Progressive supranuclear palsy: anatomoclinical and biochemical considerations.
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Biomedical subjects
B Scatton
Publications and source records attributed to B Scatton.
Evidence for the involvement of presynaptic alpha-2 adrenoceptors in the regulation of norepinephrine metabolism in the rat brain.
In an attempt to evaluate the possible functional role of alpha-2 adrenoceptors located on noradrenergic nerve endings in the regulation of cerebral norepinephrine metabolism, we have measured the effects of clonidine and idazoxan on cerebral free 3,4-dihydroxyphenylethyleneglycol (DOPEG) levels (an index of norepinephrine turnover) in the rat after surgical and experimental manipulations that allow an exclusive interaction of the alpha-2 adrenergic agents with presynaptic alpha-2 autoreceptors. The possible contribution of distant (to cell bodies) transsynaptic feedback mechanisms triggered by stimulation of postsynaptic alpha-2 adrenoceptors and of somatodendritic alpha-2 autoreceptor-mediated regulatory mechanisms was eliminated by a local infusion of tetrodotoxin (50 ng) into the ascending noradrenergic bundle followed by electrical stimulation (at a frequency of 8 Hz) of this pathway distally to the neurotoxin injection site in chloral hydrate-anesthetized rats. Under these conditions, systemic injection of idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.) provoked an increase and a decrease, respectively, in free DOPEG levels in the hypothalamus, cerebral cortex and medial septum which were similar to those measured in naive rats. Moreover, in these animals the effect of idazoxan (1 mg/kg i.p.) was surmounted by a large dose of clonidine (0.3 mg/kg i.p.). The possible contribution of feedback mechanisms triggered by activation of postsynaptic alpha-2 adrenoceptors and mediated via local (to terminals) circuits (or a putative humoral agent released postsynaptically) was eliminated subsequently by a local injection of ibotenic acid in noradrenergic projection areas. Systemic administration of idazoxan (20 mg/kg i.p.) to ibotenate-lesioned rats elicited an increase in septal- and hypothalamic-free DOPEG levels comparable to that found in sham-operated rats. The effectiveness of the lesion was attested by a massive neuronal depopulation in the lesioned areas. Finally, ibotenic acid-induced destruction of noradrenergic target cells and local infusion of tetrodotoxin into followed by electrical stimulation of the ascending noradrenergic pathways were combined. Under these conditions, idazoxan still increased hypothalamic- and septal-free DOPEG levels, the extent of this alteration being similar to that found in normal rats. Altogether, these results suggest that irrespective of their low density, presynaptic alpha-2 autoreceptors play a cardinal role in the regulation of central nervous system norepinephrine metabolism.
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GABA receptor agonists and extrapyramidal motor function: therapeutic implications for Parkinson's disease.
GABA receptor agonists display a dual action on DA-mediated events. One includes a decrease in DA release, reduction in DA receptor density, and decreased response of postsynaptic cells to dopaminergic stimulation; it results in antidopaminergic effects. The other consists of a reduction of striatal cholinergic activity resulting in a facilitation of dopaminergic effects. These two effects could be dissociated depending on the dose of GABA receptor agonists. This dual action probably explains the results of clinical trials showing either amelioration of parkinsonian symptoms with aggravation of L-DOPA-induced dyskinesia or improvement of dyskinesia without or with aggravation of parkinsonian symptoms.
Acetylcholine↗
Fengabine, a novel antidepressant GABAergic agent. II. Effect on cerebral noradrenergic, serotonergic and GABAergic transmission in the rat.
