Biomedical subjects

Andreas Moser

Publications and source records attributed to Andreas Moser.

11 recordsLinked to original sources

PubMed2006

K(ATP)-dependent neurotransmitter release in the neuronal network of the rat caudate nucleus.

K(ATP) channels can couple the bioenergetic metabolism of the cell to membrane excitability. Here, we show gamma-aminobutyric acid (GABA) mediated inhibition of dopamine outflow from slices of the rat caudate nucleus that is regulated by extracellular glucose via high- and low-affinity K(ATP) channels. During glucose reduction, a biphasic dopamine effect could be observed with first a dopamine increase followed by a decline at low glucose concentrations. Both phases were inhibited by glibenclamide. Pinacidil decreased DA outflow without an effect of glucose reduction implying an overall activation of K(ATP) channels. The first phase with dopamine increase was related to reduced GABAergic activity and could be blocked by bicuculline. Our results may be explained by different types of K(ATP) channels with low affinity of ATP and glibenclamide on inhibitory GABAergic and high-affinity on excitatory DAergic neurons. This led us to suggest a biological principle through which neuronal networks are functioning.

Animals↗

PubMed2005

Modulation of a neuronal network by electrical high frequency stimulation in striatal slices of the rat in vitro.

The effects of the GABA(A) receptor antagonist bicuculline, the D2-like receptor antagonist sulpiride and the D1-like receptor antagonist SCH-23390 on the electrical high frequency stimulation (HFS)-evoked gamma-aminobutyric acid (GABA) and dopamine (DA) release were measured from slices of the rat striatum by means of HPLC method with electrochemical detection. HFS with 130Hz stimulated veratridine-activated GABAergic neurons resulting in an increased GABA outflow while DA outflow decreased. In the presence of the GABA(A) receptor antagonist bicuculline extracellular GABA and DA outflow were enhanced. When the competitive dopamine D2-like receptor antagonist S-(-)-sulpiride was added to incubation medium, the HFS-evoked stimulatory effect on GABA outflow declined to values found after veratridine (1microM) without HFS. After co-incubation of sulpiride and the competitive D1-like receptor antagonist R-(+)-SCH-23390, the effect of sulpiride on HFS plus veratridine-evoked GABA outflow was completely reversed. Neither sulpiride nor SCH-23390 had any influence on the effect of HFS on veratridine-induced DA outflow. No effect of HFS on glutamate outflow was observed in all experiments. These results led us to suggest that in our model HFS primarily affects GABAergic neurons. These neurons are embedded in a neuronal network with a GABA-dopamine circuit, and thus, HFS interacts with a neuronal network, not only with one neurotransmitter system or one neuron population.

Animals↗

PubMed2004

Neuronal electrical high frequency stimulation modulates presynaptic GABAergic physiology.

Electrical high frequency deep brain stimulation (DBS) of the globus pallidus internus (GPi) or the subthalamic nucleus (STN) has dramatic beneficial motor effects in advanced Parkinson's disease (PD). However, the mechanisms underlying these clinical results remain unclear. It is proposed that the gamma-aminobutyric acid (GABA) system is involved in the effectiveness of DBS. To prove this hypothesis, rat striatal slices were stimulated electrically (130 Hz) in vitro; GABA and glutamate (GLU) outflow from striatal slices of normal or kainic acid-lesioned rats were measured after o-phthaldialdehyde sulphite derivatization using HPLC with electrochemical detection. Our results could demonstrate that high frequency stimulation (HFS) did not modulate basal GABA outflow in the perfusate. In the presence of submaximal concentrations of the voltage-gated sodium channel opener veratridine, HFS significantly enhanced GABA outflow. When the GABA transporter inhibitor, nipecotic acid, was added to the incubation medium, the HFS effects decreased to nearly control values. Destruction of striatal GABAergic neurons by kainic acid completely reversed the effects of HFS on GABA outflow. In the present study no effect of HFS on glutamate outflow was observed under any condition. These results suggest that HFS has a specific effect on GABAergic neuronal terminals resulting in an enhancement of extracellular GABA in the caudate nucleus. This effect is probably due to an inhibitory effect of HFS on the GABA uptake system rather than to stimulation of vesicular GABA release from GABAergic neurons, which are both associated with the presynaptic GABAergic physiology.

