PubMed Health⌕ Search

Biomedical subjects

R M Wightman

Publications and source records attributed to R M Wightman.

At least 127 records · Page 7Linked to original sources
PubMed1987

Dopaminergic neurons: simultaneous measurements of dopamine release and single-unit activity during stimulation of the medial forebrain bundle.

Simultaneous electrical and chemical recordings have been made of dopamine neuronal activity in the rat brain during electrical stimulation of the medial forebrain bundle. Tungsten recording electrodes were placed at the level of the substantia nigra and carbon-fiber, Nafion-coated, voltammetric electrodes were placed in the neostriatum. Dopamine units, verified by histology to be in the zona compacta of the substantia nigra, were identified by previously established electrophysiological criteria. Dopamine release was detected by fast-scan cyclic voltammetry, a technique which allows dopamine to be determined in vivo on a sub-second time scale. The majority of dopamine cells examined (7 out of 10) were antidromically activated by 60 Hz stimulation of the medial forebrain bundle. The same stimulus also elicits dopamine overflow in the caudate nucleus. Following stimulation, dopamine concentrations in the extracellular fluid of the neostriatum rapidly declined to prestimulus levels. In addition, impulse flow in dopaminergic neurons was inhibited for 20 s following stimulation. These measurements represent the first direct observation from a neuronal tract of simultaneous unit activity and chemical release of a neurotransmitter in real time.

Action Potentials↗
PubMed1986

Unilateral, intranigral infusions of amphetamine produce differential, bilateral changes in unit activity and extracellular levels of ascorbate in the neostriatum of the rat.

Simultaneous recordings of single-unit activity and oxidation current were obtained bilaterally from the neostriatum of rats in response to a unilateral infusion of D-amphetamine (2.0 microliters of 10 micrograms/microliter) into the substantia nigra. Whereas neuronal activity increases ipsilaterally and decreases contralaterally, the electrochemical signals, which reflect extracellular ascorbate, increase bilaterally. In each case, changes in unit activity precede the change in ascorbate release. Systemic administration of haloperidol (0.2 mg/kg) blocks the increase in oxidation current bilaterally, but reverses the neuronal activity response only on the ipsilateral side. These results lend further support to the view that intranigral amphetamine facilitates neostriatal ascorbate release, but this effect is not correlated with changes in single-unit activity.

Animals↗
PubMed1986

Real-time measurement of dopamine release in rat brain.

Dopamine release at the submicromolar level has been observed in the striatum of an anesthetized rat on a millisecond time scale. Fast-scan cyclic voltammetry with Nafion-coated microelectrodes has been synchronized with electrical stimulation of the medial forebrain bundle, and synaptic overflow is observed following a burst of 15 impulses. The rapid appearance of dopamine following this stimulus indicates that the source of dopamine is very close (approximately 10 micron) to the electrode. The rapid disappearance of released dopamine reflects the potency of cellular uptake for dopamine. Inhibition of dopamine uptake with nomifensine allows the measurement of dopamine overflow as a result of a single stimulus impulse or with low-frequency stimulations, both comparable to physiological dopaminergic impulse flow.

Animals↗
PubMed1986

Crus cerebri lesions abolish amphetamine-induced ascorbate release in the rat neostriatum.

An increase in the concentration of ascorbate in the extracellular fluid of the rat striatum following systemic amphetamine administration previously has been demonstrated with the use of in vivo electrochemistry, push-pull cannula and in vivo dialysis. In this report, the effect of infusions of amphetamine into the substantia nigra on extracellular ascorbate levels in the striatum is further investigated by in vivo electrochemistry. Electrolytic lesions in the crus cerebri of the striatonigral pathway abolish this effect. Furthermore, these lesions abolish the effect of systemic amphetamine in the striatum ipsilateral to the lesion but not on the contralateral side. This phenomenon is independent of neostriatal dopamine or gamma-aminobutyric acid since levels were shown to be unchanged relative to the intact side. These results lend further support to the hypothesis that ascorbate secretion in the striatum after amphetamine is mediated in the central nervous system, and indicate that a pathway that courses through the crus cerebri is necessary for this release.