The effects of fengabine (a novel benzylidene derivative possessing clinically demonstrated antidepressant action) on neurochemical parameters related to norepinephrine, serotonin and gamma-aminobutyric acid (GABA) neurons have been investigated in the rat and mouse brain. When given acutely, fengabine (50-1000 mg/kg i.p.) does not alter norepinephrine uptake but accelerates the turnover rate of norepinephrine in the rat brain as demonstrated by the enhancement of: the alpha-methyl-p-tyrosine-induced disappearance of norepinephrine in the hypothalamus; 3,4-dihydroxyphenylacetic acid levels in noradrenergic cell body areas; the pargyline-induced accumulation of normetanephrine in the hypothalamus; and 3,4-dihydroxyphenylethyleneglycol levels in the hypothalamus, septum and spinal cord. No tolerance to the effect of fengabine on the latter biochemical parameter was observed after repeated treatment for 2 weeks at doses of 100 or 200 mg/kg i.p., b.i.d. Fengabine (100 or 200 mg/kg i.p., b.i.d.), given for 14 days, causes a desensitization of isoprenaline-stimulated adenylate cyclase in septal and cortical slices of the rat but fails to modify cortical beta, alpha-1 or alpha-2 adrenoceptor binding sites. Fengabine (up to 400 mg/kg i.p.) has no effect on rat cerebral serotonin uptake, synthesis or metabolism. Moreover, when given subacutely (100 or 200 mg/kg i.p., b.i.d. for 2 weeks), it fails to alter rat cortical serotonine receptors or [3H]imipramine binding sites. Fengabine (up to 50-100 microM) is also inactive in vitro on [3H] GABA binding to GABAA or GABAB receptors in the rat brain or on GABA transaminase activity in the mouse brain.(ABSTRACT TRUNCATED AT 250 WORDS)
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Presynaptic alpha-2 adrenoceptors play a major role in the effects of idazoxan on cortical noradrenaline release (as measured by in vivo dialysis) in the rat.
Transcortical dialysis in awake unrestrained rats has been used to evaluate the functional role of differently located alpha-2 adrenoceptors in mediating the action of the alpha-2 adrenoceptor antagonist idazoxan on cerebral noradrenaline release. Basal efflux of noradrenaline collected by a cortically implanted dialysis fiber was stable over a period of 4 days. Systemic injections of idazoxan (20 mg/kg i.p.) increased cortical noradrenaline efflux. This effect was potentiated by pretreatment with the noradrenaline uptake blocker desipramine (20 mg/kg i.p.). Local cortical infusion of (10(-4) M idazoxan which provides a theoretical extracellular administration of 4 to 48 microM) via the dialysis fiber, thus eliminating the potential contribution of somatodendritic alpha-2 adrenoceptors, also elevated cortical noradrenaline efflux. Desipramine (20 mg/kg i.p.) potentiated this effect. Four days after lesioning cortical cell bodies with ibotenic acid (20 min infusion of 10(-4) M ibotenic acid via the dialysis fiber), both systemic injections and local cortical infusions of idazoxan were still effective in increasing cortical noradrenaline efflux. Lesion of serotonergic afferents to the cerebral cortex (by i.c.v. injection of 5,7-dihydroxytryptamine) or of cortical cholinergic afferents (by bilateral electrocoagulation of the nucleus basalis magnocellularis) did not affect the ability of cortical idazoxan infusion to stimulate noradrenaline efflux. The results suggest that the effects of idazoxan on cortical noradrenaline release are mediated primarily by alpha-2 adrenoceptors on noradrenergic nerve terminals, rather than by those located postsynaptically, somatodendritically or on the terminals of other neuronal inputs to the cerebral cortex.
5,7-Dihydroxytryptamine↗
Cerebral circulatory and metabolic effects of perivascular neurotransmitters.
In this article we review the most recent literature that concerns the various neurotransmitters that are known to innervate the cerebral circulation. The best characterized of these systems (the adrenergic and serotonergic pathways) are discussed extensively, but other putative neurovascular pathways (cholinergic and peptidergic nerves) was covered. The review will be divided into five major sections: the origin and nature of the perivascular nerve fibers in the cerebrovascular bed (this section encompasses both morphological and biochemical investigations); the response of isolated cerebral vessels to neurotransmitters and transmural nerve stimulation (covering the uptake and release of transmitters by brain vessels as well as the pre- and postsynaptic effects of these agents on cerebrovascular smooth muscle); the effects of neurotransmitter and other vasoactive agents on cerebral perfusion and metabolism in vivo. This section includes the effects of perivascular nerve stimulation or ablation on cerebral blood flow as well as on capillary (i.e., blood-brain barrier) properties. The regional metabolic effects of neurotransmitters are compared to their known effects on neuronal function; the involvement of various neurotransmitters in a number of cerebrovascular diseases (in particular, migraine, cerebral vasospasm following subarachnoid hemorrhage and cerebral ischemia, or stroke); and we attempt to synthesize the ever-increasing literature on the origin and function of the multiple innervation of two other noncerebral, intracranial tissues: the choroid plexus and the dura mater.
