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J R Walters

Publications and source records attributed to J R Walters.

At least 91 records · Page 5Linked to original sources
PubMed1988

Regulatory effects of Ca-binding proteins on the Ca-pump of rat intestinal basolateral membranes.

1. CaBP-9k affected Ca uptake by actions on both the apparent affinity of the pump for Ca and on the maximum Ca transport rate giving stimulation or inhibition at different Ca concentrations. 2. Ca uptake by vesicles prepared from a number of different sites was stimulated similarly. 3. Batches of CaBP that had been run on HPLC did not give the same results. 4. CaBP-28k increased Ca uptake by an effect on the ATP-independent binding of Ca. 5. The complex effects of CaBP-9k on the intestinal Ca-pump may be a method by which 1,25-dihydroxycholecalciferol controls the exit of Ca from the enterocyte during Ca absorption.

Animals↗
PubMed1987

D1 dopamine receptor activation required for postsynaptic expression of D2 agonist effects.

D1 and D2 dopamine receptors exert synergistic effects on the firing rates of basal ganglia neurons and on the expression of stereotyped behavior in rats. Moreover, the ability of D2 agonists to induce changes in basal ganglia single unit activity and spontaneous motor activity is dependent upon the presence of endogenous dopamine to stimulate D1 receptors; in rats treated with alpha-methyl-rho-tyrosine to reduce endogenous dopamine levels, the neurophysiological and behavioral effects of the D2 agonist quinpirole are significantly attenuated, while the effects of nonselective agonists like apomorphine, which stimulate both D1 and D2 receptors, or combinations of a D2 agonist and a D1 agonist are not attenuated. Thus, the previously held view that D2 receptors alone are responsible for evoking the changes in behavior and basal ganglia output induced by nonselective dopamine agonists and endogenous dopamine is not supported by these results, which indicate that these phenomena require concurrent stimulation of both dopamine receptor subtypes.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Effects of D1 and D2 dopamine receptor stimulation on the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats: D1/D2 coactivation induces potentiated responses.

Extracellular single unit recording techniques were used to compare the effects of selective and non-selective dopamine agonists on substantia nigra pars reticulata activity in rats with 6-hydroxydopamine induced lesions of the nigrostriatal dopamine pathway. As previously shown, apomorphine (0.32 mg/kg), a dopamine agonist that interacts with both D1 and D2 dopamine receptor subtypes, produced consistent inhibitions of substantia nigra pars reticulata activity in these animals. The D1-receptor agonist, SKF 38393 (RS-SKF 38393, 10 mg/kg), also induced significant inhibitions in the activity of these neurons in 6-hydroxydopamine lesioned rats, although less consistently than did apomorphine. The effects of SKF 38393 were reversed by the D1-antagonist, SCH 23390. The D2 selective agonist quinpirole was considerably less effective than apomorphine at inhibiting substantia nigra pars reticulata activity at doses up to 1 mg/kg. Since comparable experiments have shown that quinpirole is as effective as apomorphine at producing dopamine D2-autoreceptor-mediated effects on dopamine neuron activity, quinpirole's lack of efficacy in the present study relative to that of apomorphine does not appear to be related to differences in relative potency for central D2-receptors using this route of administration. Rather, the relative effectiveness of SKF 38393 on pars reticulata activity suggests that selective stimulation of D1-receptors is at least, if not more, efficacious than selective stimulation of D2-receptors at inducing alterations in the activity of substantia nigra pars reticulata neurons in 6-hydroxydopamine lesioned rats. The simultaneous stimulation of both receptors, however, was considerably more effective than selective stimulation of either receptor subtype: doses of SKF 38393 and quinpirole which had no significant effect on nigral activity when administered alone brought about marked inhibition of the firing of these cells when administered simultaneously. No such inhibition was seen when the inactive enantiomer, S-SKF 38393, was substituted for the racemic form of SKF 38393 in this protocol. These observations in 6-hydroxydopamine lesioned rats support other recent findings indicating that the two dopamine receptor subtypes can interact in a synergistic way to affect basal ganglia output.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Stimulation of both D1 and D2 dopamine receptors appears necessary for full expression of postsynaptic effects of dopamine agonists: a neurophysiological study.

