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At least 1,657 records · Page 92Linked to original sources
PubMed2003

Neurochemical and anatomical identification of fast- and slow-firing neurones in the rat dorsal raphe nucleus using juxtacellular labelling methods in vivo.

GABA neurones in the dorsal raphe nucleus (DRN) influence ascending 5-hydroxytryptamine (5-HT) neurones but are not physiologically or anatomically characterised. Here, in vivo juxtacellular labelling methods in urethane-anaesthetised rats were used to establish the neurochemical and morphological identity of a fast-firing population of DRN neurones, which recent data suggest may be GABAergic. Slow-firing, putative 5-HT DRN neurones were also identified for the first time using this approach. Fast-firing, DRN neurones were successfully labelled with neurobiotin (n=10) and the majority (n=8/10) were immunoreactive for the GABA synthetic enzyme glutamic acid decarboxylase. These neurones were located in the DRN (mainly lateral regions), and consistently fired spikes with short width (1.1+/-0.1 ms) and high frequency (12.1+/-2.0 Hz). In most cases spike trains were regular but displayed low frequency oscillations (1-2 Hz). These neurones were morphologically heterogeneous but commonly had branching axons with varicosities and dendrites that extended across DRN subregions and the midline. Slow-firing DRN neurones were also successfully labelled with neurobiotin (n=24). These neurones comprised a population of neurones immunopositive for 5-HT and/or tryptophan hydroxylase (n=12) that fired broad spikes (2.2+/-0.2 ms) with high regularity and low frequency (1.7+/-0.2 Hz). However, a slow-firing, less regular population of neurones immunonegative for 5-HT/tryptophan hydroxylase (n=12) was also apparent. In summary, this study chemically identifies fast- and slow-firing neurones in the DRN and establishes for the first time that fast-firing DRN neurones are GABAergic. The electrophysiological and morphological properties of these neurones suggest a novel function involving co-ordination between GABA and 5-HT neurones dispersed across DRN subregions.

Action Potentials↗
PubMed2005

Focal cerebral ischemia preferentially affects neurons distant from their neighboring microvessels.

Developing cerebral infarction obscures the relationship of neurons to their local supply microvessels. We tested the notion that in the basal ganglia (i) an ordered relationship between neurons and their nearest neighboring microvessel exists, and (ii) focal ischemia predictably affects neuron integrity based on microvessel-neuron proximity. Distances between individual microvessels and their nearest neurons ([m-n distance]s) were measured in normal primates and ischemic subjects undergoing middle cerebral artery occlusion for 2 hours. An ordered microvessel-neuron relationship exists in the normal nonischemic basal ganglia within the early hours of focal ischemia. During ischemia normal (n) and sensitive (n*) neurons are interspersed. On average, neurons more distant from their nearest microvessel are most sensitive ([m-n distance]=16.2+/-11.2 microm versus [m-n* distance]=22.2+/-13.0 microm, 2P<0.00000001). Neurons not expressing glutamic acid decarboxylase were more likely to be sensitive than those with a normal microvessel-neuron relationship. In contrast, the [m-n distance] distribution of injured tyrosine hydroxylase-containing neurons was similar to those without tyrosine hydroxylase. Hence, the [m-n distance] relationship in the normal and ischemic basal ganglia is highly ordered, and distant neurons are consistently perturbed by ischemia, although this is not uniformly dependent on neurotransmitter type.

Animals↗
PubMed1986

Serotonin initiates and autoamplifies its own synthesis during mouse central nervous system development.

