Biomedical subjects

T Dennis

Publications and source records attributed to T Dennis.

At least 55 records · Page 3Linked to original sources

PubMed1986

Degeneration of noradrenergic and serotonergic but not dopaminergic neurones in the lumbar spinal cord of parkinsonian patients.

To investigate the possible alterations of spinal cord monoaminergic pathways in Parkinson's disease, the levels of dopamine, homovanillic acid, noradrenaline, serotonin and 5-hydroxyindoleacetic acid have been measured in different subregions of the lumbar spinal cord in control subjects and parkinsonian patients. Substantial amounts of these compounds were found in the dorsal, intermediate and ventral grey matter portions and in the white matter of the spinal cord; the levels of serotonin and its metabolite being the highest. In parkinsonian patients, lumbar spinal cord dopamine and homovanillic acid levels were similar to those in the control subjects, whereas the concentrations of noradrenaline, serotonin and its metabolites were clearly subnormal in the different parts of the cord, the depletion of noradrenaline being the most pronounced. These data suggest that lumbar spinal cord noradrenergic and serotonergic, but not dopaminergic, systems are damaged in Parkinson's disease.

Aged↗

PubMed1986

Lack of circadian rhythm in plasma levels of 3,4-dihydroxyphenylethyleneglycol in healthy human subjects.

In order to investigate the possible existence of a circadian rhythm in plasma free and sulfate-conjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the plasma levels of this metabolite (and for comparison, of melatonin and cortisol) were measured in seven healthy volunteers at 4-h intervals over a period of 24 h. Plasma concentrations of melatonin and cortisol showed distinct diurnal variations with acrophases at 2.5 h and 8.5 h, respectively. In contrast, plasma free DOPEG levels were relatively stable over the 24-h period studied. Sulfate-conjugated and free + sulfate-conjugated DOPEG levels showed a slight, non-significant increase in the early afternoon. These results indicate that in contrast to plasma 3-methoxy 4-hydroxyphenylethyleneglycol, plasma free and conjugated DOPEG levels do not exhibit a circadian rhythm.

Adult↗

PubMed1986

Decrease in plasma levels of 3,4-dihydroxyphenylethyleneglycol in major depression.

Plasma levels of free and sulfoconjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of norepinephrine, were measured in a group of 45 hospitalized patients presenting a major depression and a group of 45 healthy subjects, matched for sex and age. Compared to healthy subjects, depressed patients had significantly lower plasma levels of free and sulfoconjugated DOPEG. The ratio of free over conjugated DOPEG was not statistically different in the two groups. The reduction of plasma DOPEG levels in the depressed patients did not appear to be related to the duration of drug-free period and was similar in males and females. There was no statistically significant correlation between plasma DOPEG levels and total score on the Hamilton Rating Scale for Depression. Finally, plasma DOPEG levels did not differ in unior bipolar patients. The present data provides further evidence for a reduced CNS noradrenergic transmission in major depression.

Adolescent↗

PubMed1986

Urinary 3-methoxy, 4-hydroxyphenylethylene glycol and therapeutic response to maprotiline and indalpine in major depression.

The potential value of pretreatment urinary 3-methoxy, 4-hydroxyphenylethyleneglycol (MHPG) levels to predict the therapeutic response to antidepressants was studied by measuring urinary MHPG output in 42 depressed inpatients treated with a selective inhibitor of serotonin (Indalpine) or noradrenaline (Maprotiline) reuptake. Among the 42 depressed inpatients there were 33 cases of major depressive episode. Patients were treated for at least 3 weeks, firstly with intravenous infusions of maprotiline or indalpine which have been administered at random. No difference in pretreatment urinary MHPG levels was found between the responders to indalpine (1.08 +/- 0.48 micrograms/24 h/mg of creatinine) and the responders to maprotiline (1.15 +/- 0.62 micrograms/24 h/mg of creatinine). However, there was a difference in the pretreatment levels of urinary MHPG between the non-responders to indalpine (0.56 +/- 0.28 microgram/24 h/mg of creatinine) and the non-responders to maprotiline (1.37 +/- 0.68 micrograms/24 h/mg of creatinine). No correlation between this biochemical parameter and HDRS score was found. These results indicate that, in this study, there is no obvious relationship between the pretreatment urinary MHPG levels in depressed patients and their therapeutic response to specific inhibitors of noradrenaline or serotonin reuptake. However, there was a positive trend towards a lower pretreatment MHPG level to be associated with lack of response to indalpine.

