clonidine altered NE concentrations in these regions. Immobilization of rats in the supine position increased MHPG concentrations in the PVN and SON, and this was accompanied by a decrease in NE concentrations in the SON. The results of the present study reveal that experimental procedures that increase or decrease the activity of noradrenergic neurons terminating in the PVN and SON produce corresponding changes in the concentrations of MHPG in these nuclei, and suggest that MHPG concentrations (and the ratio of MHPG to NE) can be used as indices of the activity of noradrenergic neurons terminating in these hypothalamic regions.

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.

Treatment of Tension-Type Headache with Ttzanidine Hydrocloride; Relationship Between Plasma Mhpg Concentration and Clinical Effects

Treatment of Tension-Type Headache with Ttzanidine Hydrocloride; Relationship Between Plasma Mhpg Concentration and Clinical Effects

CSF monoamine metabolite concentrations vary according to age, rearing, and sex, and are influenced by the stressor of social separation in rhesus monkeys

In humans, CSF monoamine metabolite concentrations have been shown to vary as a complex function of age, sex, psychiatric diagnosis, and stress. To test for such relationships in rhesus monkeys, 28 subjects, reared either in anxiety producing peer-only groups or in mother-infant dyads, were studied at 6, 18 or 50 months of age. Each monkey underwent a series of four 4-day social separations, each followed by 3 days of reunion. Prior to and during the first and fourth separations, CSF was obtained from the cisterna magna and assayed for the serotonin metabolite 5-HIAA, the dopamine metabolite HVA, and the norepinephrine metabolite MHPG. CSF 5-HIAA showed an age-related decline which was greater in the mother-reared subjects. Peer-only-reared males had an increased 5-HIAA concentration relative to females, and higher 5-HIAA levels than mother-reared males. MHPG was also higher in peer-only-reared monkeys than in mother-reared subjects at all ages. In both groups HVA declined across the three ages, and MHPG increased from the 18- to the 50-month measurements. Both MHPG and 5-HIAA concentrations increased during the initial social separation, although only MHPG remained elevated across the repeated separations; HVA, on the other hand declined during social separation. These results are discussed in terms of established anxiety and aggression differences between peer-only and mother-reared monkeys.

Plasma 3, 4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4- hydroxyphenylglycol (MHPG) are insensitive indicators of α2-adrenoceptor mediated regulation of norepinephrine release in healthy human volunteers

The usefulness of the plasma concentrations of two major metabolites of norepinephrine (NE), 3, 4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG), as indicators of neuronal NE release was investigated. The potent α 2-adrenoceptor agonist, dexmedetomidine, induced only about 15% maximal reductions in the metabolite concentrations, in spite of almost total inhibition of neuronal NE release, as evidenced by 90% reductions in plasma NE concentrations. Similarly, administration of the α 2-adrenoceptor antagonist atipamezole was followed by only small increases in plasma DHPG and no change in MHPG levels, in spite of almost six-fold, albeit short- lasting, increases in plasma NE. In contrast, a single dose of the reversible monoamine oxidase type A (MAO-A) inhibitor moclobemide reduced plasma DHPG levels by 78% and MHPG levels by 51%. It is concluded that the plasma concentrations of DHPG and MHPG are largely determined by intraneuronal, MAO-A-dependent metabolism of NE, and do not accurately reflect acute alterations in neuronal NE release. The concentration of NE in venous plasma is clearly a more sensitive indicator of α 2-adrenoceptor- mediated regulation of NE release.

Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin

In order to evaluate serotonin (5-HT) function in panic disorder, a double blind placebo controlled study was conducted with ritanserin, a specific 5-HT2 receptor antagonist, and fluvoxamine, a selective 5-HT reuptake inhibitor, in 60 patients with panic disorder. Patients were treated for 8 weeks with 150 mg fluvoxamine, 20 mg ritanserin or placebo; these dose levels were reached after 1 week. In addition, as an index of 5-HT function in panic disorder, plasma concentration of beta-endorphin, cortisol and 5-hydroxyindolacetic-acid (5-HIAA) were measured. Furthermore, 5-HT uptake in blood platelets was assessed. Noradrenergic function was assessed by measuring plasma MHPG concentration. In addition, plasma melatonin concentration was measured. Treatment with fluvoxamine resulted in a profound reduction in the number of panic attacks, followed by a decrease in avoidance behavior. Treatment with ritanserin appeared to be ineffective. During treatment no significant changes were observed in plasma concentrations of beta-endorphin, cortisol, 5-HIAA and MHPG. With respect to 5-HT kinetics in blood platelets, a substantial increase in Km was observed after treatment with fluvoxamine, whereas Vmax decreased. After treatment with fluvoxamine, plasma concentration of melatonin was significantly increased, which suggests that melatonin synthesis is in part under serotonergic control. The findings of the present study do not support the hypothesis that 5-HT2 receptors are supersensitive in patients suffering from panic disorder, but allow no conclusions about the involvement of other 5-HT receptor subtypes.

A cerebrospinal fluid study of the pathophysiology of panic disorder associated with alcoholism

In order to investigate the neurochemistry of panic disorder in alcoholics, we measured various cerebrospinal fluid (CSF) parameters in subjects with both conditions and compared them with an age- and sex-matched population of alcoholics and normal controls. When height, age and weight were covaried, subjects with panic disorder had higher levels of B-endorphin in CSF. There were no differences in other CSF measures between the groups. Alcoholics with panic disorder had higher plasma MHPG concentrations compared with alcoholics without panic disorder but these were not statistically different from controls.

Correlations between cisternal CSF and plasma concentrations of HVA, MHPG, 5-HIAA, DA, and NA

In the present work we compared the levels of HVA, MHPG, 5-HIAA, DA, and NA in cisternal CSF (cCSF) with their plasma concentrations. Our question was whether or not the levels of these substances are in good accordance with the levels in cisternal CSF

Long-term effects of early social isolation in Macaca mulatta: changes in dopamine receptor function following apomorphine challenge

The hypothesis that early social isolation results in long-term alterations in dopamine receptor sensitivity was tested using older adult rhesus monkeys. Isolated and control monkeys were challenged with apomorphine (0.1 and 0.3 mg/kg), and the drug effects on spontaneous blink rate, stereotyped behavior, and self-injurious behavior were quantified using observational measures. Monoamine metabolites were quantified from cisternal CSF by HPLC-EC, prior to pharmacological challenge. Isolated and control monkeys did not differ in CSF concentrations of HVA, 5-HIAA, or MHPG. At the higher dose, apomorphine significantly increased the rate of blinking, the occurrence of whole-body stereotypies, and the intensity of stereotyped behavior (as measured by observer ratings) in isolated monkeys. The frequency of occurrence of self-injurious behavior was too low to allow for meaningful comparisons. These significant differences in response to apomorphine challenge support the hypothesis that long-term or permanent alterations in dopamine receptor sensitivity, as assessed by drug challenge, are a consequence of early social deprivation.

Neuroendocrine and Monoaminergic Responses to Acute Administration of Alprazolam in Normal Subjects

The effect of a single dose (3 mg) of alprazolam on plasma cortisol, growth hormone (GH), prolactin, norepinephrine (NE) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was studied in 10 healthy males. Alprazolam and placebo were administered orally in a crossover design and blood was sampled for 24 h. In comparison to placebo, alprazolam significantly reduced plasma cortisol levels and raised plasma GH levels. Prolactin levels were elevated by 100% from 2 to 8 h after alprazolam administration. The robust increase in prolactin levels is less consistent with previously reported data on traditional benzodiazepines. Plasma NE levels following alprazolam were lower than following placebo administration only at one time point, and MHPG concentrations were not affected. The lack of change in NE and MHPG levels suggests that the acute effect of alprazolam in normal subjects is not mediated via the central noradrenergic system.