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Different neuronal location of [3H]SCH 23390 binding sites in pars reticulata and pars compacta of the substantia nigra in the rat.
The precise neuronal localization of D1 receptors in the substantia nigra has been studied autoradiographically in the rat by measuring the alterations of [3H]SCH 23390 binding site densities in this brain area after 6-hydroxydopamine (6-OHDA) induced destruction of nigrostriatal dopaminergic neurons and after ibotenate-induced lesion of striatal afferents. 6-OHDA-induced nigral lesion provoked a total loss of [3H]SCH 23390 binding sites in the pars compacta and pars lateralis (but not in the pars reticulata) of the substantia nigra. In contrast, ibotenate-induced striatal lesion caused a large diminution of the [3H]ligand binding site density in the pars reticulata but not in the pars compacta and pars lateralis of the substantia nigra. These results suggest that D1 receptors in the pars compacta or pars lateralis of the substantia nigra are located on the dopaminergic perikarya whereas those D1 receptors present in the pars reticulata of the substantia nigra lie on the terminals of nigral afferents of striatal origin.
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2-Oxo-[14C]glutarate is taken up by glutamatergic nerve terminals in the rat striatum.
High affinity uptake of [14C]glutamate into rat striatal synaptosomes was reduced by 33% after bilateral cortical ablation. The lesion had no effect on striatal [14C]GABA uptake, but reduced 2-oxo-[14C]glutarate uptake by 67%. The results demonstrate the existence of a high-affinity uptake site for 2-oxoglutarate on glutamatergic nerve terminals and support the contention that this Krebs cycle intermediate may be used to replenish the neuronal pool of neurotransmitter glutamate. 2-Oxo-[14C]glutarate uptake may serve as a selective marker for glutamatergic neurones.
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Functional mapping of the effects of lesions of the habenular nuclei and their afferents in the rat.
Through the use of the quantitative autoradiographic 2-[14C]deoxyglucose technique, we have investigated the functional significance of the habenular nuclei by the measurement of local cerebral glucose utilization (LCGU) in discrete brain areas of conscious rats following 3 kinds of lesioning. Bilateral electrolytic lesions of the habenular nuclei decreased LCGU in a limited number of well-defined brain areas (the interpeduncular nucleus, median and dorsal raphe, mammillary body and dorsal tegmental nucleus) at 7 and 14 days after lesions. These changes were also observed 180 days following lesioning except that of the dorsal tegmental nucleus. At 14 days after bilateral ibotenic acid-induced lesions of the lateral habenula, LCGU was significantly decreased in the median and dorsal raphe, mammillary body and interpeduncular nucleus. In further studies, bilateral electrolytic lesions of the stria medullaris (which conveys the major afferents to the habenula) decreased glucose use in the interpeduncular nucleus less than that observed after bilateral electrolytic lesions of the habenular nuclei. A highly significant positive correlation was observed between LCGU and choline acetyltransferase activity in the interpeduncular nucleus after all types of lesion. These results further support the view that the medial and the lateral habenula exert a major influence upon functional activity in the interpeduncular nucleus and the mesencephalic raphe nuclei, respectively.
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Lesion of nucleus basalis magnocellularis decreases [3H]hemicholinium-3 binding (as measured by autoradiography) in the amygdala and frontal cortex of the rat.