Adult↗

PubMed1986

Lack of correlation between plasma DOPEG and urinary MOPEG levels in depressed patients.

Twenty-four-hour urinary excretion of 3-methoxy,4-hydroxyphenylethyleneglycol (MOPEG) and levels of free and conjugated plasma 3,4-dihydroxyphenylethyleneglycol (DOPEG) were measured in 56 depressed patients to find a possible correlation between these two peripheral indices of cerebral noradrenergic activity. Plasma DOPEG was measured at 9:00 AM on the same day that urine was collected for the measurement of MOPEG. All depressed patients were diagnosed as having affective disorders according to DSM-III. No correlation was found between plasma free or conjugated DOPEG levels and urinary MOPEG output. This lack of correlation was found in the total sample of depressed patients (56), in 45 patients diagnosed as having major depressive episodes, and in 24 depressed patients diagnosed as major depressive with melancholia. The authors discuss the significance of this lack of correlation between two peripheral indices of central noradrenergic metabolism.

Adult↗

PubMed1986

Measurement of endogenous noradrenaline release in the rat cerebral cortex in vivo by transcortical dialysis: effects of drugs affecting noradrenergic transmission.

The release of endogenous noradrenaline was measured in the cerebral cortex of the halothane-anesthetized rat by using the technique of brain dialysis coupled to a radioenzymatic assay. A thin dialysis tube was inserted transversally in the cerebral cortex (transcortical dialysis) and perfused with Ringer medium (2 microliter min-1). Under basal conditions, the cortical output of noradrenaline was stable over a period of at least 6 h and amounted to 8.7 pg/20 min (not corrected for recovery). Histological control of the perfused area revealed very little damage and normal morphology in the vicinity of the dialysis tube. Omission of calcium from the perfusion medium caused a marked drop in cortical noradrenaline output. Bilateral electrical stimulation (for 10 min) of the ascending noradrenergic pathways in the medial forebrain bundle caused a frequency-dependent increase in cortical noradrenaline output over the range 5-20 Hz. Stimulation at a higher frequency (50 Hz) resulted in a levelling off of the increase in cortical noradrenaline release. Systemic administration of the dopamine-beta-hydroxylase inhibitor bis-(4-methyl-1-homopiperazinylthiocarbonyl) disulfide (FLA 63) (25 mg/kg i.p.) markedly reduced, whereas injection of the monoamine oxidase inhibitor pargyline (75 mg/kg i.p.) resulted in a progressive increase in, cortical noradrenaline output. d-Amphetamine (2 mg/kg i.p.) provoked a sharp increase in cortical noradrenaline release (+450% over basal values within 40 min). Desmethylimipramine (10 mg/kg i.p.) produced a twofold increase of cortical noradrenaline release. Finally, idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.), respectively, increased and decreased the release of noradrenaline from the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1986

Plasma 3,4-dihydroxyphenylethyleneglycol and therapeutic response to maprotiline and indalpine in major depression.

Plasma levels of free and conjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of norepinephrine, were assayed in 48 depressed patients before initiating a treatment with either maprotiline, an inhibitor of norepinephrine reuptake, or indalpine, a specific inhibitor of serotonin reuptake. The two groups of depressed patients were comparable. The therapeutic effect was evaluated by using the Hamilton Rating Scale for Depression. No difference in pretreatment plasma free and conjugated DOPEG levels was found between the responders and the nonresponders to maprotiline or indalpine. Neither was there any difference in the pretreatment levels of plasma free DOPEG between the two groups of responders and the two groups of nonresponders to either drug. Finally, there was no difference in the therapeutic response to maprotiline or to indalpine between the patients with high and low plasma DOPEG levels before treatment. These results indicate that there is no relationship between the initial plasma levels of DOPEG in depressed patients and their therapeutic response to a norepinephrine or a serotonin reuptake blocker.

