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Biomedical subjects

R N Adams

Publications and source records attributed to R N Adams.

At least 19 recordsLinked to original sources
PubMed1992

In vivo voltammetric evidence for the detection of norepinephrine release in the thalamus of freely moving rats.

The ventrobasal complex (VB) of the thalamus was monitored in awake rats for the presence of norepinephrine (NE) overflow following pharmacological manipulations and physiological stimulation. Overflow was detected using chronoamperometry with electrochemically pretreated, Nafion-coated carbon fiber microelectrodes. In vivo evaluation of the electrode responses to systemic drug administration showed that alpha-methyl-p-tyrosine (alpha-MPT) and FLA-63 caused decreases in baseline current. Increases in baseline current in the VB were observed in animals treated with pargyline, yohimbine and yohimbine injected 2 h postpargyline. The results suggest that an electrochemical signal primarily due to NE overflow can be monitored in thalamic regions. Vigorous somatosensory stimulation induced small, long-lasting (approximately 30 min), reproducible electrochemical signals in the VB which were suppressed by alpha-MPT or FLA-63. These studies provide in vivo evidence which suggests that stressful somatosensory input to the VB initiates the release of NE.

Animals↗
PubMed1992

Electrochemical monitoring of brain ascorbic acid changes associated with hypoxia, spreading depression, and seizure activity.

In vivo electrochemistry has been a valuable tool in detecting real time neurochemical changes in extracellular fluid. Absolute selectivity has been difficult to achieve previously, but we report here a carbon fiber electrode and measurement technique which is specific for one oxidizable species: ascorbic acid. Ascorbic acid is highly concentrated in extra- as well as intracellular brain spaces, and appears to undergo dynamic changes in response to a variety of physiological and pathophysiological circumstances. Recent studies have implicated glutamatergic mechanisms which give rise to extracellular changes in brain ascorbate, and we confirm and extend these observations. Preliminary studies, directed towards examining ascorbic acid as an index and/or result of hypoxia, spreading depression, and seizure activity, have been undertaken and the results are reported herein.

Animals↗
PubMed1992

Intracerebral infusion of DOPAC decreases striatal dopamine.

The purpose of this study was to determine whether elevated levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the major metabolite of dopamine (DA) in the brain, could decrease the DA content in the striatum. Levels of DA were determined by high pressure liquid chromatography with electrochemical detection (HPLC-EC) in the striatum of male rats 24 h following a single intracerebral administration of DOPAC into the right striatum. DOPAC at 16.8 micrograms reduced the DA content of the infused side by 17%, p = 0.01. In contrast, infusion of 1.68 micrograms of DOPAC or the vehicle had no effect on striatal DA levels. Coapplication of the antioxidant, ascorbic acid, at 0.2 mg/ml with 16.8 micrograms of DOPAC prevented the decrease in DA content. Furthermore, infusion of 18.2 micrograms of homovanillic acid (HVA), the product of DOPAC methylation, had no effect on striatal DA. These results indicate that DOPAC may undergo autoxidation in vivo to produce neurotoxic species which may result in reduction of striatal DA. Formation of such an autoxidation product(s) of endogenous DOPAC was verified in the extracellular fluid of striatal slices in vitro.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Neuroleptic treatment is an unlikely cause of elevated dopamine in thalamus of schizophrenic subjects.

Previous studies have indicated a marked increase in the dopamine/norepinephrine ratio in thalami of schizophrenic patients compared with those of control subjects. Since these results all came from patients who were receiving neuroleptic drugs, the possibility exists that the increased dopamine concentrations are an effect of medication. To address this question, similar analyses were done on thalami from Huntington's Disease patients who had received neuroleptic treatment. The results showed no differences between the thalami of Huntington's Disease patients and controls, strongly suggesting that chronic treatment with neuroleptic drugs does not result in an increase of endogenous dopamine in the thalami of human subjects.

Adult↗
PubMed1991

The pharmacological profile of glutamate-evoked ascorbic acid efflux measured by in vivo electrochemistry.