The effects of a unilateral electrolytic lesion of the nucleus basalis magnocellularis on [3H]hemicholinium-3 binding sites in discrete brain regions of the rat were studied through the use of quantitative autoradiography. When compared to the contralateral side this lesion caused a decrease in the density of [3H]hemicholinium-3 binding sites in the medial prefrontal cortex, frontoparietal cortex and basolateral nucleus of the amygdala but not in the caudate-putamen, nucleus accumbens, olfactory tubercle, hippocampus and auditory cortex. These results add further weight to the view that the cholinergic innervation of the rostral cerebral cortex and amygdala originates from the nucleus basalis magnocellularis and suggest that [3H]hemicholinium-3 autoradiography is a suitable means of visualizing cholinergic nerve terminals.
Amygdala↗
Opposing effects of D-1 and D-2 receptor antagonists on acetylcholine levels in the rat striatum.
In contrast to D-2 or mixed D-1/D-2 receptor antagonists which decrease rat striatal acetylcholine levels, the D-1 receptor antagonist SCH 23390 increased this biochemical parameter (ED50 = 0.04 mg/kg s.c.) suggesting a reduction of acetylcholine turnover. SCH 23390 blocked the ability of haloperidol or sulpiride to diminish striatal acetylcholine levels and potentiated the increase in this biochemical parameter induced by the selective D-2 receptor agonist LY 141865. These findings indicate that blockade of D-1 and D-2 receptors causes opposite actions on striatal cholinergic neurons.
Acetylcholine↗
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.
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In vivo voltammetric measurement of extracellular DOPAC levels in the anteromedial prefrontal cortex of the rat.
Differential pulse voltammetric recordings with carbon fiber electrodes performed in vivo in the anteromedial prefrontal cortex of the rat yielded 3 oxidation peaks at -100, +100 and +300 mV, respectively. Pharmacological manipulations revealed that 3,4-dihydroxyphenylacetic acid (DOPAC) is the main contributor to the oxidation current recorded at +100 mV (peak 2). Thus, systemic administration of FLA 63 did not alter whereas pargyline caused a disappearance of cortical peak 2. Moreover, haloperidol and sulpiride increased peak 2 amplitude both in normal and in N-(2-chloroethyl)N-ethyl-2-bromobenzylamine (DSP4)-lesioned rats. Peak 2 was detected only in those prefrontal cortex regions known to receive a dopamine input. It is concluded that in vivo voltammetry with carbon fiber electrodes is a useful means of monitoring dopaminergic activity in the prefrontal cortex of the rat.
3,4-Dihydroxyphenylacetic Acid↗
Temporal effects of habenular lesions on glucose utilization in the anterior raphé nuclei of the rat.
The effects of bilateral electrolytic lesions of both lateral and medial habenular nuclei on local cerebral glucose utilization have been examined in conscious rats by the use of the quantitative 2-deoxy[14C]glucose autoradiographic technique. Habenular lesions markedly reduced the use of glucose in the median raphé and, to a lesser extent, in the dorsal raphé nuclei (which receive major afferents from the lateral habenula) at 7, 14 and 180 days after the lesion. Habenular lesions failed to alter the use of glucose in the entopeduncular nucleus, lateral hypothalamic area and the nucleus of the diagonal band of Broca which project to the habenula. These data add further support to the view that the habenula exerts a major facilitatory influence upon functional activity in the anterior raphé nuclei.
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Autoradiographic localization of D1 dopamine receptors in the rat brain with [3H]SCH 23390.