The abilities of 4 dopamine agonists to inhibit the tonic single unit activity of substantia nigra dopamine neurons and stimulate tonic activity of globus pallidus neurons were compared to study the agonists' effects on pre- and postsynaptic dopamine receptors, respectively. The agonists studied were apomorphine and pergolide, which interact with both D1 and D2 receptors, and the selective D2 agonists quinpirole and RU 24926. Drugs were administered systemically. The 4 dopamine agonists were equipotent and equiefficacious at inhibiting the firing rates of dopamine neurons. In contrast, their effects on pallidal cells were not identical; apomorphine and pergolide induced significantly greater increases in pallidal cell activity than did quinpirole and RU 24926. In addition, pretreatment with a small dose of quinpirole did not attenuate the excitatory effect of apomorphine on globus pallidus cell activity, as low doses of apomorphine have previously been shown to do. Possible mechanisms underlying the differences in efficacy between the non-selective and D2 selective dopamine agonists in the globus pallidus were investigated. Coadministering quinpirole with apomorphine did not significantly attenuate the effect of apomorphine, suggesting that quinpirole is not a partial agonist at postsynaptic dopamine receptors. In addition, prazosin pretreatment did not attenuate the stimulatory effect of pergolide on firing rates of pallidal cells, indicating that the greater efficacy of the non-selective agonists was not due to concurrent stimulation of alpha 1 adrenergic receptors and dopamine receptors. However, the effect of quinpirole on pallidal cell activity was significantly potentiated by pretreatment with the D1 agonist RS-SKF 38393 but not its inactive enantiomer S-SKF 38393. These results suggest that concurrent D1 and D2 receptor stimulation may be necessary for the full expression of postsynaptic receptor-mediated effects of dopamine and dopamine agonists in the basal ganglia.

Adrenergic beta-Antagonists↗
PubMed1987

Neurophysiological investigation of effects of the D-1 agonist SKF 38393 on tonic activity of substantia nigra dopamine neurons.

The effects of the D-1 agonist SKF 38393 on tonic activity of rat substantia nigra pars compacta dopamine neurons were studied using extracellular, single-unit recording techniques. Unlike nonselective D-1/D-2 dopamine agonists or the D-2 agonist quinpirole, SKF 38393 did not inhibit dopamine neuronal activity when applied iontophoretically or when administered intravenously in doses up to 20 mg/kg to chloral hydrate-anesthetized rats. Moreover, pretreatment with SKF 38393 did not alter the inhibitory response of these neurons to apomorphine or the D-2 agonist quinpirole. However, in locally anesthetized, gallamine-treated, artificially respired rats, dopamine cell activity was significantly altered by i.v. administration of SKF 38393; firing rate increases and decreases were observed. Administration of the inactive enantiomer of SKF 38393, S-SKF 38393, did not induce similar changes in parallel experiments. These results support the idea that unlike D-2 autoreceptor stimulation, D-1 receptor stimulation does not exert a direct local effect on dopamine neurons in the substantia nigra pars compacta and suggest that D-1 receptor stimulation at sites postsynaptic to the dopamine cells may indirectly affect the activity of some dopamine neurons through long-loop feedback mechanisms.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

D-1 dopamine receptor stimulation potentiates neurophysiological effects of bromocriptine in rats with lesions of the nigrostriatal dopamine pathway.

