The use of in vivo voltammetry to investigate functional recovery with transplants and neurotransmitter interactions in the rat brain.
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Animals↗
Biomedical subjects
B Scatton
Publications and source records attributed to B Scatton.
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↗
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↗
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↗
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↗
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↗
Neurochemical studies on the existence, origin and characteristics of the serotonergic innervation of small pial vessels.
Substantial concentrations of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), comparable to those found in brain tissue, were measured in the small pial vessels of the rat, rabbit and cat. Both rat and rabbit pial vessels exhibited a high affinity uptake process with kinetic parameters similar to those identified for the cerebral cortex. Labelled 5-HT, taken up by isolated rabbit pial vessels was released, in a calcium-dependent manner, by potassium-induced depolarization. Various pharmacological manipulations were carried out in the rat. Systemic administration of the 5-HT precursor, 5-hydroxytryptophan and the monoamine oxidase inhibitor, pargyline, significantly increased the concentration of 5-HT in the pial vessels; in contrast, two depleting agents (p-chloroamphetamine and reserpine) and the tryptophan hydroxylase inhibitor, p-chlorophenylalanine, all decreased the perivascular 5-HT levels. A serotonergic antagonist (methysergide) and a 5-HT receptor agonist (MK 212) respectively increased and decreased the concentrations of 5-HIAA in the pial vessels. These pharmacologically induced changes observed in pial vessels were not dissimilar from those noted for cortical tissue. Electrolytic lesions of the nuclei raphes medianus and/or dorsalis markedly decreased the levels of 5-HT and 5-HIAA in these small cerebral arterioles. Electrical stimulation of these nuclei decreased 5-HT although 5-HIAA concentrations tended to increase. A number of conclusions may be drawn from these studies. Thus, there is a serotonergic innervation of the cerebral circulation in several laboratory species which unequivocally originates in the raphé nuclei. Furthermore, these perivascular fibres possess synthetic, storage, release, inactivation and autoregulatory processes for 5-HT which, when further elucidated, may offer some rationale for the treatment of those cerebrovascular diseases in which this neurotransmitter and vasoactive agent is believed to be of pathological importance.
Animals↗
GABA mimetics decrease extracellular concentrations of 5-HIAA (as measured by in vivo voltammetry) in the dorsal raphe of the rat.
The effect of gamma-aminobutyric acid (GABA) mimetics on extracellular concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (as measured by differential pulse voltammetry with carbon fiber electrodes) in the dorsal raphé has been investigated in the rat. Systemic administration of dipropylacetamide decreased extracellular 5-HIAA to a similar extent, and within a comparable time course, in the dorsal raphé and striatum. Similar results were obtained after intradorsal raphé infusion of muscimol (100 ng). In contrast, local infusion of tetrodotoxin into the dorsal raphé failed to alter serotonin metabolism in this area. It is concluded that GABA depresses serotonin metabolism not only in nerve endings, but also in dendrites (and/or cell bodies) of serotonergic neurons.
Animals↗
[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↗
Heterogeneous distribution of dopamine D2 receptors within the rat striatum as revealed by autoradiography of [3H]N-n-propylnorapomorphine binding sites.
The precise topographical distribution of dopamine D2 receptors in the rat striatum has been studied autoradiographically through the use of [3H]N-n-propylnorapomorphine (NPA) as a ligand. The highest densities of [3H]NPA binding sites were found in the ventrolateral aspect and medial margin of the striatum, while sparse grain densities were present in the medial and latero-dorsal striatum. Moreover, a clear gradient of [3H]NPA binding was observed along the rostro-caudal axis of the striatum. These heterogeneities in the distribution of dopamine receptors provide further evidence for a functional compartmentalization of the striatum.
Animals↗
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↗
Subchronic administration of GABAergic agonists elevates [3H]GABA binding and produces tolerance in striatal dopamine catabolism.
Directly and indirectly acting GABAergic agonists were assessed for their ability to alter striatal dopamine catabolism after subchronic administration (7-14 days) via subcutaneously implanted osmotic minipumps. THIP, kojic amine and baclofen failed to alter striatal DOPAC and HVA concentrations, but THIP and kojic amine were effective after a single acute dose. Striatal GABA levels proved difficult to elevate when inhibitors of GABA transaminase were released from minipumps, but a high dose of gamma-vinyl GABA increased GABA by 44% of control, although striatal dopamine and DOPAC levels were unaltered. [3H]GABA binding studies revealed that THIP and kojic amine, but not baclofen or gamma-acetylenic GABA, produced large increases in [3H]GABA 'A' binding (150 and 228% of control respectively) which were attributable to altered densities of binding sites without changes in affinity. Despite alterations in GABAergic function, nigrostriatal dopaminergic neurones seem to develop tolerance to the effects of GABAergic drugs.