Some cells from cultured embryonic mouse hypothalamus were found to express aromatic-L-amino acid decarboxylase (EC 4.1.1.28) activity and serotonin uptake and storage. These neuron-like cells differed from serotoninergic neurons in cultured embryonic mouse brain stem since they did not contain tryptophan hydroxylase. We studied the effect of the serotonin agonist 8-hydroxy-2-[di-(n-propyl)amino]tetralin on neuronal differentiation of hypothalamic cells from 12- to 15-day embryos. Repeated treatment of cultures with the serotonin agonist for 10 days resulted in an increased number of serotonin cells containing high levels of decarboxylase activity. Both the increase in cell numbers and the elevated decarboxylase activity could be suppressed by the addition of the serotonin antagonist metergoline to the culture medium. These data show that serotonin (or an agonist), acting on specific receptors, can initiate and amplify its own synthesis in embryonic hypothalamic neurons, as observed in the primitive hypothalamic nerve cell line F7 [De Vitry, F., Catelon, J., Dubois, M., Thibault, J., Barritault, D., Courty, J., Bourgoin, S. & Hamon, M. (1986) Neurochem. Int. 9, 43-53]. Such an autocrine-like mechanism may be active during nervous system development and may represent an example of learning at the cellular level.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1978

Kainic acid lesions of the striatum dissociate amphetamine and apomorphine stereotypy: similarities to Huntingdon's chorea.

Kainic acid lesion of cell bodies in the dorsal striatum enhanced the stereotypy-producing effects of d-amphetamine without affecting the sterotypy produced by the direct receptor agonist apomorphine. This pattern of results parallels that found in patients suffering from Hungtington's chorea, thus strengthening the parallels between the kainic acid animal model and the human disease state initially suggested on biochemical gounds. The present results further suggest a dissociation of the mechanisms involved in the production of stereotypy by these two drugs, perhaps in terms of differential involvement of the striato-nigral negative feedback loop.

Animals↗
PubMed1988

[Adrenocortical hormone rhythm in blood and metabolism of the hypothalamic biogenic amines in rats].

Restricted daily feeding (RF), in which free access to food and water is restricted to a fixed time of the day, has been demonstrated to elevate the plasma corticosterone level in rats prior to meal (prefeeding corticosterone peak). But the central mechanism for the hormone peak is unknown. In this study, the metabolism of the hypothalamic biogenic amines was investigated to know whether or not it was associated with the prefeeding corticosterone peak under RF. Male rats were subjected to RF (meal time from 10:00 to 12:00 h) under the light-dark cycle (lights from 06:00 to 18:00 h). Norepinephrine metabolism was estimated from the rate of decrease in norepinephrine content after the administration of a synthesis blocker, alpha-methyl-p-tyrosine (alpha-MPT). Dopamine and serotonin metabolisms were estimated from the accumulation rate of precursor amine after the inhibition of aromatic L-amino acid decarboxylase by m hydroxybenzylhydrazine (NSD 1015). Rats were sacrificed by decapitation and four hypothalamic nuclei (SCN, PVN, VMH, LH) were punched out according to Palkovits method. Amine contents in each nucleus were measured by HPLC. Results obtained are as follows; 1) Catecholamine was significantly involved in the formation of prefeeding corticosterone peak under RF in rats. 2) Norepinephrine metabolism was different in each hypothalamic nucleus. Especially, that in PVN seems to be parallel with the plasma corticosterone level under RF. This result suggests that norepinephrine in PVN stimulates corticotropin releasing hormone (CRH). 3) Dopamine metabolism in the four hypothalamic nuclei showed similar changes; prefeeding rise (except for VMH), high activity during feeding, decrease after food deprivation, and persistence of high activity during fast. 4) Serotonin metabolism in the four hypothalamic nuclei showed similar changes; prefeeding rise (except for VMH), decrease during feeding, and persistence of high activity during fast.

Animals↗
PubMed1976

Central action of a catechol-amide seizure-inducing agent: opposing effect on tyrosine and tryptophan hydroxylase activity in vivo.