Neurophysiological techniques were used to examine the possibility that the effects of bromocriptine, a direct acting dopamine agonist, can be potentiated by D-1 receptor stimulation in an animal model of parkinsonism. Single unit activity of substantia nigra pars reticulata neurons was recorded in rats with 6-hydroxydopamine induced lesions of the nigrostriatal pathway. The results showed that the coadministration of bromocriptine with the selective D-1 agonist SKF 38393 greatly attenuated pars reticulata neuronal activity at doses that did not produce significant effects when administered alone. Thus, processes elicited by D-1 receptor stimulation and bromocriptine exert synergistic effects in these 6-hydroxydopamine lesioned rats. This observation may be relevant to the mechanism underlying l-DOPA's ability to potentiate the therapeutic effects of bromocriptine in parkinsonian patients.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Calcium transport by rat duodenal villus and crypt basolateral membranes.

Rat duodenal cells were isolated sequentially to give fractions enriched for villus and crypt cells. From each of these fractions, basolateral-enriched membrane vesicles were prepared and ATP-dependent calcium uptake was studied. Calcium uptake was sensitive to temperature, was inhibited by vanadate and by A23187, and was lower in vitamin D-deficient animals. In normal animals, calcium transport was approximately twofold greater in villus-tip than in crypt cell-fraction basolateral membranes though the affinity of the uptake for calcium was similar (Km = 0.3 microM). In vitamin D-deficient animals, the crypt-to-villus gradient was reduced, and in all fractions, calcium transport was similar to or lower than that in the crypts of normal animals. Six hours after vitamin D-deficient animals were repleted with 1,25-dihydroxycholecalciferol, a significant increase in calcium transport by everted gut sacs was present; however, basolateral calcium transport was significantly increased in only the mid-villus fractions, and no change was seen in the villus-tip fractions. Thus vitamin D appears necessary for the development of increased basolateral membrane calcium pump activity in duodenal villus cells, but not all cells in vitamin D-deficient rats are able to respond to 1,25-dihydroxycholecalciferol.

Adenosine Triphosphate↗
PubMed1986

Intestinal basolateral membrane Ca-ATPase activity with properties distinct from those of the Ca-pump.

The Ca-pump in rat intestinal basolateral membranes had been studied previously as vesicular ATP-dependent Ca-uptake. In the present studies, Ca-stimulated ATP hydrolysis (Ca-ATPase activity) was measured and found to differ from the Ca-pump in having higher activity and being insensitive to vanadate. Whereas the pump was specific for ATP, hydrolytic activity was found with ATP, GTP or ADP but not with AMP or p-nitro-phenyl-phosphate. In contrast to Ca-pump activity, Ca-ATPase activities were similar for different intestinal segments, for duodenal villus/crypt cell-fractions and for vitamin D-deficient animals. Thus, as usually measured, intestinal basolateral membrane Ca-ATPase activity is not equivalent to the Ca-pump.

Adenosine Diphosphate↗
PubMed1986

Differential electrophysiological effects of 3-PPP and its enantiomers on dopamine autoreceptors and postsynaptic receptors.

The activities of substantia nigra pars compacta dopamine and globus pallidus neurons have been examined following the systemic administration of ( +/- )-3-PPP and the enantiomers of 3-PPP to investigate the relative effects of these putative dopamine agonists on dopamine autoreceptors and postsynaptic dopamine receptors. ( +/- )-3-PPP inhibited the firing rates of 7 out of 10 dopamine cells completely (ED50 = 0.18 +/- 0.06 mg/kg) but caused no consistent or significant alterations in the firing rates of globus pallidus neurons, exhibiting an apparent selectivity for the dopamine D-2 autoreceptors. However, (+)-3-PPP effectively inhibited the activity of all dopamine neurons studied (ED50 = 0.09 +/- 0.03 mg/kg) and, like d-amphetamine, apomorphine and other dopamine agonists, significantly stimulated pallidal activity. (-)-3-PPP was less effective at inhibiting dopamine cell activity; it had no effect on firing rates of pallidal cells when given alone, but it reversed the pallidal rate increases induced by (+)-3-PPP and also blocked the rate increases induced by systemically administered apomorphine. The results show that (-)-3-PPP, given systemically, acts as a partial agonist in the substantia nigra pars compacta and as an antagonist on postsynaptic dopamine receptors. These effects of (-)-3-PPP appear to account for the apparent dopamine autoreceptor selectivity demonstrated by racemic 3-PPP and further indicate that the autoreceptors and postsynaptic dopamine receptors may be differentially affected by a drug with mixed agonist/antagonist properties. These conclusions are consistent with those obtained from other techniques and support the idea that the effects of dopamine agonists on the activity of dopamine neurons and globus pallidus cells can provide an indication of the relative selectivity of these drugs for pre- or postsynaptic dopamine receptors.