Adult↗

PubMed1986

Plasma 3,4-dihydroxyphenylethyleneglycol levels in depressed patients with and without abnormal dexamethasone suppression.

Escape from dexamethasone-induced suppression of plasma cortisol is an abnormality found in about half of patients with major depression. It has been hypothesized that this hyperactivity of the hypothalamo-pituitary-adrenal axis might be related to a central noradrenergic hypofunction. The present study was designed to test this hypothesis by measuring plasma 3,4-dihydroxyphenylethyleneglycol (DOPEG) levels (free and conjugated forms), an index of central noradrenergic activity, and by simultaneously carrying out a dexamethasone suppression test. Forty-five patients with a diagnosis of major depression (according to the DSM-III) were investigated. Plasma DOPEG levels (measured at 8 a.m.) were found to be similar in dexamethasone suppressor and nonsuppressor depressed patients. These results do not support the hypothesis that central noradrenergic hypoactivity underlies nonsuppression of dexamethasone in major depression.

Adult↗

PubMed1986

Zolpidem, a novel nonbenzodiazepine hypnotic. II. Effects on cerebellar cyclic GMP levels and cerebral monoamines.

The effect of zolpidem, a novel nonbenzodiazepine short-acting hypnotic, on cerebellar cyclic GMP (cGMP) and biochemical indices of cerebral norepinephrine, serotonin and dopamine metabolism has been investigated in the rat and mouse. Zolpidem diminished the levels of cerebellar cGMP in the rat markedly (ED50 = 0.7 mg/kg i.p.). This effect was antagonized, in a competitive manner, by the benzodiazepine antagonist Ro 15-1788. The zolpidem-induced decrease of cerebellar cGMP levels was rapid in onset and of short duration (less than 1 hr). When given in combination with muscimol (in a dose which by itself did not alter cerebellar cGMP content) zolpidem potentiated the diminution of the cyclic nucleotide levels induced by the gamma-aminobutyric acid mimetic. Zolpidem (up to 30 mg/kg i.p.) failed to alter the rate of utilization of norepinephrine or the levels of total 3,4-dihydroxyphenylethyleneglycol or 3-methoxy, 4-hydroxyphenylethyleneglycol sulfate in the rat brain. However, the compound (10-30 mg/kg) diminished serotonin synthesis in the hippocampus, striatum and frontal cortex. At high doses (30-100 mg/kg i.p.), zolpidem also decreased the rate of utilization of dopamine and 3,4-dihydroxyphenylacetic acid levels in the rat striatum. Moreover, zolpidem (10 mg/kg i.p.) prevented partially the haloperidol-induced increase in 3,4-dihydroxyphenylacetic acid concentrations in both striatum and frontal cortex. Finally, zolpidem prevented the increase in 3,4-dihydroxyphenylacetic acid levels in the frontal cortex induced by electric footshock stress in rats (ED50 = 2 mg/kg i.p.) and BALB/C mice. This effect was antagonized by coadministration of Ro 15-1788.

Animals↗

PubMed1986

Pharmacological studies on stress-induced increase in frontal cortical dopamine metabolism in the rat.