3,4-Dihydroxyphenylacetic Acid↗
Autoradiographic localization of D1 dopamine receptors in the rat brain with [3H]SKF 38393.
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2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Inhibitory influence of GABA on central serotonergic transmission. Involvement of the habenulo-raphé pathways in the GABAergic inhibition of ascending cerebral serotonergic neurons.
In order to explore the anatomical nature of the inhibitory GABAergic control of cerebral serotonergic neurons exerted at the level of the anterior raphé cells in the rat, we have studied the effect of GABA agonist agents (given systemically or infused locally into the raphé dorsalis or medianus) on cerebral 5-hydroxytryptophan (5-HTP) accumulation after lesion or pharmacological manipulation of various raphé inputs. Destruction of noradrenergic pathways by local injection of 6-hydroxydopamine in the pedunculus cerebellaris superior or by systemic injection of DSP-4 (50 mg/kg i.p.), or alteration of central dopaminergic transmission (by systemic administration of apomorphine or haloperidol) failed to modify the ability of progabide (400 mg/kg i.p.) or dipropylacetamide (150 mg/kg i.p.) to diminish 5-HTP accumulation in the striatum, hippocampus and substantia nigra. In contrast, electrolytic lesion of the habenular nuclei blocked the ability of these compounds (given systemically) to reduce 5-HTP accumulation both in serotonergic nerve terminal and cell body (raphé dorsalis and medianus) areas. A similar blockade of the effects of GABA mimetics was seen after ibotenate-induced lesion of the habenula but not after electrolytic lesion of the stria medullaris (which conveys most of the afferents to the habenula). Acute cessation of impulse flow in the habenulo-raphé tract also prevented the depamide-induced diminution of cerebral 5-HTP accumulation. Finally, interruption of nerve transmission in the habenulo-raphé pathways (by means of electrolytic lesion of the habenula or fasciculus retroflexus) blocked the ability of GABA (100 micrograms) or muscimol (50 ng) injected into the raphé dorsalis or medianus to reduce 5-HTP accumulation in the corresponding serotonergic nerve terminal areas. It is concluded that the GABAergic inhibition of ascending serotonergic neurons exerted in the raphé dorsalis and medianus depends upon an ongoing neuronal activity in the habenulo-raphé pathways; GABA may exert its inhibitory control over serotonergic neurons by tuning down a facilitatory influence on these cells exerted by the habenula.
Animals↗
Inhibitory influence of GABA on central serotonergic transmission. Raphé nuclei as the neuroanatomical site of the GABAergic inhibition of cerebral serotonergic neurons.
Acute injection of the gamma-aminobutyric acid (GABA) mimetics progabide, aminooxyacetic acid, gamma-acetylenic GABA and dipropylacetamide reduced 5-hydroxytryptophan (5-HTP) accumulation in serotonergic nerve terminal regions (prefrontal cortex, olfactory tubercle, septum, striatum, hypothalamus, hippocampus, substantia nigra, cerebellum and spinal cord) as well as in corresponding cell body areas (raphé dorsalis, medianus, pontis and magnus). This effect was antagonized by bicuculline. The inhibition of serotonin (5-HT) synthesis induced by a single progabide administration was accentuated on repeated treatment in the striatum, prefrontal cortex and cerebellum but was similar to that seen after acute treatment in the other areas. Local infusion of high concentrations of GABA or GABA mimetics into the striatum, septum or substantia nigra failed to modify 5-HTP accumulation in these areas. Cerebral hemitransection antagonized the ability of progabide (1200 mg/kg i.p.) to diminish 5-HTP accumulation in the striatum, hippocampus and prefrontal cortex. Intra-raphé dorsalis infusion of muscimol (0.1-100 ng) or GABA (1-100 micrograms) decreased 5-HT synthesis in the corresponding projection areas (e.g. striatum, substantia nigra, cortex) but not in the hippocampus or cerebellum. Conversely, intra-raphé medianus infusion of these drugs diminished 5-HTP accumulation in the corresponding projection areas (e.g. hippocampus, septum, cortex) but not in the striatum or cerebellum. Intra-raphé dorsalis or medianus injection of GABA antagonists (bicuculline, picrotoxinin, RU-5135) was without effect on cerebral 5-HT synthesis but antagonized the diminution of the amine synthesis observed in corresponding projection areas after intra-raphé dorsalis or medianus infusion of muscimol or GABA. These results suggest that GABA exerts an inhibitory (non-tonic) control over central serotonergic neurons which is mediated via GABA receptors located in the raphé nuclei.