Action Potentials↗
PubMed1986

Neurophysiological evidence that D-1 dopamine receptor blockade attenuates postsynaptic but not autoreceptor-mediated effects of dopamine agonists.

The putatively selective D-1 dopamine receptor antagonist SCH 23390 was used to study the role of the D-1 dopamine receptor in mediating the pre- and postsynaptic effects of dopamine agonists in the basal ganglia. SCH 23390 (1 mg/kg) had no significant effect on the tonic activity of substantia nigra dopamine neurons in 47% of the 19 cells studied, while the firing rates of 53% of the cells were increased. SCH 23390 did not shift the dose response of these cells to apomorphine, whereas the selective D-2 antagonist, YM-09151-2 completely blocked apomorphine's inhibitory effects on nigral dopamine cell activity. These results suggest that SCH 23390 does not interact with the D-2 dopamine autoreceptors, but does excite a subpopulation of dopamine neurons presumably through postsynaptic actions. In contrast to its inability to modify the effects of apomorphine on dopamine autoreceptors, SCH 23390 partially to fully reversed the effects of apomorphine on globus pallidus and substantia nigra pars reticulata cell activity and significantly attenuated the effects of apomorphine, pergolide, quinpirole (LY 171555) and d-amphetamine on firing rates of globus pallidus neurons. The D-1 antagonist alone had no significant effect on tonic globus pallidus neuronal activity. SCH 23390 was more potent than haloperidol in its ability to attenuate the effects of apomorphine on pallidal activity, but unlike haloperidol, was unable to totally inhibit these effects, suggesting that the two antagonists block the excitatory effects of apomorphine on pallidal cell firing rates by different mechanisms. The serotonin2 receptor antagonist, ketanserin, had no effect on pallidal or dopamine cell activity, indicating that the effects of SCH 23390 were not mediated through interactions with serotonin2 receptors. These results suggest that D-1 receptor blockade attenuates the postsynaptic, but not autoreceptor-mediated effects of dopamine agonists.

Animals↗
PubMed1986

Preparation of subcellular membranes from rat intestinal scrapings or isolated cells. Different Ca2+ binding, nonesterified fatty acid levels, and lipolytic activity.

Basolateral, brush-border, and Golgi-enriched subcellular membrane fractions, prepared from homogenates of rat small intestinal mucosa obtained by scraping, had unusually high concentrations of nonesterified fatty acids. These fatty acids appear to be responsible for the large amount of calcium binding, an effect that previously was shown to be reduced in vitamin D deficiency. In contrast, basolateral and Golgi membranes prepared from isolated cells had low levels of nonesterified fatty acids and calcium binding. Intermediate levels were found with isolated cells that were not put through the usual washing procedures. Addition to homogenates of scrapings of a lipase inhibitor, diethyl-p-nitrophenyl phosphate, reduced calcium binding and nonesterified fatty acids to levels similar to those in membranes prepared from isolated cells. Phospholipase A activity was low in homogenates of isolated cells and high in scrapings; this was reduced in intestinal scrapings of vitamin D-deficient rats. Ileal membranes had more calcium binding than duodenal membranes, and ileal homogenates also had greater phospholipase A activity. Preparation of subcellular membranes from rat intestinal scrapings can result in altered lipid composition, probably due to lipolytic enzyme activity; in addition to increasing cation-binding, these high levels of fatty acids may affect other membrane properties and enzyme function.

Animals↗
PubMed1986

Effects of anticonvulsant drugs on substantia nigra pars reticulata neurons.