The effects of a variety of minor tranquilizers and of benzodiazepine inverse agonists on the stress-induced increase in frontal cortical dopamine metabolism have been studied in the rat. Electric footshock stress increased 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the frontal (but not parietal) cortex and in the nucleus accumbens but not in the striatum or ventral tegmental area. Similar stress-induced alterations of frontal cortical DOPAC levels were observed after DSP4-induced noradrenergic denervation or after adrenalectomy. Other types of stress, e.g. conditioned fear (exposure to an environment paired previously with footshock) or swim stress also provoked an elevation of DOPAC levels in the prefrontal cortex. When administered systemically, the anxiolytic agents meprobamate, CL 218,872, CGS 9896, suriclone and the hypnotic/anxiolytic drugs zolpidem and zopiclone all prevented the electric footshock stress-induced augmentation of cortical DOPAC levels whereas the gamma-aminobutyric acid receptor agonists progabide, muscimol and depamide or the sedative alpha-1 adrenoceptor antagonist prazosin were ineffective. The preventive effect of diazepam and zolpidem on the stress-induced biochemical response was antagonized by the benzodiazepine antagonist CGS 8216 but not by the gamma-aminobutyric acid receptor antagonist bicuculline. In nonstressed rats, systemic administration of the anxiogenic benzodiazepine inverse agonists beta-CCM (methyl-beta-carboline-3-carboxylate) and beta-CCE (ethyl-beta-carboline-3-carboxylate), but not of the benzodiazepine antagonists Ro 15-1788 or CGS 8216, caused an increase in frontal cortical DOPAC similar to that provoked by stress and which was antagonized by zolpidem.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

[Cerebral noradrenaline metabolism and classification of depression].

Disturbed noradrenaline (NA) metabolism is thought to play a causal role in certain types of endogenic depression. This study was based on data from 88 patients with depression. The metabolism of NA was investigated by measuring urinary MHPG and plasma DOPEG concentrations and platelet nonoamine oxidase activity to determine if there were any differences in subgroups of depression defined by the DSM3. There was no difference in plasma DOPEG concentrations or of MAO activity in the different subgroups of depression, especially between episodes of major and non-major depression. On the other hand, depressed patients with an episode of major depression had significantly higher urinary MHPG concentrations than those with non-major depression.

Blood Platelets↗

PubMed1985

Distribution of dopamine, noradrenaline and adrenaline in coronal sections of the rat lower brainstem.

The concentration of the three major catecholamines (CAs) were determined in 500 micron thick coronal sections of the rat medulla oblongata dissected into microcubes. Noradrenaline (NA) concentrations were always found much higher than the levels of the two other CAs in the same microcube. The highest concentrations of the three CAs were found in the dorso-medial region of the lower brainstem, more exactly in the more caudally located parts of the nucleus tractus solitarii (NTS). In the ventro-lateral region, the CA concentrations were lower and, except for adrenaline (A), did not exhibit any substantial change in their rostro-caudal distribution. Conversely, in the dorso-medial region, there was a clear rostro-caudal pattern of distribution of the three CAs. This distribution was similar for the three amines, since only a small difference (about 500 micron) was found between the maximal NA and A concentrations. Since the three CAs are present in highest concentrations within the same dorso-medial or ventro-lateral groups of microcubes, a microdissection of these two areas seems suitable to study simultaneously the metabolism of the three CAs in the rat lower brainstem. These data also suggest a microdissection procedure to study A metabolism within the C2-C3 A cell bodies and within a region more caudally located, rich in A terminals.

Adrenergic Fibers↗

PubMed1985

[Study of the metabolism of cerebral noradrenaline in depressed patients by the assay of plasma dihydroxyphenylethylene glycol].

Dihydroxy-phenyl-ethylene-glycol (DOPEG or DHPG), a deaminated catabolite of noradrenaline formed after presynaptic re-uptake, is a good marker of metabolic activity in noradrenergic pathways. Plasma levels of free, conjugated and total DOPEG were measured by a radioenzymatic method in 45 patients with major depression selected according to the DSM 3 criteria and in 45 matched controls. A significant decrease in man DOPEG levels was observed in all depressive patients. A dexamethasone suppression test performed in these patients showed no difference in DOPEG levels between responders and non-responders, thus failing to support the hypothesis that subjects with low noradrenergic drive escape suppression. There was no correlation between plasma DOPEG levels and urinary excretion of methoxy-hydroxy-phenylglycol (MOPEG), another marker of noradrenaline metabolic activity. Thirty-one patients were treated with a specific monoaminergic antidepressant: maprotiline or indalpine; contrary to urinary MOPEG levels, plasma DOPEG levels had no predictive value concerning the response to this category of antidepressants. The various possible reasons for the fall in DOPEG observed in depressive patients are discussed.