Amphetamine↗
PubMed1986

In vivo comparison of the regulation of releasable dopamine in the caudate nucleus and the nucleus accumbens of the rat brain.

In vivo voltammetry has been used to measure the release of dopamine evoked by electrical stimulation of the medial forebrain bundle (MFB). Simultaneous measurements have been made with voltammetric-sensing electrodes ipsilateral to the stimulating electrode in the nucleus accumbens and the caudate nucleus of the anesthetized rat. During the stimulation, the species observed in both regions is voltammetrically identical to dopamine. Further evidence for the identity of dopamine is provided by anatomical, physiological, pharmacological, and postmortem data. Postmortem analysis of these brain regions after a single stimulation demonstrates that dopamine levels are unchanged, while dihydroxyphenylacetic acid (DOPAC) levels are increased in both regions. Systemic application of synthesis inhibitors results in a decrease in evoked release for each brain region. Amfonelic acid results in a restoration of stimulated release after synthesis inhibition. Evoked release is affected differently by pargyline in the two brain regions. The evoked release of dopamine is significantly elevated in the nucleus accumbens as a result of pargyline administration, but similar effects are not seen in the caudate nucleus. Tissue levels of dopamine are increased in both brain regions by pargyline, but the increase is significantly greater in the accumbens. Electrolytic lesions of the striatonigral pathway or systemic administration of picrotoxin eliminates the pargyline-induced difference in evoked release of dopamine. Amphetamine causes a reduction in stimulated release in the caudate nucleus with little effect on that observed in the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Modulation of neostriatal activity by iontophoresis of ascorbic acid.

Iontophoresis (20-80 nA) of ascorbic acid (AA) accelerated the firing rate of approximately one-third of the neurons tested in the anteromedial neostriatum of anesthetized rats. When administered to neostriatal neurons that were activated by the simultaneous ejection of glutamic acid (GLU), AA excited more than two-thirds of the cells examined, including many that were not excited by AA alone. At ejection currents above 80 nA, AA further increased the activity of some GLU-activated neurons, but suppressed the firing rate of others. Electrochemical quantification of AA ejection during iontophoresis indicated that the concentration of AA at the tip of the recording electrode was within reasonable physiological limits. It is concluded that endogenous AA may modulate neuronal activity in the neostriatum.

Animals↗
PubMed1985

Systemic and nigral application of amphetamine both cause an increase in extracellular concentration of ascorbate in the caudate nucleus of the rat.

Unmodified microvoltammetric electrodes and electrochemically modified cylindrical electrodes, both constructed from carbon fibers, were used to determine changes in ascorbate concentration in the caudate nucleus of the anesthetized rat following administration of amphetamine. The increased ascorbate levels with systemic amphetamine originate from a CNS source, since the response is not eliminated in adrenalectomized animals, and does not occur when p-hydroxyamphetamine, an agent with peripheral actions similar to amphetamine, is used as a stimulus. Local application of amphetamine in the caudate nucleus results in an increase in catechols. However, this procedure results in a decrease of the extracellular concentration of ascorbate. Unilateral nigral infusion of dopamine or amphetamine leads to a significant increase in the concentrations of ascorbate detected bilaterally in the caudate nuclei with in vivo electrochemistry. In contrast, the paradigm causes a decrease in extracellular catechols on the ipsilateral side and an increase on the contralateral side. These experiments demonstrate that the extracellular level of ascorbate is not correlated with dopamine secretion. Furthermore, the data show that the action of amphetamine on ascorbate concentration in the caudate nucleus is in part mediated by the nigral actions of amphetamine.

Adrenal Glands↗
PubMed1985

Electrochemical, pharmacological and electrophysiological evidence of rapid dopamine release and removal in the rat caudate nucleus following electrical stimulation of the median forebrain bundle.

Fast cyclic voltammetry was used to monitor the release of electroactive material in the striatum following electrical stimulation of the median forebrain bundle. The released material was shown to be dopamine by electrochemical, pharmacological and neurophysiological means. The material gave a voltammogram identical to that of iontophoretically applied dopamine but not DOPAC. Release was increased by L-DOPA, the metabolic precursor of dopamine. NSD 1015, an inhibitor of dopa decarboxylase, and alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor decreased release. Reserpine, which disrupts vesicular dopamine storage, abolished release. Parachlorophenylalanine, a tryptophan hydroxylase inhibitor, had no effect. Finally, square wave stimulation was only effective when pulses longer than 0.5 ms were used. This indicated stimulation of very fine unmyelinated fibres, consistent with the known morphology of nigrostriatal dopamine fibres.