The audiogenic seizure-inducing drug H13/04 was found to elicit opposing effects on the in vivo accumulation of 5-HTP (5-hydroxytryptophan) and DOPA (3,4-dihydroxyphenylalanine) in the brain following inhibition of L-amino acid decarboxylase. In strains of mice that normally do not exhibit audiogenic seizures, H13/04 retarded the accumulation of 5-HTP in the telencephalon, diencephalon and brainstem and enhanced the accumulation DOPA in the diencephalon and brainstem. The duration of the biochemical action of H13/04-correlated with the duration of the behavioral effect. When H13/04 is administered to strains of mice with a genetically-determined susceptibility to audiogenic seizures, but at an age when they are developing resistance to seizures, H13/04 does not alter the incidence of sound-induced seizures. The effect on the accumulation of 5-HTP and DOPA was similar to that noted in the genetically-resistant strain; a retardation of the accumulation of 5-HTP in the telencephalon and brainstem and an enhancement of DOPA accumulation in the brainstem. Since the rate of accumulation of 5-HTP and DOPA is a measure of the in vivo rates of tryptophan and tyrosine hydroxylase, respectively, the results may reflect changes in neural activity with consequent effects on the synthesizing enzymes. These results emphasize the usefulness of the drug in analyzing central mechanisms underlying audiogenic seizure activity and in studying functional properties and interactions of the central catechol-and indoleamine systems.

Amides↗
PubMed1993

Evidence for L-dopa relevant to modulation of sympathetic activity in the rostral ventrolateral medulla of rats.

By microdialysis in the rostral ventrolateral medulla (RVLM) of anesthetized rats, the spontaneous L-3,4-dihydroxyphenylalanine (DOPA) release was partially Ca(2+)-dependent and tetrodotoxin-sensitive and was markedly reduced by alpha-methyl-p-tyrosine (alpha-MPT; 200 mg/kg, i.p.). K+ (50 mM) Ca(2+)-dependently evoked L-DOPA. By microinjections into unilateral RVLM, L-DOPA (30-300 ng) produced dose-dependent hypertension and tachycardia similarly in rats untreated, treated with i.p. 3-hydroxybenzylhydrazine, a central DOPA decarboxylase inhibitor, or with i.v.t. 6-hydroxydopamine. These responses were antagonized by L-DOPA methyl ester (1.5 micrograms), a competitive L-DOPA antagonist. D-DOPA, dopamine, noradrenaline or adrenaline (300 ng) produced no effect. Furthermore, L-DOPA methyl ester alone microinjected into bilateral RVLM (2 micrograms x 2) produced prolonged hypotension and bradycardia, which were abolished by alpha-MPT. These data suggest that L-DOPA is relevant to modulation of sympathetic activity in the rat RVLM.

Animals↗
PubMed2001

Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models.

This article reviews the mechanism of dopamine delivery in the CNS in order to determine the optimal set of genes for effective gene therapy in Parkinson's disease (PD). Systematic neurobiological investigation of the biochemical steps has revealed that tyrosine hydroxylase (TH), which has been used in earlier studies, functions only when the essential cofactor, tetrahydrobiopterin (BH1) is present. Transduction of the gene for GTP cyclohydrolase I, the first and rate-limiting step in BH1 synthesis, along with the TH gene, generated cells that are capable of producing L-DOPA spontaneously both in vitro and in vivo. When the aromatic L-amino acid decarboxylase (AADC) gene was added as a third gene, in an attempt to increase the conversion of L-DOPA to dopamine, feedback inhibition by the end product, dopamine, on TH activity resulted. To circumvent this problem, we employed a complementary strategy. Gene transfer of the vesicular monoamine transporter was combined with AADC and produced genetically modified cells that can convert L-DOPA to dopamine and store it for gradual release. This approach provided a means to regulate final dopamine delivery by controlling precursor doses and to achieve more sustained delivery of dopamine. Our investigation into determining the genes necessary for optimal dopamine delivery has been facilitated by in vivo biochemical assays using microdialysis. This technique has provided us with a clear and quantitative tool to compare the effects of various genes involved in dopamine synthesis and processing.

