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Biomedical subjects

J R Walters

Publications and source records attributed to J R Walters.

At least 127 records · Page 7Linked to original sources
PubMed1981

Single unit responses of substantia nigra and globus pallidus neurons to GABA agonist and antagonist drugs.

The studies reported here shed some new light upon the role of GABA within the basal ganglia. Although the proposed inhibitory interaction between the striatonigral GABA pathway and nigral dopamine neurons has, over the years, received the greatest attention, it now appears that this interaction may constitute only one part of a more extensive and perhaps more physiologically significant network of GABA-mediated effects upon populations of non-dopaminergic neurons. Specifically, evidence has been presented which indicates that the substantia nigra pars reticulata and the globus pallidus, two regions known to receive striatal GABAergic fibers, each contain groups of cells with a more marked ability to be affected by GABA and GABAmimetic drugs than the nigrostriatal dopamine neurons. Since reticulata and pallidal neurons seem at least as likely as dopamine neurons to be targets of this striatal GABAergic pathway, a much more expanded role for GABA within the basal ganglia might now be explored. Given their marked sensitivities to GABA, if reticulata and pallidal cells do lie postsynaptic to GABA terminals then function in several motor-related areas to which these cells project might be greatly affected by striatal and pallidal GABAergic efferents. Future studies aimed at elucidating the nature and importance of these GABA-mediated interactions may ultimately provide new clues about how the basal ganglia influence motor function.

Animals↗
PubMed1980

Intravenous GABA agonist administration stimulates firing of A10 dopaminergic neurons.

Increasing intravenous doses of two gamma-aminobutyric acid (GABA) agonists, muscimol and 4,5,6,7-tetrahydroisoxazolo-[5,4-c]-pyridin-3-ol (THIP), caused dose-related increases in extracellular, single unit activity of A10 dopaminergic neurons of the ventral tegmental area. Muscimol, the more potent of the two compounds, stimulated firing at doses approximately 15-20 times lower than the doses of THIP required to elicit equivalent excitatory effects. The maximum stimulation achieved was approximately 150 and 140% of the baseline firing rate for muscimol and THIP, respectively.

Animals↗
PubMed1980

GABAergic actions of THIP in vivo and vitro: a comparison with muscimol and GABA.

GABAmimetic actions of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]-pyridin-3-ol (THIP) were evaluated both in vivo and in vitro and compared with the actions of muscimol and GABA. The GABAergic potencies of these agents were assessed in vivo by measuring their ability to inhibit firing of rat substantia nigra pars reticulata neurons after systemic administration and iontophoretic applications, and in vitro by measuring their ability to inhibit 3H-GABA binding to rat cerebellar membranes. The effects of THIP were found to be similar to those of muscimol and GABA with regard to inhibition of reticulata cell firing and 3H-GABA binding. The order of potency was muscimol > GABA > THIP. The magnitude of the differences between drug potencies in iontophoretic studies closely paralleled their relative potencies in binding studies, with muscimol approximately 3 times more potent than GABA and 25-40 times more potent than THIP. After systemic (i.v.) administration, however, muscimol was only 3 times more potent than THIP in inhibiting reticulata cell firing, possibly because THIP passes the blood-brain barrier more readily.

Animals↗
PubMed1980

Effects of muscimol and picrotoxin on single unit activity of substantia nigra neurons.