Animals↗
PubMed1985

Comparison of release of endogenous dopamine and gamma-aminobutyric acid from rat caudate synaptosomes.

Release of endogenous dopamine (DA) and gamma-aminobutyric acid (GABA) from superfused rat caudate synaptosomes was monitored with liquid chromatography with electrochemical detection. Dopamine was analyzed by oxidative detection following alumina extraction while GABA was analyzed with reductive detection following pre-column derivatization with trinitrobenzenesulfonic acid and extraction. Both spontaneous and K+-stimulated (40 mM) release were examined as well as the effect of several possible neuromodulatory agents (DA, GABA, muscimol, ascorbic acid, acetylcholine). The content of GABA in the sample and the amount released by K+ were approximately fifty times those of DA although the relative amounts released by repetitive K+ stimulations were similar. Muscimol and DA significantly attenuated both the spontaneous and stimulated release of GABA while ascorbate and acetylcholine had no effect. Acetylcholine significantly increased both the stimulated and spontaneous release of DA while the other agents had no effect. Dopamine showed an absolute dependence on calcium for stimulated release while GABA exhibited a significant calcium-independent release. These results indicate that profound differences exist in the factors which modulate the release of endogenous DA and GABA.

Acetylcholine↗
PubMed1985

Amphetamine attenuates the stimulated release of dopamine in vivo.

Carbon-fiber voltammetric electrodes have been used to measure the release of dopamine in the caudate nucleus of an anesthetized rat. Release is induced by electrical stimulation of the medial forebrain bundle. The amplitude of the observed release is attenuated by i.p. injection of amphetamine. A similar attenuation is induced by reserpine; however, at a slower rate. The combined regimen of amphetamine (1 or 10 mg/kg) and electrical stimulation does not deplete striatal dopamine levels and thus the decreased release of dopamine is not a result of depleted dopamine stores. Benztropine (25 mg kg-1) is able to cause a short term inhibition of the action of amphetamine (1 mg kg-1). The dopamine agonist pergolide (0.5 mg kg-1) does not affect the stimulated release. Haloperidol (1.0 mg kg-1) increases the amount of DA release, but is unable to attenuate the inhibition caused by amphetamine. Thus, it appears that the actions induced by amphetamine are a result of interaction with the neuronal uptake carrier and subsequent transport of dopamine from a functional to nonfunctional pool. In isolated striatal synaptic vesicles, amphetamine is found to block dopamine uptake and induce its release. This in vitro evidence provides a possible mechanism for the observed in vivo actions of amphetamine.

Animals↗
PubMed1984

Striatal dopamine uptake in the rat: in vivo analysis by fast cyclic voltammetry.

Electrical stimulation of the median forebrain bundle of the chloral hydrate anaesthetised rat evoked dopamine release in the ipsilateral striatum, which was monitored with fast cyclic voltammetry. On cessation of stimulation, the extracellular concentration of dopamine fell to sub-detectable levels over a period of about 15 s. This fall appeared to be due to a saturable, low affinity uptake system that could be inhibited by nomifensine (20 mg/kg i.p.). These experiments constitute the first characterisation of a dopamine uptake mechanism obtained in the intact animal.

Animals↗
PubMed1984

In vitro comparison of the selectivity of electrodes for in vivo electrochemistry.

The properties of 4 types of carbon electrodes designed for use as in vivo sensors of easily oxidized species in the mammalian brain have been evaluated in aqueous solutions at physiological pH. The electrodes are formed from a graphite-epoxy mixture, carbon paste, or carbon fibers, and have the geometries of a disk or a cylinder. The voltammetric properties of several catecholamines, some of their metabolites and precursors, uric acid, and ascorbic acid are reported at unmodified carbon surfaces. The problem of overlap of the voltammetric waves of ascorbate and catechols is addressed, and two different methods which minimize this problem are examined. These are the use of disk-shaped electrodes fabricated from carbon fibers, which facilitate the use of subtracted voltammograms to determine small changes in the concentration of catecholamines in the presence of ascorbic acid, and the use of electrochemically modified, cylindrically-shaped electrodes also fabricated from carbon fibers. Voltammetry at the modified electrodes gives evidence the catechols can be resolved from ascorbate, and that catechols, but not ascorbic acid, adsorb to the electrode surface.