Enhancement of gamma-aminobutyric acid transmission within the substantia nigra has been shown to prevent the motor manifestations of chemically induced and kindled seizures. These findings raise the possibility that the substantia nigra might constitute a site of anticonvulsant drug action if these drugs share an ability to suppress propagation of seizure activity from the nigra to motor effector sites. The current studies monitored effects of a diverse group of anticonvulsant drugs on the extracellular, single unit activity of nondopaminergic neurons of the substantia nigra pars reticulata in awake, paralyzed and locally anesthetized male rats. Intravenous phenytoin (1.25-160 mg/kg) and carbamazepine (1.25-40 mg/kg) did not alter neuronal firing at any dose. Conversely, both diazepam (31.25-8,000 micrograms/kg) and clonazepam (2-500 micrograms/kg) partially inhibited firing (to 46 +/- 11% and 59 +/- 6% of base-line rates, respectively), although clonazepam was approximately 16 times more potent in eliciting equivalent degrees of inhibition. Valproic acid (5-640 mg/kg) and phenobarbital (1.25-80 mg/kg) also slowed firing to 65 to 70% of base-line rates, but did so only at the highest doses administered. However, the anesthetic barbiturate pentobarbital (0.3125-80 mg/kg) completely suppressed firing by the highest dose tested. Of those drugs used exclusively for treatment of absence seizures, trimethadione (12.5-800 mg/kg) caused dose-related inhibitions to 37.6 +/- 9.8% of base-line, whereas ethosuximide (12.5-800 mg/kg) markedly stimulated firing, nearly doubling firing rates after the 200 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Activation of substantia nigra neurons: role in the propagation of seizures in kindled rats.

The substantia nigra (SN) is crucial to the propagation of seizures in kindled rats and in other experimental seizure models. However, the mechanisms by which the SN acts to facilitate the propagation of seizures are unknown. To investigate these mechanisms we quantified the activity of SN neurons during seizures in kindled and naive rats in a paralyzed, ventilated state and examined the relationship between activity of neurons in the SN and the seizure-facilitating action of this structure. Our principal findings were that the majority of both SN dopamine and SN pars reticulata neurons, in kindled rats, fired in bursts temporally correlated to EEG waveforms recorded outside the SN during seizures; this response was only rarely found in SN neurons of naive rats during seizures elicited by stimulation of the amygdala; unlike kindled rats, lesions of the SN in naive rats did not suppress seizures. The finding that SN neurons fired in bursts during seizures in kindled, but not naive, rats indicates that seizure activity propagated into SN only in kindled rats. The correlation between seizure-suppressant effects of lesions and SN activation during seizures leads us to propose that one mechanism by which the SN promotes seizure propagation involves SN activation and transmission of seizure activity to targets of SN.

Animals↗
PubMed1986

Endogenous dopamine can modulate inhibition of substantia nigra pars reticulata neurons elicited by GABA iontophoresis or striatal stimulation.

Previous reports from this laboratory have described an ability of iontophoretically applied dopamine to attenuate the inhibitory effects of iontophoresed GABA on neurons of the substantia nigra pars reticulata. This finding raised the question of whether endogenous dopamine, released from dendrites of neighboring pars compacta dopamine neurons, might act as a neuromodulator which diminishes the inhibition of pars reticulata neurons evoked by either GABA iontophoresis or electrical stimulation of the striatonigral GABAergic pathway. Extracellular, single-unit activity of pars reticulata neurons was recorded in male rats anesthetized with chloral hydrate. In one set of studies, d-amphetamine, a drug reported to release dopamine from nigral dendrites, was administered intravenously (1.6 mg/kg) during regular, intermittent iontophoretic pulses of GABA. As had been previously observed with iontophoresed dopamine, i.v. amphetamine significantly lessened the inhibition of reticulata neurons produced by GABA application. This change was reflected by a decrease in GABA's inhibitory potency by 22% relative to the control level of inhibition achieved prior to amphetamine administration. Amphetamine caused no decreases in GABA's effectiveness, however, in animals that had previously received treatments that depleted or destroyed nigral dopamine stores, i.e., in rats pretreated with reserpine and alpha-methyl-p-tyrosine, or in rats with 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. In a second set of experiments, amphetamine or dopamine was delivered iontophoretically while monitoring the GABA-mediated (bicuculline-reversible) inhibition of reticulata neurons that can be elicited by striatal stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Decrease by cycloheximide of calcium binding and nonesterified fatty acids in rat-intestinal Golgi-enriched membrane fractions.