A recently described in vivo voltammetric electrode selectively records rapid changes in extracellular fluid (ECF) levels of ascorbic acid. Using this detector, the nature of glutamate-induced efflux of ascorbate into ECF was investigated using pharmacological tools. Ascorbate signals were shown to be directly related to amounts of microinjected glutamate. Blockers of glutamate reuptake, homocysteic acid and D,L-threo-beta-hydroxy-aspartic acid, virtually eliminate the ascorbate signal. A more specific reuptake blocker (the stilbene isothiocyano derivative (SITS) does not completely inhibit ascorbate efflux, suggesting that the glutamate uptake which is coupled to ascorbic acid exchange is both neuronal and glial in nature. Other pharmacological experiments indicate that excitatory amino acid receptors are not involved in the glutamate-elicited ascorbate efflux; it is primarily a function of the glutamate/ascorbate heteroexchange process as described earlier. The possible role(s) of brain ascorbate in the general functioning of the pervasive glutamate neurotransmitter systems are discussed.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1991

Antioxidants prevent the interaction of 3,4-dihydroxyphenylacetic acid at the dopamine D2 receptor.

Antioxidants such as ascorbic acid (AA) and dithiothreitol (DTT), can prevent 3,4-dihydroxyphenylacetic acid (DOPAC) inhibition of [3H]spiperone binding to neuronal dopamine D2 receptors. The DOPAC quinone produced from auto-oxidation is believed to be responsible for the irreversible inhibition noted. Quinone conjugation to proteins occurs readily in vivo, and thus, auto-oxidation of DOPAC and other endogenous catechol containing compounds could be an important component of protein modification during on-going neuronal physiology.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Dynamic changes in extracellular fluid ascorbic acid monitored by in vivo electrochemistry.

Voltammetric carbon fiber electrodes and a measuring protocol were designed to monitor extracellular changes in rat brain ascorbic acid (AA). Very fast variations of AA (less than 60 s in duration) as well as much slower changes can be followed. Basal and stimulated levels of AA, determined with the enzyme ascorbate oxidase (AAO), confirm the detection is selective for AA. Microinjections of glutamate (Glu) into various brain regions gave rise to rapid electrochemical signals ascribed to the efflux of AA into the extracellular fluid.

Animals↗
PubMed1991

Simultaneous high-performance liquid chromatographic determination of ascorbic acid and dehydroascorbic acid in biological samples.

The ascorbic acid (AA)-dehydroascorbic acid redox couple is an important component of many biological systems, and various physiological roles have been described for this vitamin. Simultaneous measurement of both AA and dehydroascorbate using high-performance liquid chromatography (HPLC) has proven difficult owing to detection problems. A simple, single-step HPLC assay for the simultaneous detection of both AA and dehydroascorbate was developed without the burden of derivatization of either compounds. This has proven to be a reliable technique and should be applicable to a wide variety of biological samples.

Animals↗
PubMed1990

Effect of L-glutamate on the release of striatal dopamine: in vivo dialysis and electrochemical studies.

Microdialysis and in vivo voltammetry combined with K(+)-selective microelectrodes were utilized to study the effect of L-glutamate (GLU) on the in vivo release of dopamine (DA) from the rat striatum. Perfusion of 500 nM-5 mM GLU through the microdialysis probe was without an effect on DA outflow whereas 10 mM GLU resulted in a significant (295%) increase in the basal level of DA. This increase was blocked in the presence of 2-amino-5-phosphonopentanoic acid, an N-Methyl-D-aspartate (NMDA) receptor antagonist. Repetitive local applications of 10 mM GLU were also required to observe an increase in extracellular DA measured by in vivo voltammetry. These signals were accompanied with a massive increase in extracellular K+ and a large negative shift in the field potential resembling the ionic changes seen after the phenomenon spreading depression. These studies suggest that high concentrations of GLU are required to enhance the extracellular concentration of DA in vivo. Further, pathophysiological conditions such as spreading depression may be responsible for the observed increase in extracellular DA concentration.

Animals↗
PubMed1990

Rapid chemical sampling of endogenous species from brain slice preparations.