Animals↗

PubMed2003

Modulation of striatal serotonin and opioid receptor mRNA expression following systemic N-methyl-norsalsolinol administration.

The dihydroxylated tetrahydroisoquinoline derivative, 2(N)-methyl-norsalsolinol (NMNorsal), was identified in L-DOPA-treated patients with Parkinson's disease and proposed to be responsible for behavioral changes. In the present study, we investigated the effect of NMNorsal on serotonin and opioid receptors gene expression in caudate nucleus of Wistar rats. Using RT-PCR, serotonin 5-HT2A, micro- and delta-opioid receptor mRNA levels were determined after NMNorsal administration (40 mg/kg, i.p.). There was a marked increase of 5-HT2A and delta-opioid receptor mRNA levels with a maximum after 48 h. In contrast, micro-opioid receptor mRNA levels were significantly decreased to 10% after 24 h and 21% after 48 h, respectively. Our present results demonstrate for the first time that the atypical heterocylic L-DOPA/dopamine metabolite NMNorsal is able to modify long-term regulation of serotonin and opioid receptor expression in striatum. Since the occurrence of hallucinosis or psychosis following L-DOPA treatment is related to the serotonergic system, these results probably reflect a link between NMNorsal and L-DOPA side effects in Parkinson's disease. However, further experiments are needed.

Animals↗

PubMed2003

Magnetic tuning of biquadratic exchange coupling in magnetic thin films.

The effective interlayer coupling between antiferromagnetically coupled hard and soft ferromagnetic thin films is investigated as a function of the magnetic bit length in the hard layer, which is controlled using a magnetic recording system. The interlayer coupling is explored by studying the magnetization reversal of the soft layer. As the bit length decreases, the coupling evolves from antiferromagnetic to biquadratic to uncoupled. These results are reproduced using a micromagnetic model and determine the applicability range of Slonczewski's fluctuation model of biquadratic coupling.

Journal Article↗

PubMed2003

Deep brain stimulation: response to neuronal high frequency stimulation is mediated through GABA(A) receptor activation in rats.

High frequency stimulation (HFS) of deep brain regions such as globus pallidus internus or subthalamic nucleus can reverse Parkinson's symptoms probably through activation of gamma-aminobutyric acid (GABA)ergic neurotransmission. To prove the hypothesis, rat striatal slices were stimulated electrically (130 Hz) in vitro and dopamine (DA) outflow was measured using high performance liquid chromatography. HFS induced an attenuation in basal DA release in perfusate. Veratridine-induced DA outflow was blocked by the simultaneous application of HFS. Addition of bicuculline, a GABA(A) receptor antagonist, reversed the effect of HFS on DA outflow. In addition, destruction of striatal GABAergic neurons with kainic acid also reversed the effect of HFS. In conclusion, our present data provide strong evidence that HFS does not only need presynaptic GABA(A) receptors but also intact GABAergic nerve terminals coupled to GABA(A) receptors to exert an inhibitory effect and give a rationale of HFS effectiveness in the treatment of Parkinson's disease.

Animals↗

PubMed2003

N-methyl-norsalsolinol modulates serotonin metabolism in the rat caudate nucleus: correlation with behavioural changes.