Effects of insulin on hypothalamic monoamine metabolism

The concentration of monoamines and/or their metabolites has been measured using in vivo microdialysis in the ventromedial and lateral hypothalamus following the parenteral administration of insulin. Similar measurements were made in rats with lateral hypothalamic microdialysis cannulas in which insulin was given but food intake delayed for 6 h. Serum norepinephrine and epinephrine both increased following injection of insulin, and food intake rose after a delay of 30–60 min. Norepinephrine rose in both the ventromedial and lateral hypothalamus with peaks at 60–90 min. 3-Methoxy-4-hydroxy-phenylglygol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) increased in the dialysis from the lateral but not the ventromedial hypothalamus. Serotonin was unchanged following the injection of insulin, but its metabolite, 5-hydroxy-3-indole acetic acid (5-HIAA), fell gradually in both areas. In animals which had recovered from the hypoglycemia during the 6 h after insulin injection, but had not been allowed to eat, the concentration of norepinephrine, serotonin, MHPG and 5-HIAA were all increased in the lateral hypothalamus. DOPAC, however, showed no elevation. With the beginning of food ingestion, all monoamines and their metabolites fell to or toward normal within 30–60 mins. These data are consistent with the hypothesis that glucoprivation may involve increased turnover of norepinephrine and serotonin. Changes in DOPAC, however, appear to be related to the ‘stress’ components rather than the food intake.

Semistarvation-induced hyperactivity compensates for decreased norepinephrine and dopamine turnover in the mediobasal hypothalamus of the rat

Male Wistar rats were housed in running wheel cages and were restricted in their food intake, in order to reduce the initial body weight by 30% within 10 days. Rats increased their daily running up to distances between 7 and 11 km compared to the maximum 2.5 km in controls fed ad libitum. The hypothalamic noradrenaline (NE) turnover, as estimated by the concentration of the major metabolite MHPG, was significantly decreased in semistarved sedentary rats compared to controls. Hyperactivity resulted in marked elevation of NE turnover at all time points examined. Semistarvation-induced decreases of dopamine (DA) turnover as estimated by the concentrations of its major metabolite DOPAC, could also be compensated by hyperactivity. The circadian pattern of NE turnover parallels the pattern of running activity. MHPG levels at times of high activity were even higher than in controls fed ad libitum (p less than 0.01). The availability of the precursor tyrosine, as indicated by the ratio of plasma tyrosine to the large neutral amino acids, was significantly decreased in semistarvation (p less than 0.0001); hyperactivity caused a further decrease (p less than 0.001), indicating that tyrosine availability is not, under these conditions, a limiting factor for noradrenaline turnover. The combined influence of semistarvation and hyperactivity on central catecholamine turnover in the rat is discussed as an animal model for the effects of malnutrition and heavy exercise often observed in anorexia nervosa.

Postmortem changes in the levels of monoamine metabolites in human cerebrospinal fluid

Four monoamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA), were determined in the cerebrospinal fluid (CSF) of cadavers, whose causes of death had been suicidal hanging (SH) or ischemic heart failure (IHF). The concentration of DOPAC increased in parallel with the increment of the postmortem interval (PMI) ( r = 0.626), whereas the concentrations of HVA, MHPG and 5-HIAA did not. The correlation coefficient was further increased by considering each cause of death separately: i.e., SH, r = 0.761; IHF, r = 0.705. These findings suggest the possible usefulness of the DOPAC level in CSF for estimating PMI.

Relationship between plasma and cerebrospinal fluid norepinephrine and dopamine metabolites in a nonhuman primate.

Major and minor pathways of metabolism in the mammalian CNS result in the formation of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NMN) from norepinephrine (NE), and homovanillic acid (HVA) and 3-methoxytyramine (3-MT) from dopamine (DA), respectively. The correlational relationships between HVA and 3-MT and between MHPG and NMN in primate CSF and plasma have not been described. These relationships may help to elucidate the usefulness of CSF and plasma metabolites as indices of CNS NE and DA activity. In addition, because NMN is unlikely to cross the blood-brain barrier. CSF NMN concentrations would not be confounded by contributions from plasma, which is a major issue with CSF MHPG. We have obtained repeated samples of plasma and CSF from drug-naive male squirrel monkeys and have measured the concentrations of MHPG, HVA, NMN, and 3-MT to define their correlational relationships. For the NE metabolites, significant correlations were obtained for CSF MHPG and NMN (r = 0.806, p less than 0.001), plasma MHPG and CSF NMN (r = 0.753, p less than 0.001), and plasma and CSF MHPG (r = 0.776, p less than 0.001). These results suggest that CSF and plasma MHPG and CSF NMN may reflect gross changes in whole brain steady-state noradrenergic metabolism. Only a single significant relationship was demonstrated for the DA metabolites, with CSF 3-MT correlating with plasma HVA (r = 0.301, p less than 0.025). The results for the DA metabolites probably reflect regional differences in steady-state brain dopaminergic metabolism.