Animals↗
PubMed1994

The relationship between MRNA levels and the locomotor response to novelty.

Differences in behavioral and neurochemical responses to drugs of abuse and environmental stress have been observed between rats that have a greater locomotor response in a novel environment (high responders: HR) compared to those that have a low response to novelty (low responders: LR). This study examined nuclei associated with the nigrostriatal and mesolimbic systems for differences in mRNA content between HR and LR using Northern blot analysis. These brain regions were chosen because of their role in both drug abuse and stress responses. The mRNAs examined code for either peptide transmitters that interact with the dopaminergic system or components of the dopaminergic system that have not been previously examined for differences between HR and LR. HR rats had approximately 50% lower levels of mRNA for beta-preprotachykinin (PPT) in the core of the nucleus accumbens (NACC) compared to LR. No differences between HR and LR in mRNA levels for dynorphin (DYN), preproenkephalin (PPE), glutamic acid decarboxylase (GAD) or neurotensin (NT) were observed in the core of the NACC. In the shell region of the NACC, HR exhibited a 25% reduction in the level of mRNA for NT compared to LR. No differences between HR and LR in mRNA levels for PPT, DYN, PPE or GAD were observed in the shell of the NACC. In the medial frontal cortex and the dorsal striatum, no differences between HR and LR in mRNA levels for PPT, DYN, PPE, GAD or NT were found. In the substantia nigra and ventral tegmental area no differences between HR and LR in mRNA levels for tyrosine hydroxylase, GAD, cholecystokinin, or NT were noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Nociceptin/orphanin FQ and opioid receptor-like receptor mRNA expression in dopamine systems.

Although nociceptin/orphanin FQ (N/OFQ) influences dopamine (DA) neuronal activity, it is not known whether N/OFQ acts directly on DA neurons, indirectly by means of local circuitry, or both. We used two parallel approaches, dual in situ hybridization (ISH) and neurotoxic lesions of DA neurons by using 6-hydroxydopamine (6-OHDA), to ascertain whether N/OFQ and the N/OFQ receptor (NOP) mRNA are expressed in DA neurons in the ventral tegmental area (VTA) and substantia nigra compacta (SNc). In the VTA and SNc, small populations (approximately 6-10%) of N/OFQ-containing neurons coexpressed mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme for DA synthesis. Similarly, very few (1-2%) TH-positive neurons contained N/OFQ mRNA signal. A majority of NOP-positive neurons (approximately 75%) expressed TH mRNA and roughly half of the TH-containing neurons expressed NOP mRNA. Many N/OFQ neurons (approximately 50-60%) expressed glutamic acid decarboxylase 65 and 67 mRNAs, markers for gamma-aminobutyric acid (GABA) neurons. In the 6-OHDA lesion studies, NOP mRNA levels were nearly 80 and 85% lower in the VTA and SNc, respectively, on the lesioned side. These lesions appear to lead to compensatory changes, with N/OFQ mRNA levels approximately 60% and 300% higher in the VTA and SNc, respectively, after 6-OHDA lesions. Finally, N/OFQ-stimulated [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate levels were decreased in the VTA and SNc but not the prefrontal cortex after 6-OHDA lesions. Accordingly, it appears that N/OFQ mRNA was found largely on nondopaminergic (i.e., GABA) neurons, whereas NOP mRNA was located on DA neurons. N/OFQ is in a position to influence DA neuronal activity by means of the NOP located on DA neurons.

Animals↗
PubMed2003

Inhibition of aromatic amino acid decarboxylase by a group of new potential nonsteroidal anti-inflammatory drugs with antileukotrienic effects.