A very simple method of chemical sampling from the surface of brain slices is described. This procedure utilizing micropipets involves no sample dilution, and thus has very high sensitivity. Basal and stimulated concentrations of neurotransmitters and their metabolites are sampled from a thin fluid layer on the slice surface and appear to be in mobile equilibrium with the brain slice extracellular fluid levels. Rapid sampling allows one to follow the time course of stimulated release and reuptake phenomena.

Amino Acids↗
PubMed1989

Patterns of serum IgM antibodies to GM1 and GD1a gangliosides in amyotrophic lateral sclerosis.

We studied the incidence and clinical correlates of serum antibodies to GM1 and GD1a gangliosides in patients with classical amyotrophic lateral sclerosis (ALS) and other "motor nerve" syndromes. Serum antibodies to GM1 and GD1a gangliosides were measured using enzyme-linked immunosorbent assays. Our results showed that polyclonal immunoglobulin M (IgM) antibodies to the GM1 or GD1a ganglioside or both were present at serum dilutions of 1:25 to 1:4,000 in 78% (57/73) of patients with ALS. Only 8% of normal controls had similar antibodies. The pattern of serum antibody reactivity correlated with the pattern of clinical involvement in our patients. Selective reactivity to GD1a ganglioside was common when upper motor neuron signs were prominent. IgM reactivity to GM1 ganglioside was common in ALS patients with prominent lower motor neuron signs. Most patients with motor neuropathies had serum reactivity to both GM1 and GD1a gangliosides. These results provide further evidence of ongoing autoimmune processes in ALS patients. There is a strong relationship between serum antiganglioside antibodies and patterns of clinical involvement in ALS.

Adult↗
PubMed1989

Differential effects of prednisone and cyclophosphamide on autoantibodies in human neuromuscular disorders.

We compared the effects of treatment of patients with prednisone or cyclophosphamide on a series of different types of autoantibodies. Levels of antiacetylcholine receptor (anti-AChR) antibodies and of antibodies to GM1 and GD1a gangliosides were measured in patients with a variety of neuromuscular disorders before and after treatment. Most patients had several autoantibodies present. We showed that prednisone treatment resulted in a reduction in titers of anti-AChR but not antiganglioside antibodies. Cyclophosphamide treatment produced a reduction of antiganglioside antibody titers. An intravenous and oral regimen was more effective than a single intravenous course of cyclophosphamide. We conclude that an immunosuppressive medication such as prednisone may reduce levels of some autoantibodies while producing no change in others, even in an individual patient. In addition, cyclophosphamide can suppress autoantibodies that prednisone does not. These differences in immunopharmacologic responses suggest that there are several distinct mechanisms of autoantibody production in humans. The utility of immunosuppressive medications in specific disease processes may be related in part to the mechanism of production of pathogenic antibodies.

Autoantibodies↗
PubMed1988

Spreading depression induced by 100 mM KCl in caudate is blocked by local anesthesia of the substantia nigra.

Pressure-ejection of 100 mM KCl was used to induce voltammetric signals in the rat caudate. The signals, detected chronoamperometrically with Nafion-coated carbon fiber microelectrodes, were reproducibly generated at 20-min intervals up to distances of 1600 micron from the KCl stimulus site. Unilateral 6-hydroxydopamine lesions of the substantia nigra (SN) demonstrated that over 90% of the voltammetric signal generated was dopamine. Evaluation of the signal onset at two widely spaced electrodes suggested that injection of nl volumes of 100 mM KCl into the rat caudate generates voltammetric signals which resemble spreading depression (SD) produced by more classical methods (e.g. 1 M KCl). We further investigated this phenomenon by simultaneous evaluation of extracellular K+ ion concentration changes, field potential (FP) and voltammetric signals or multiunit activity following stimulation with 100 mM or 1 M KCl. The results show that the signals generated by 100 mM KCl have many of the attributes of 'classical' SD, although the extracellular K+ ion concentration changes and FP changes were smaller in magnitude. However, the characteristic burst of multiunit activity followed by a marked quiescent period found during 1 M KCl stimulation was not observed with 100 mM KCl stimulation. Furthermore, application of 0.5% lidocaine to the SN reversibly blocked all signals generated by 100 mM KCl in the caudate while similar treatment with up to 2% lidocaine was ineffective when 1 M KCl was used as the stimulus. The results suggest that the signals generated by 100 mM KCl may represent an attenuated form of SD which requires a functioning SN, and that this stimulation could be a useful model for studying neurotransmitter interactions in the propagation of the SD phenomena.