Rat intestinal Golgi-enriched membrane fractions bind more Ca2+ than do basolateral and microvillus-enriched membrane fractions, and this uptake is reduced by vitamin D-deficiency. The effect of the protein synthesis inhibitor, cycloheximide, on this Ca2+ binding was determined in rat fed a normal, vitamin D-sufficient diet. Cycloheximide, 1.5 mg/kg, rapidly reduced protein synthesis (measured by [3H]leucine incorporation) to 12% of control values within 15 min, but Ca2+ binding diminished gradually to 50% of control values by 60 min. Ca2+ transport across gut sacs was also decreased. The reduction in Ca2+ binding was not due to an alteration in vesicle morphology or to a direct effect of cycloheximide. Nonesterified (free) fatty acids, the probable binding sites for Ca2+ in these membrane fractions, were reduced by cycloheximide to 48% of control values by 60 min. There was no significant change in total lipid phosphate. Cycloheximide may affect the synthesis of proteins necessary for the presence of nonesterified fatty acids in these Golgi membranes.

Animals↗
PubMed1984

A physiological role for dopamine as modulator of GABA effects in substantia nigra: supersensitivity in 6-hydroxydopamine-lesioned rats.

Dopamine has been reported to attenuate the inhibitory effects of gamma-aminobutyric acid (GABA) on substantia nigra pars reticulata neurons. Five to six weeks after rats received 6-hydroxydopamine lesions of the nigral dopamine neurons, the ability of iontophoretically applied dopamine to attenuate pars reticulata responses to GABA was increased by 40% (P less than 0.05) with respect to that of unlesioned rats. These results suggest that the dopamine sites which mediate this modulatory interaction may become supersensitive in animals with dopamine-deficient nigras.

Animals↗
PubMed1984

Dopamine attenuates the effects of GABA on single unit activity in the globus pallidus.

Studies were conducted to assess whether stimulation of dopamine receptors located in the globus pallidus might play a role in mediating the enhanced pallidal activity seen after systemic administration of dopamine agonists or D-amphetamine. Dopamine, applied iontophoretically, had modest effects on the activity of pallidal neurons; the baseline firing rates of 32% of cells recorded increased by an average of 23 +/- 2%, 18% decreased in rate and the remaining cells showed no significant rate change. More significantly, dopamine consistently attenuated the inhibitory actions of gamma-aminobutyric acid (GABA) in the globus pallidus. When dopamine was simultaneously iontophoresed with GABA, GABA's effectiveness at inhibiting pallidal activity was reduced by an average of 50%. Norepinephrine or acetylcholine, applied iontophoretically at equimolar concentrations and ejected at the same current as dopamine, caused no consistent attenuation of pallidal responses to GABA's rate effects. To determine whether the attenuation of GABA's inhibitory action by iontophoresed dopamine could be mimicked by systemic drug administration, apomorphine, 80 micrograms/kg, or D-amphetamine, 0.8 mg/kg, was given i.v. while GABA was iontophoresed. Apomorphine markedly decreased pallidal responses to the inhibitory effects of GABA in 75% of the cells by an average of 50%; haloperidol reversed this effect. Modulatory interactions between GABA and D-amphetamine were also observed in 5 of the 11 pallidal cells tested; GABA's inhibitory effect on pallidal cell activity was reduced by an average of 66% on these neurons. These results suggest that one way in which dopamine and dopamine agonists may affect basal ganglia function is by modulating GABAergic transmission in the globus pallidus.

Acetylcholine↗