The regional distribution of D1 dopamine (DA) receptors in the rat brain has been studied by quantitative autoradiography using the specific D1 antagonist [3H]SCH 23390 as a ligand. The binding of [3H]SCH 23390 to striatal sections was saturable, stereospecific, reversible and of high affinity (Kd = 2.05 nM); it occurred at a single population of sites and possessed the pharmacological features of the D1 DA receptor. The highest densities of [3H]SCH 23390 binding sites were found in the caudate-putamen, olfactory tubercle, nucleus accumbens and substantia nigra (especially in the pars compacta). High densities were also observed in the nucleus interstitialis striae terminalis, the anterior olfactory nucleus, the entopeduncular nucleus, the subthalamic nucleus, the claustrum and the amygdalohippocampal area. An intermediate labelling was found in the anteromedial and suprarhinal DA terminal fields of the cerebral cortex, the basolateral, medial and lateral amygdaloid nuclei, the endopiriform nucleus, the primary olfactory cortex, the globus pallidus, the superior colliculus (especially the superficial layer), the nucleus amygdaloideus corticalis and the dorsal hippocampus (molecular layer of the CA1 and dentate gyrus). In the anteromedial and suprarhinal cortices, [3H]SCH 23390 binding was more concentrated in layers V and VI. Moderate levels of [3H]SCH 23390 were found in the thalamus, hypothalamus, the habenula, the ventral tegmental area, the posterior cingulate and entorhinal cortices, the supragenual dopamine terminal system and the cerebellum (molecular layer). This regional distribution of [3H]SCH 23390 closely correlated (except for the cerebellum) with the reported distribution of dopaminergic terminals. The topographical distribution of [3H]SCH 23390 has also been studied in detail in striatal subregions. The density of D1 receptors was much greater in the ventrolateral sector and medial margin of the striatum than in the ventromedial and dorsolateral sectors. A rostrocaudal decrease in the densities of D1 sites was also found along the rostrocaudal axis of the caudate-putamen. These lateral to medial and anteroposterior gradients overlapped with the density of the dopaminergic afferents.
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Autoradiographic localization and quantification of dopamine D2 receptors in normal human brain with [3H]N-n-propylnorapomorphine.
The precise distribution of dopamine receptors has been studied autoradiographically in the normal human brain using [3H]N-n-propylnorapomorphine ([3H]NPA) as a ligand. Preliminary experiments aimed at optimizing the binding assay conditions revealed that preincubation washing of caudate nucleus sections was a prerequisite to obtain a good ratio of specific to non-specific binding. The binding of [3H]NPA to caudate-putamen sections was saturable, stereospecific, reversible, of high affinity (Kd = 0.27-0.35 nM) and occurred at a single population of sites. Competition experiments with various drugs indicated that in the caudate-putamen the specific [3H]NPA binding sites possess the pharmacological features of the dopamine D2 receptor. The highest levels of [3H]NPA binding sites were found in the caudate nucleus, putamen, globus pallidus and nucleus accumbens. There were also intermediate to low concentrations of the 3H-ligand in the hippocampus, the insular and cingular cortices and in the occipito-temporal gyrus, while almost undetectable levels of binding were found in the anterior frontal cortex. Thorough examination of the subregional distribution of [3H]NPA binding sites in the caudate-putamen-pallidum complex revealed heterogeneous patterns of radioactivity. In these brain regions, the distribution of autoradiographic grains was punctate and islands of high and low densities were observed. Moreover, in the caudate nucleus, there was a subtle high lateral to low medial gradient in the topography of the [3H]NPA binding sites and a more pronounced gradient along the rostrocaudal axis; the highest levels of binding being located at the midbody of the nucleus. No gradients of [3H]NPA binding were observed in the putamen. The present data indicate that [3H]NPA is a suitable ligand for accurate autoradiographic labeling of dopamine D2 receptors in human postmortem brain tissue and that dopamine receptors are heterogeneously distributed and topographically organized in patches and gradients in the basal ganglia regions.
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Evidence for, and nature of, the tonic inhibitory influence of habenulointerpeduncular pathways upon cerebral dopaminergic transmission in the rat.