Intravenous administration of the GABA agonist, muscimol, caused dose-dependent increases in the unit activity of substantia nigra pars compacta (dopamine) neurons and an inhibition of nigral pars reticulata cells. The depressant effects of the drug upon reticulata neurons were reversible by subsequent administration of the GABA antagonists, picrotoxin and bicuculline HCl. However, the stimulatory effects of i.v. muscimol upon dopamine neurons were not abolished by these agents. Intravenous administration of picrotoxin alone caused only moderate increases in the activity of dopamine neurons (31% over baseline at 7.0 mg/kg), but markedly stimulated the firing of pars reticulata cells (154% over baseline at 7.0 mg/kg). In spite of the stimulation of dopamine neurons after i.v. muscimol, microiontophoresis of GABA and muscimol could inhibit the firing of both pars compacta and pars reticulata cells, although the reticulata neurons were much more sensitive to the inhibitory actions of these agents than the dopamine neurons. Considered together, these studies suggest that a population of neurons in the substantia nigra pars reticulata have the capacity to be more affected by a major GABA input to the nigra than the pars compacta dopamine neurons. The results further suggest that if the dopamine cells are regulated by GABAergic neurons of the striatonigral pathway, their regulation must be indirect and could involve a second inhibitory neuron within the nigra.

Animals↗
PubMed1979

Dopamine neurons: effect of lergotrile on unit activity and transmitter synthesis.

Intravenous administration of increasing doses of the ergoline, lergotrile mesylate, caused a rapid, dose-dependent and haloperidol-reversible inhibition of unit activity of dopamine cells in the pars compacta of the rat substantia nigra. 6 microgram/kg caused significant depression of dopamine cell firing rates; 50% inhibition was achieved with a cumulative dose of 100 microgram/kg. 60% of the cells were completely inhibited by increasing doses of the drug, the remainder became resistant to further inhibition after reaching rates 25--50% of baseline. Pretreatment with reserpine and alpha-methylparatyrosine did not significantly attenuate the lergotrile-induced inhibition. Lergotrile had no consistent effect on firing rates of cells in the pars reticulata of the substantia nigra. The ergoline reduced the apparent activation of striatal dopamine synthesis associated with complete cessation of impulse flow in nigral-striatal dopamine neurons induced by gamma-butyrolactone treatment. These effects are compared with those of apomorphine and amphetamine. The results are consistent with the idea that lergotrile is a direct acting dopamine agonist.

Action Potentials↗
PubMed1979

Synaptosomal uptake and release of dopamine in substantia nigra: effects of gamma-aminobutyric acid and substance P.

Nigral tissue prepared as synaptosomes demonstrates both high and low affinity uptake of [3H]dopamine. Recently accumulated [3H]dopamine is releasable by 35 mN K+. Substance P increases both uptake and release of dopamine by nigral synaptosomes; gamma-aminobutyric acid (GABA) inhibits release with no effect on uptake at concentrations less than 10-(4) M. In the striatum, substance P inhibits both uptake and release of dopamine. The results support the existence of dopamine-containing terminals in substantia nigra tissue. The differences in response to substance P and GABA found between nigra and striatum may reflect structural differences in dopamine-containing processes in these areas, related to their proposed origin as dendtritic (substantia nigra) and axonal (striatal) terminal.

Animals↗
PubMed1978

Dopaminergic neurons: effect of acute and chronic morphine administration on single cell activity and transmitter metabolism.

At various time points following acute and chronic administration of morphine to rats, dopamine transmitter metabolism and neuronal activity were determined. Following acute injection of morphine (20 mg/kg intraperitoneally), dopamine cell firing rates increased slowly and steadily. This slow increase was accompanied by a similar slow increase in the accumulation of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC). Apparent in vivo tyrosine hydroxylase activity, measured by dopa accumulation following inhibition of dopa decarboxylase, also increased. In chronically treated animals the average firing rate of dopamine cells was measured two hours after the last injection of morphine. The distribution of dopamine cell firing rates was significantly higher than in controls. DOPAC levels and in vivo tyrosine hydroxylase activity were also increased at this time. When morphine (100 mg/kg intraperitoneally) was administered to chronically treated animals 12 hours after the last injection a slow increase of firing rates was observed similar to that seen in naive animals after an acute morphine injection. In chronically morphine treated animals naloxone caused a rapid dose-dependent decrease in firing rates and DOPAC levels. In vivo tyrosine hydroxylase activity was not changed.

3,4-Dihydroxyphenylacetic Acid↗