In earlier studies the dihydroxylated tetrahydroisoquinoline derivative 2(N)-methyl-norsalsolinol (NMNorsal) was identified in patients with Parkinson's disease. In the present study, NMNorsal (20 or 40 mg/kg) was given intraperitoneally to rats kept under normal light-dark cycles. Using brain microdialysis technique, serotonin (5-HT), 5-hydroxyindolacetic acid (HIAA), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the dialysate from caudate nucleus in vivo and from tissue in vitro at various times following NMNorsal administration. Even after high-dose NMNorsal administration (40 mg/kg) and measurements up to 48 h after administration, levels of DA and its metabolite DOPAC were not modified. In contrast to the DA metabolism, 5-HT levels in the dialysate increased to approx. 2-fold during the 48 h following administration of a single high-dose of NMNorsal while HIAA decreased to approx. 50%. These changes of 5-HT and HIAA were nearly identical in the homogenate preparation of the caudate nucleus when compared to the amounts present in the dialysate. During assessment controls and low-dose-treated animals were almost always sleeping. Only high-dose NMNorsal-treated rats were active, with maximum activity after 48 h, however, behavioural activity was clearly different to the classical 5-HT behavioural syndrome. Taken together, increased 5-HT levels in the striatum found in our studies seem to be linked to the behavioural activity induced by high-dose NMNorsal, and NMNorsal appeared to perturb normal diurnal rhythms of spontaneous locomotor activity. The precise mechanism by which NMNorsal acts on 5-HT metabolism and behaviour is, however, unclear and further investigation is required.

Animals↗

PubMed2003

Modeled ligand-protein complexes elucidate the origin of substrate specificity and provide insight into catalytic mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase.

NMR spectroscopy and X-ray crystallography have provided important insight into structural features of phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH). Nevertheless, significant problems such as the substrate specificity of PAH and the different susceptibility of TH to feedback inhibition by l-3,4-dihydroxyphenylalanine (l-DOPA) compared with dopamine (DA) remain unresolved. Based on the crystal structures 5pah for PAH and 2toh for TH (Protein Data Bank), we have used molecular docking to model the binding of 6(R)-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and the substrates phenylalanine and tyrosine to the catalytic domains of PAH and TH. The amino acid substrates were placed in positions common to both enzymes. The productive position of tyrosine in TH.BH4 was stabilized by a hydrogen bond with BH4. Despite favorable energy scores, tyrosine in a position trans to PAH residue His290 or TH residue His336 interferes with the access of the essential cofactor dioxygen to the catalytic center, thereby blocking the enzymatic reaction. DA and l-DOPA were directly coordinated to the active site iron via the hydroxyl residues of their catechol groups. Two alternative conformations, rotated 180 degrees around an imaginary iron-catecholamine axis, were found for DA and l-DOPA in PAH and for DA in TH. Electrostatic forces play a key role in hindering the bidentate binding of the immediate reaction product l-DOPA to TH, thereby saving the enzyme from direct feedback inhibition.

Amino Acid Sequence↗

PubMed2002

N-methyl-norsalsolinol, a putative dopaminergic neurotoxin, passes through the blood-brain barrier in vivo.

In earlier studies the dihydroxylated tetrahydroisoquinoline derivatives salsolinol and 2(N)-methyl-norsalsolinol (NMNorsal), a 2(N)-analogue of salsolinol, were identified as putative endogenous neurotoxins in patients with Parkinson's disease. Since a prominent blood-brain barrier (BBB) was described to exist for salsolinol, in the present study microdialysis experiments were performed to investigate the penetration of NMNorsal through the BBB into the caudate nucleus of the rat brain. After i.p. administration of NMNorsal (20 mg/kg), it could be detected in the dialysate of the caudate nucleus with a mean maximum after 40 min. There was no alteration in extracellular dopamine or 3,4-dihydroxyphenylacetic acid levels. Addition of the monoamine oxidase inhibitor pargyline (10 microM) to the perfusate did not modify NMNorsal levels in the caudate nucleus. To corroborate the microdialysis results, homogenates of the contralateral caudate nucleus were prepared and NMNorsal could also be detected. These findings indicate that NMNorsal is indeed able to pass through the blood-brain barrier of the rat brain.