Comparison of the Effects of the Novel Antipsychotic Agent Remoxipride on Dopamine and Noradrenaline Turnover in the Rat Brain

The ex vivo effects of the antipsychotic dopamine receptor antagonist remoxipride on dopamine and noradrenaline turnover in the rat brain have been compared. Remoxipride (5-125 mumol/kg intraperitoneally) produced large increases in striatal DOPAC and HVA concentrations with only maginal effects on striatal, hippocampal and hypothalamic MHPG concentrations. Both remoxipride (5.6 mumol/kg intraperitoneally) and haloperidol (0.23 mumol/kg intraperitoneally) increased the rate of striatal dopamine disappearance following inhibition of tyrosine hydroxylase by H 44/68 without corresponding effect on hypothalamic and frontal cortical noradrenaline disappearance. It is concluded that at doses of remoxipride producing compensatory increases in dopamine turnover, there is little or no effect on noradrenaline turnover, confirming the in vitro dopamine:noradrenaline selectivity of this compound.

Modulation by corticotropin-releasing factor of monoamine metabolism in the lateral hypothalamus

Corticotropin-releasing factor (CRF) was injected into the lateral hypothalamus of conscious unrestrained rats and the local concentration of monoamines in the vicinity of the microinjection monitored by microdialysis. The concentration of norepinephrine and MHPG in the dialysis fluid from the lateral hypothalamic areas of rats fasted for 24 h was nearly 4 times higher than in fed rats. Following the injection of 2 μg of CRF into the lateral hypothalamus of fasted rats there was a rapid decline in levels of both norepinephrine and 3-methoxy-4-hydroxyphenylglycol (MPHG) to the level in fed rats after 60–90 min. The changes in MHPG and norepinephrine in the fed rats were not significant. There was no difference in serotonin concentration between fasted and fed animals, although the mean value for 5-hydroxyindoleacetic acid (5-HIAA) was slightly increased. Following the injection of CRF, there was a fall in serotonin in the fed rats but not in the fasted animals. There was a fall in the concentration of 5-HIAA in both the fasted and fed rats so that at 30, 60 and 90 min their concentrations were not significantly different. The concentration of DOPAC in the lateral hypothalamus was twice as high in the fasted as in the fed rats. Following injection of CRF there was a rapid decline in DOPAC concentrations in the fasted rats and a small decline in the fed rats. By the end of 30 min after the injection of CRF, concentrations of DOPAC were similar in fed and fasted rats. The studies are consistent with the hypothesis that CRF may depress feeding by altering monoamine metabolism in the lateral hypothalamus to the pattern of a fed rat.

Biogenic amine metabolites in human CSF after hypoxia due to cardiac arrest

The concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) were determined in CSF of patients with hypoxia due to circulatory arrest. Patients were divided into neurologically disabled and recovered according to the Glasgow Coma Scale. CSF was collected 4, 28, 76 and 172 h after commencement of resuscitation and once from control patients subjected to spinal anaesthesia. The initial concentrations of MHPG, 5-HIAA and HVA were significantly higher in a subgroup of neurologically disabled patients who died within 76 h. In recovered patients the concentration of MHPG declined with time to the value of the control group, whereas it increased in neurologically disabled patients. In the latter group the concentration of 5-HIAA also showed an increase with time, whereas in recovered patients it declined after an initial rise. It is concluded that high concentrations of MHPG, 5-HIAA and HVA in CSF may be prognostic for hypoxic brain injury after cardiac arrest.