Animals↗
PubMed1984

Monitoring the stimulated release of dopamine with in vivo voltammetry. I: Characterization of the response observed in the caudate nucleus of the rat.

Microvoltammetric electrodes were employed in the brain of an anesthetized rat to monitor chemical substances in extracellular fluid following electrical stimulation of the medial forebrain bundle. An increase in concentration of an easily oxidized substance is observed in the caudate nucleus and in the nucleus accumbens. A large amount of evidence suggests that the substance that is observed following stimulation is dopamine. (1) The location of the stimulating electrode must be in known dopaminergic tracts to induce release. (2) Release is most easily observed in brain regions that contain significant numbers of dopamine-containing neurons. (3) Two voltammetric electrodes with very different electrochemical responses provide voltammograms of the released species that are unique for catechols in one case and catecholamines in another case. (4) The amount of 3,4-dihydroxyphenylacetic acid found in striatal tissue by postmortem analysis correlates with the calculated amount of dopamine released. (5) Inhibition of tyrosine hydroxylase, and thus dopamine synthesis, decreases the observed release while inhibition of monoamine oxidase, and thus formation of dopamine metabolites, does not. (6) The dependence of release on stimulation parameters agrees with results obtained with perfusion techniques. Thus, a new method has been developed to characterize endogenous dopamine release in the rat brain and can be used on a time scale of seconds.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Monitoring the stimulated release of dopamine with in vivo voltammetry. II: Clearance of released dopamine from extracellular fluid.

Microvoltammetric electrodes implanted in the caudate nucleus of the anesthetized rat have been used to monitor dopamine released following electrical stimulation of the medial forebrain bundle. These electrodes are fabricated from unmodified carbon fibers and have been used with normal pulse voltammetry. Dopamine appears in the vicinity of the electrode when the stimulation is initiated, and disappears almost immediately when the stimulation is terminated. The data suggest that the effective diffusion distance is less than 100 micron. Postmortem analysis using liquid chromatography with electrochemical detection shows that dopamine released in this manner is metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC); however, neither substance is observed electrochemically in the extracellular fluid within seconds after the stimulation. In addition, inhibitors of neuronal uptake of dopamine, amphetamine (1.8 or 15 mg X kg-1) or benztropine (25 mg X kg-1), or of dopamine metabolism, pargyline (150 mg X kg-1) or tropolone (100 mg X kg-1), do not significantly affect the rate at which dopamine disappears from extracellular fluid, although they can affect the amount released. These results suggest that dopamine cannot freely diffuse in the extracellular fluid because an extraneuronal uptake mechanism exists that clears dopamine from extracellular fluid into an extraneuronal pool where metabolism to 3,4-dihydroxyphenylacetic acid occurs. Dopamine can be observed during electrical stimulation of the ascending fibers because neuronal and extraneuronal uptake systems are unable to remove dopamine on these short time scales.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Gamma-aminobutyric acid stimulates the release of endogenous ascorbic acid from rat striatal tissue.

Gamma-aminobutyric acid (GABA) was found to induce the release of ascorbic acid from rat striatal homogenates and minces. This release was studied with the use of a rapid superfusion system with an on-line amperometric detector that monitors for the presence of easily oxidized substances (i.e., ascorbate, 3,4-dihydroxyphenylethylamine). The release was found to be calcium-independent and depolarization-dependent. This releasable pool of ascorbate could be replenished through nonstereospecific uptake. The releasing action of GABA was mimicked by the GABA agonist, muscimol, and was completely inhibited by the GABA antagonist, picrotoxin. The structural analogues of GABA, beta-alanine and gamma-hydroxybutyric acid, had no effect. These data indicate that ascorbate release is GABA-receptor mediated and synaptically localized.

Animals↗