Animals↗

PubMed2002

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related derivatives: chemistry and biochemical effects on catecholamine biosynthesis.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo, 2) is a mammalian alkaloid that readily originates in the human organism, by Pictet-Spengler condensation of endogenously present tryptamine (Ta) and the non-natural hypnotic agent trichloroacetaldehyde (chloral, Clo). Due to its structural analogy to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1), TaClo is discussed to possibly contribute to the pathogenesis of Parkinson's disease acting as an environmental toxin. Previous investigations on rats and neuronal cell cultures revealed 2 to be capable of inducing severe disturbances on the dopamine metabolism. In this paper, we report on the effects of 2 on the activity of tyrosine hydroxylase [L-tyrosine, tetrayhydropteridine/oxygen oxidoreductase (3-hydroxylating), EC 1.14,16.2; TH] in vitro using rat brain homogenates prepared from the TH-rich nucleus accumbens. TaClo (2) dose-dependently inhibited basal TH activity (IC(50)=3 microM), and after enzyme activation by pituitary adenylate cyclase-activating polypeptide (PACAP-27), it also reduced L-DOPA formation (IC(50)=15 microM). Moreover, two presumable TaClo metabolites, 2-methyl-TaClo (N-Me-TaClo, 3) and 1-dichloromethylene-1,2,3,4-tetrahydro-beta-carboline (1-CCl(2)-TH beta C, 4), which were synthesized in good yields, also proved to be potent inhibitors of TH, with the strongest effect on basal activity (similar to TaClo) being observed for 3 (IC(50)=3 microM). In contrast to TaClo, however, 3 and 4 showed biphasic effects after TH activation with PACAP-27, inducing a marked increase of enzyme activity in the nanomolar range (<0.1 microM), while TH activity was nearly completely blocked at high concentrations (IC(100)=0.1mM). An X-ray diffraction investigation on the 3-dimensional structure of the 1-CCl(2)-TH beta C-derived trifluoroacetamide 7 revealed the voluminous and quite rigid dichloromethylene substituent to be only moderately twisted out of the beta-carboline ring 'plane', thus resulting in an increased ring strain of the partially hydrogenated pyrido moiety accompanied by a strong steric hindrance of Cl(1), Cl(2), C(13), and N(2), which pushes the N-trifluoroacetyl group upwards to an even higher extent than for the TaClo-related trifluoroacetamide 8.

Animals↗

PubMed2002

Modification of tyrosine hydroxylase activity by chloral derived beta-carbolines in vitro.

Beta-carbolines have been suggested to be involved in the pathogenesis of Parkinson's disease as a result of their structural similarity to the neurotoxin N -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The chloral-derived beta-carboline derivative 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) causes cell loss in neuronal and glial cell cultures and induces a slowly developing neurodegenerative process in rats. In our experiments, effects of TaClo and its derivatives 2-methyl-TaClo (2-Me-TaClo), and 1-dichloromethylene-1,2,3,4-tetrahydro-beta-carboline (1-CCl(2) -THbetaC) on tyrosine hydroxylase (TH) activity were investigated in TH assays using homogenate preparations of the rat nucleus accumbens and recombinant human TH (hTH1). TH activity was determined in vitro by measuring l-DOPA production with HPLC-ECD. Using homogenate preparations, TaClo, 2-Me-TaClo, and 1-CCl(2) -THbetaC inhibited TH in concentrations of 0.1 mm, while 1-CCl(2) -THbetaC in low concentrations enhanced TH activity. When TH was activated by PACAP-27, TaClo, 2-Me-TaClo, or 1-CCl(2) -THbetaC also inhibited activated enzyme activity in high concentrations. However, in the case of 2-Me-TaClo and 1-CCl(2) -THbetaC a biphasic effect was observed with a marked increase of TH activity in the nanomolar range. In our experiments using recombinant hTH1, TaClo, 2-Me-TaClo, or 1-CCl(2) -THbetaC did not modify enzyme activity. After activation of hTH1 by PKA all the tetrahydro-beta-carbolines investigated in this study decreased l-DOPA formation. We suggest that these beta-carbolines modulate dopamine synthesis by interacting with a protein kinase TH-activating system.

Animals↗