Possible in vitro inhibition of aromatic amino acid decarboxylase (AAD, EC 4.1.1.28) by a group of phenylsulfonylbenzoic acid derivatives VUFB 19363, 19369, 19370, 19371, and 19760 as new potential anti-inflammatory compounds was studied using the substrate L-tyrosine. Enzyme inhibition by 2.7 x 10(-5) M concentration of compound VUFB 19363 (Quinlukast) was 17%, AAD inhibition at 3.75 x 10(-5) M concentration of compounds VUFB 19369, 19370, 19371, and 19760 ranged between 9-23%. There were distinct differences between individual compounds. Evaluation of inhibition kinetics suggested full reversibility with VUFB 19369 and the uncompetitive type of inhibition in the case of compound VUFB 19363. Considering the anti-inflammatory activity of the compounds studied, the weak AAD inhibition found is rather favourable for their prospective pharmacological effect.

Animals↗
PubMed1979

Ibotenic acid-induced neuronal degeneration: a morphological and neurochemical study.

Possible neurotoxic actions of intracerebral injections of ibotenic acid, a conformationally restricted analogue of glutamic acid, have been evaluated in rat brain and compared with those of kainic acid. Light microscopical analysis revealed that ibotenic acid produced a marked disappearance of nerve cells in all areas studied, namely striatum, the hippocampal formation, substantia nigra and piriform cortex. Lesions in areas distant to the injection site were not seen. Axons of passage and nerve terminals of extrinsic origin did not seem to be damaged, since, e.g., no apparent degeneration of the dopaminergic terminals in the neostriatum was observed except for a small area surrounding the cannula. In the neostriatum, enkephalin immunoreactive neuronal cell bodies as well as nerve terminals disappeared after injection of ibotenic acid into this nucleus. After injection into the substantia nigra tyrosine hydroxylase immunoreactive cell bodies in the zona compacta disappeared, whereas no certain effect could be seen on the enkephalin immunoreactive nerve fibers. In vitro experiments, conducted with striatal synaptosomal and membrane preparations, showed that ibotenic acid differed from kainic acid by being devoid of a significant inhibitory effect on high affinity glutamate uptake and by having a low affinity for 3H-kainic acid binding sites. Furthermore, ibotenic acid did not interfere with the binding of a number of radioligands for other transmitter receptors. As compared to kainic acid, ibotenic acid has the advantage of being less toxic to the animals and of producing more discrete lesions, possibly due to faster metabolism and/or other fundamental biochemical differences. Because of these special features, ibotenic acid seems to represent a valuable new tool in the morphological and functional analysis of central neuronal systems.

Animals↗
PubMed1996

Tetrahydrobiopterin and biogenic amine metabolism in the hph-1 mouse.

hph-1 mice, which have defective tetrahydrobiopterin biosynthesis due to decreased GTP cyclohydrolase I activity, have been used to investigate the effects of tetrahydrobiopterin deficiency on aromatic L-amino acid monooxygenases and brain monoamine metabolism. Liver tetrahydrobiopterin levels were decreased, and tetrahydrobiopterin deficiency and reduced levels of dopamine, norepinephrine, serotonin, and their metabolites in the brain occurred both pre- and postnatally. Chronic subcutaneous tetrahydrobiopterin elevated brain levels to values higher than those seen in controls but had no effect on monoamine metabolism. In vivo activities of tyrosine hydroxylase and tryptophan hydroxylase were significantly decreased. There was a 30% decrease in the in vitro activity of striatal tyrosine hydroxylase and 50% decrease in liver phenylalanine hydroxylase. Western blotting demonstrated that the lower monooxygenase activities resulted from a reduced absolute amount of tyrosine hydroxylase and phenylalanine hydroxylase protein. The findings suggest involvement of tetrahydrobiopterin in the control of the steady-state concentration of the aromatic L-amino acid monooxygenases. In addition, demonstration of central monoamine changes in the hph-1 mouse make it a possible model system for the investigation of the neuropathological mechanisms in Dopa-responsive dystonia, which has recently been linked with mutations in the gene for GTP cyclohydrolase I.

Animals↗