The potential role of the habenula in the transsynaptic regulation of the activity of ascending dopaminergic systems has been investigated in the rat by studying the effect of an acute interruption of impulse traffic in the diencephalic conduction system (stria medullaris-habenula-fasciculus retroflexus) and of pharmacological manipulation of various neurotransmitter systems in the interpeduncular nucleus on dopamine metabolism in several dopaminergic projection fields. The bilateral infusion of tetrodotoxin into the fasciculus retroflexus (which conveys the habenulointerpeduncular tract) of conscious rats markedly increased homovanillic acid levels and dopamine synthesis and utilization in the medial prefrontal cortex, nucleus accumbens, olfactory tubercle and striatum. Similar changes in dopamine metabolism were observed in these areas after bilateral infusion of tetrodotoxin into the stria medullaris (which conveys most of the afferents to the habenula). Infusion of atropine (0.4-1 micrograms) into the interpeduncular nucleus increased homovanillic acid concentrations and dopamine utilization in the medial prefrontal cortex and nucleus accumbens but not in the olfactory tubercle and striatum. Moreover, intra-interpeduncular injection of oxotremorine (17 micrograms) antagonized the increase in dopamine utilization in the nucleus accumbens (but not in the olfactory tubercle) induced by an intrafasciculus retroflexus infusion of tetrodotoxin. Local infusion of naloxone (20 micrograms) into the interpeduncular nucleus increased homovanillic acid concentrations in the nucleus accumbens and olfactory tubercle but not in the medial prefrontal cortex and striatum. In contrast, intra-interpeduncular nucleus infusion of the substance P antagonist D-Arg1, D-Pro2, D-Trp7,9, Leu11-substance P or of substance P antiserum failed to alter homovanillic acid levels in the 4 dopamine-rich areas investigated. Finally, intraraphé medianus (but not intraraphé dorsalis) infusion of muscimol (25 ng) moderately increased dopamine synthesis in the nucleus accumbens and striatum. The present findings suggest that the habenulointerpeduncular pathways exert a tonic inhibitory influence on mesocortical, mesolimbic and mesostriatal dopaminergic neurons. Cholinergic and/or opioid peptidergic neurons coursing through the fasciculus retroflexus as well as ascending serotonergic neurons originating in the raphé medianus could take part in this inhibitory control of ascending dopaminergic neurons.
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Neuroanatomical site of the inhibitory influence of anxiolytic drugs on central serotonergic transmission.
The neuroanatomical site of the inhibitory influence of anxiolytics on central serotonergic transmission has been investigated in the rat by studying the effect of systemic or intracerebral administration of these drugs on cerebral serotonin (5-HT) synthesis. Systemic administration of diazepam (3 mg/kg s.c.) or flunitrazepam (1 mg/kg, s.c.) caused a reduction of 5-HT synthesis (as measured by the accumulation of 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase) in the hippocampus but not in the cerebral cortex, striatum, cerebellum or spinal cord of the rat. Zopiclone (22 mg/kg, s.c.) decreased the amine synthesis in hippocampus, striatum and prefrontal cortex. The decrease of hippocampal 5-HT synthesis induced by diazepam (5 mg/kg, s.c.) was antagonized by the benzodiazepine antagonist Ro 15-1788 (2 X 30 mg/kg, s.c.) but not by bicuculline (2 X 1 mg/kg, s.c.). Acute cerebral hemitransection or electrolytic lesion of the fasciculus retroflexus did not prevent the ability of diazepam (5 mg/kg, i.p.) to diminish hippocampal 5-HT synthesis. Local infusion of diazepam (15 micrograms) of flurazepam (1.5 micrograms) into the hippocampus of conscious rats (via indwelling cannulae) markedly reduced 5-HT synthesis in this brain area whereas infusion of these drugs into the raphé medianus (origin of the serotonergic afferents to the hippocampus) failed to affect hippocampal 5-HT synthesis. In contrast, local injection of muscimol (25-150 ng) into the raphé medianus reduced 5-HT synthesis in the hippocampus. This effect of muscimol was potentiated by a systemic administration of diazepam or an intra-raphé medianus infusion of flurazepam (at doses or concentrations which exhibited no intrinsic activity). It is concluded from these data that anxiolytic drugs exert an inhibitory influence on hippocampal serotonergic neurons which is mediated primarily via GABA-independent benzodiazepine receptors located in the vicinity of serotonergic nerve terminals.
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