Adult↗

PubMed1985

The formation of deaminated metabolites of dopamine in the locus coeruleus depends upon noradrenergic neuronal activity.

The effect of manipulations of noradrenergic neuronal activity on the levels of the deaminated metabolites of dopamine in the locus coeruleus has been investigated in the rat. Antidromic stimulation of the locus coeruleus increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MOPEG) in this area. Conversely, local infusion of tetrodotoxin into the locus coeruleus reduced the levels of these metabolites in this region. After systemic injection, idazoxan increased whereas clonidine diminished DOPAC, HVA and MOPEG levels in the locus coeruleus either in normal animals or in animals bearing a lesion of A9 and A10 dopaminergic cells. These results suggest that the formation of dopamine deaminated metabolites in noradrenergic cell bodies is dependent upon, and may serve as an index of, central noradrenergic neuronal activity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

Amphetamine induced release of endogenous dopamine in vitro is not reduced following pretreatment with reserpine.

The release of endogenous dopamine evoked by electrical stimulation or by exposure to (+)-amphetamine (10 microM) was determined in superfused striatal slices of the rat. The spontaneous and the electrically-evoked release of dopamine were significantly increased in the presence of nomifensine (10 microM). After reserpine pretreatment (5 mg/kg, s.c., 24 h), the striatal dopamine content was reduced by about 90%. Exposure to 10 microM (+)-amphetamine during 2 min released similar amounts of dopamine from striatal slices of untreated or reserpine pretreated rats. Similar results were obtained when monoamine oxidase activity was inhibited in vivo with pargyline. Pretreatment with reserpine does not modify the (+)-amphetamine-induced release of dopamine, in spite of the marked reduction of the striatal dopamine content. These results provide direct evidence for the view that (+)-amphetamine releases dopamine from a special, reserpine-resistant pool of newly synthetized transmitter.

Animals↗

PubMed1985

Further evidence for, and nature of, the facilitatory GABAergic influence on central noradrenergic transmission.

In order to explore the nature of the facilitatory GABAergic control of cerebral noradrenergic neurons, we have studied the effect of a variety of GABA mimetics (given systemically or injected locally into brain areas containing noradrenergic cell bodies or terminals) on several indices of noradrenaline turnover in the rat brain. Systemic administration of both direct and indirect acting GABA mimetics enhanced; 1) the pargyline induced accumulation of normetanephrine in the hypothalamus; 2) total DOPEG levels in a number of brain regions innervated by noradrenergic neurons; 3) both DOPAC and MOPEG levels in noradrenergic cell body areas (A1, A2 and A6). These effects are probably mediated by GABAA receptors as specific GABAA or mixed GABAA/GABAB agonists but not the GABAB agonist baclofen enhanced noradrenaline turnover. Interruption of noradrenergic impulse flow (by local injection of tetrodotoxin or by hemitransection) blocked the ability of progabide to increase DOPEG concentrations in the hypothalamus and cerebral cortex. Similarly, the co-administration of clonidine with progabide antagonized the progabide-induced increase in hypothalamic total DOPEG levels. Co-administration of yohimbine with progabide provoked an additive effect on hypothalamic DOPEG levels at moderate but not at high doses of yohimbine. Thus, the acceleration of noradrenaline turnover induced by GABA mimetics appears to depend on ongoing activity in noradrenergic neurons and occurs via an increase in neuronal discharges. Local injection of muscimol into the nucleus accumbens or hypothalamus failed to affect DOPEG levels in these structures; similarly, local injection of muscimol into the locus coeruleus failed to modify DOPEG levels in corresponding noradrenergic projection areas. These data indicate that the GABAergic influence is not exerted via GABA receptors located on noradrenergic cell bodies or nerve endings. Furthermore, since systemically administered progabide still increased hypothalamic DOPEG levels after ibotenate-induced destruction of the hypothalamic neuronal cell bodies, a presynaptic modulation of noradrenergic neurons by local GABAergic interneurons is excluded. Chemical destruction of serotoninergic pathways or enhancement of 5-HT transmission by quipazine failed to alter the ability of progabide to increase cerebral DOPEG levels. Moreover, scopolamine or naloxone also failed to affect the progabide-induced increase in cerebral DOPEG levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

PubMed1985

Platelet monoamine oxidase activity and plasma 3,4-dihydroxyphenylethylene glycol levels during the menstrual cycle.