5-Hydroxytryptophan↗
Quantitative autoradiography of 3H-nomifensine binding sites in rat brain.
The distribution of 3H-nomifensine binding sites in the rat brain has been studied by quantitative autoradiography. The binding of 3H-nomifensine to caudate putamen sections was saturable, specific, of a high affinity (Kd = 56 nM) and sodium-dependent. The dopamine uptake inhibitors benztropine, nomifensine, cocaine, bupropion and amfonelic acid were the most potent competitors of 3H-nomifensine binding to striatal sections. The highest levels of (benztropine-displaceable) 3H-nomifensine binding sites were found in the caudate-putamen, the olfactory tubercle and the nucleus accumbens. 6-Hydroxydopamine-induced lesion of the ascending dopaminergic bundle resulted in a marked decrease in the 3H-ligand binding in these areas. Moderately high concentrations of the 3H-ligand were observed in the bed nucleus of the stria terminalis, the anteroventral thalamic nucleus, the cingulate cortex, the lateral septum, the hippocampus, the amygdala, the zona incerta and some hypothalamic nuclei. There were low levels of the binding sites in the habenula, the dorsolateral geniculate body, the substantia nigra, the ventral tegmental area and the periaqueductal gray matter. These autoradiographic data are consistent with the hypothesis that 3H-nomifensine binds primarily to the presynaptic uptake site for dopamine but also labels the norepinephrine uptake site.
Animals↗
Dopaminergic and cholinergic lesions in progressive supranuclear palsy.
In 9 patients with progressive supranuclear palsy and in 27 controls, dopamine and homovanillic acid concentrations, choline acetyltransferase (CAT) activity, and the number of [3H]spiperone and [3H]quinuclidinyl benzilate binding sites were measured post mortem in the striatum (caudate nucleus, putamen, and nucleus accumbens), substantia innominata, and frontal cortex. Dopamine and homovanillic acid concentrations were reduced in the caudate nucleus and putamen but not in the nucleus accumbens or frontal cortex, indicating that the nigrostriatal dopaminergic system is lesioned in patients with progressive supranuclear palsy (as in those with Parkinson's disease) but not the mesocortical and mesolimbic dopaminergic systems, which are lesioned in parkinsonian patients. CAT activity and [3H]spiperone binding decreased in parallel fashion in all the structures. In the striatum, this suggests that the cholinergic neurons, which are target cells of the nigrostriatal system, also degenerate in this disease. This might explain the decrease in the number of dopamine receptors as well as the inefficacy of levodopa or anticholinergic therapy in these patients. The decrease in CAT activity in the substantia innominata and the frontal cortex indicates that the innominatocortical cholinergic system is lesioned in patients with progressive supranuclear palsy and may play a role in the intellectual deterioration observed. This lesion is also found in demented patients with Alzheimer's and Parkinson's diseases.
Aged↗
Influence of GABA mimetics and lithium on biochemical manifestations of striatal dopamine target cell hypersensitivity.
The potential mechanisms whereby GABA mimetics and the antimanic agent lithium stabilize dopaminergic transmission are discussed. Evidence is presented that GABA mimetics, and in particular progabide, affect dopamine-mediated events in the basal ganglia on at least three levels. First, they reduce dopamine neuron activity in both the basal and the activated states. Secondly, on a long-term basis, they antagonize the proliferation of striatal dopamine receptors subsequent to chronic neuroleptic treatment. Thirdly, they modulate the expression of dopamine receptor activation by acting distally to the dopaminergic synapse. Lithium and GABA mimetics have the last two properties in common. These effects may represent the biochemical basis for the therapeutic action of GABA mimetics in iatrogenic dyskinesias. Moreover, the similarity between the biochemical effects of GABA mimetics and lithium suggest that the former drugs may have a therapeutic potential in mania.
Animals↗