Action Potentials↗
PubMed1988

Studies on the ionic mechanism for the neuromodulatory actions of adenosine in the brain.

Although much evidence exists to support the modulation of neurotransmitter release by adenosine in both the central and peripheral nervous systems, the ionic mechanisms involved in this process are still not established. In our initial series of studies, the effects of adenosine analogs on depolarization-induced 45Ca influx into synaptosomes were examined, but no reduction in 45Ca uptake was observed in the presence of these agents, regardless of whether synaptosomes were depolarized by KCl or veratridine. The possibility that synaptosomal adenosine receptors are coupled directly to K+ channels and that an increase in K+ conductance is the primary ionic event initiated by adenosine was examined in resealed synaptic plasma membranes. We followed the movement of K+ through the use of the labeled lipophilic anion [35S]thiocyanate [( 35S]SCN-), which distributes across membranes according to the existing membrane potential. Both 2-chloroadenosine and adenosine-5'-cyclopropyl carboxamide produced dose-dependent increases in SCN- uptake, indicating enhanced K+ fluxes across the synaptic membranes. These effects of adenosine receptor agonists on membrane K+ conductance were blocked by receptor antagonists such as isobutylmethylxanthine. In addition, the placement of a K+-selective microelectrode in the caudate nuclei of intact, anesthetized rats revealed a substantial increase in the extracellular K+ concentration when adenosine was released onto the cells from a pipet in the assembly containing the ion-selective microelectrode. The results of these studies at both the membrane level and in the intact brain suggest that the initial event in the neuromodulatory actions of adenosine is an increase in the membrane conductance for K+ rather than inhibition of the voltage sensitive Ca2+ channels.

1-Methyl-3-isobutylxanthine↗
PubMed1988

A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside.

We report 2 patients with a treatable, immune-mediated motor polyneuropathy associated with antibodies to defined neural antigens. In these patients asymmetrical weakness developed in one arm and progressed over 2 to 3 years to involve the other arm, legs, and trunk. Both patients were initially diagnosed as having lower motor neuron forms of amyotrophic lateral sclerosis. However, repeated electrophysiological testing eventually showed multifocal conduction blocks in motor but not sensory fibers compatible with patchy selective demyelination. Serum testing by thin-layer chromatography and enzyme-linked immunosorbent assay revealed that both patients had high titers of antibody directed against GM1 and other gangliosides. Initial therapeutic trials of prednisone (100 mg daily for 4 to 6 months) and plasmapheresis were unsuccessful. Treatment with cyclophosphamide, however, was followed by marked improvement in strength in both patients.

Adult↗
PubMed1988

Serum antibodies to GM1 ganglioside in amyotrophic lateral sclerosis.

We report the presence of serum antibodies directed against GM1 ganglioside, a defined neural antigen, in many patients with amyotrophic lateral sclerosis (ALS). We examined serum from a series of patients with well-documented clinical diagnoses. Serum antibodies to GM1 ganglioside were measured using ELISA assays. Our results showed that polyclonal IgM anti-GM1 antibodies were present at dilutions of 1:25 to 1:2,000 in 42 of 74 (57%) patients with ALS. The anti-GM1 antibodies were especially frequent in patients with prominent lower motor neuron signs (41/59; 69%). Few normal controls (2/23) and motor-sensory neuropathy patients (3/27) had similar antibodies. Anti-GM1 antibodies did occur in patients with nonneural autoimmune disorders. However, the anti-GM1 antibodies in these patients tended to differ from those in ALS based on an analysis of their light chain types. Further examination of the role and spectrum of serum antiganglioside antibody activity in motor neuron syndromes is warranted.

Adult↗