The influence of endocrine factors on monoamine oxidase activity (MAO) and on noradrenaline metabolism has been evaluated by measuring platelet MAO activity and plasma levels of 3,4-dihydroxyphenylethylene glycol (DOPEG), the major deaminated metabolite of noradrenaline, as well as serum levels of steroid hormones weekly in 9 young healthy women during one menstrual cycle. A decrease in platelet MAO activity (correlated with high serum estradiol levels) was observed during the ovulatory period. In contrast, plasma free or sulfoconjugated DOPEG remained unchanged throughout the menstrual cycle. These results indicate that the hormonal status should be taken into consideration in studies dealing with platelet MAO activity in depressed women.

Adult↗

PubMed1985

Pharmacological, hemodynamic and biochemical mechanisms involved in the blood pressure lowering effects of pergolide, in normotensive and hypertensive dogs.

In pentobarbital-anesthetized normotensive dogs, clonidine (20.0 micrograms/kg i.v.), in contrast to pergolide (30.0 micrograms/kg i.v.), reduced significantly both aortic blood pressure and plasma concentration of norepinephrine. However, in dogs that had been made hypertensive by sectioning the vagi and carotid sinus nerves, pergolide, like clonidine, lowered the blood pressure and plasma concentrations of epinephrine and norepinephrine that were enhanced markedly by deafferentation. Furthermore, in this preparation pergolide decreased the calculated resistance in vascular regions supplied by the upper abdominal aorta and the innervated femoral and renal arteries, but it increased vascular resistance in the denervated hind leg. Pergolide (1.0 microgram/kg) injected intracisternally (i.c.m.) induced a fall in blood pressure of comparable magnitude to that produced by a 30 times higher i.v. dose. Intravenously and i.c.m. administered pergolide lowered blood pressure by acting at distinct anatomical sites inasmuch as i.v. sulpiride blocked the effects of i.v. but not i.c.m. pergolide. The combination of sulpiride plus yohimbine injected i.c.m. was necessary to abolish the decrease in blood pressure evoked by i.c.m. pergolide. In atropinized spinal dogs, i.v. pergolide inhibited the vasoconstriction elicited by electrical stimulation of the lumbar sympathetic chain, an effect which was antagonized by sulpiride. Similarly, pergolide (30.0 micrograms/kg i.v.) like clonidine, reduced the heart rate and coronary venous plasma norepinephrine concentration raised by sustained electrical stimulation of the cardioaccelerator nerve. Sulpiride, but not phentolamine, antagonized this pergolide-induced inhibition of sympathetic nerve function. In chlorisondamine-pretreated dogs, pergolide produced a transient pressor response due to stimulation of postsynaptic vascular alpha-2 adrenoceptors. In conclusion, the failure of i.v. pergolide to decrease aortic blood pressure in pentobarbital-anesthetized normotensive dogs is presumably due to the inability of pergolide to produce a significant inhibition of the vascular sympathetic tone in this preparation. However, in neurogenic hypertensive dogs which are characterized by an elevated level of sympathetic drive, i.v. pergolide reduced blood pressure and aortic plasma norepinephrine concentration. These effects of pergolide are compatible with a DA-2 dopamine receptor stimulation on peripheral sympathetic nerve fibers. In contrast, the antihypertensive effects of i.c.m. pergolide would appear to be mediated by both alpha-2 adrenoceptors and DA-2 dopamine receptors located within the central nervous system.

Anesthesia↗