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R M Joy

Publications and source records attributed to R M Joy.

At least 37 records · Page 2Linked to original sources
PubMed1988

Exposure to lindane and two other hexachlorocyclohexane isomers increases free intracellular calcium levels in neurohybridoma cells.

NCB-20 neurohybridoma cells were exposed to isomers of hexachlorocyclohexane (HCH) for periods of time ranging from 5-45 min, and intracellular free calcium [Ca++]i levels were determined using the INDO1/AM method. Exposure to lindane (gamma HCH) produced a dose-dependent increase in [Ca++]i, significant increases being observed with exposures from 10-400 microM. During exposure, [Ca++]i increased to a peak and then declined over the next 45 min. After 45 min levels were still elevated above control levels. This action of the gamma isomer of HCH was shared by the alpha and beta isomers. The potencies of the isomers were alpha (0.5), beta (0.75) and gamma (1.0). The effects of HCH isomers on [Ca++]i in neurohybridoma cells are similar to those reported for the isomers using rat brain synaptosomes. The ability of lindane to increase [Ca++]i may explain the previously reported ability of lindane to increase spontaneous and evoked (under low quantal release conditions) release of transmitter from frog neuromuscular junction. The relevance of this effect to mammalian CNS hyperexcitability, however, remains unsettled. These effects occur at concentrations of lindane higher than those effective in antagonizing GABA-mediated inhibition, and they lack the specificity shown by the isomers under other circumstances.

Calcium↗
PubMed1987

Increased inhibition in dentate gyrus granule cells following exposure to GABA-uptake blockers.

Rats anesthetized with urethane had stimulating and recording electrodes placed in the perforant pathway and in the dentate gyrus. They were then exposed to increasing doses of either the vehicle control dimethylsulfoxide (DMSO) or one of two gamma-aminobutyric acid (GABA)-uptake blockers (SKF-100330A or SKF-89976A). Analysis of evoked field potentials from dentate granule cells indicated that the only effect of the GABA uptake blockers was to increase the threshold for evoking the field population spikes (PS). No other measure of excitatory postsynaptic potentials (EPSPs) or PS's were significantly affected. The lack of effect on evoked EPSP by these drugs suggests no direct effect on transmitter release at this synapse, while the increase in PS threshold suggests a slight decrease in granule cell excitability. The effects of the two GABA-uptake blockers on synaptically mediated facilitation and inhibition was tested by using paired-pulse paradigms. Both GABA-uptake blockers increased early GABA-mediated inhibition to a greater extent than they reduced synaptically mediated facilitation. Neither GABA uptake blocker appeared to effect the late inhibition seen at paired-pulse intervals of 400-1000 ms which is presumably associated with calcium-activated increases in potassium conductance. These effects on granule cell responses occurred at doses found previously not to be associated with side effects and yet to be anticonvulsant in unanesthetized rats. These data confirm in vivo that SKF-100330A and SKF-89976A increase GABA-mediated inhibition. The effect on granule cell excitability and late inhibition are minimal. Although facilitation was reduced by exposure to these drugs, the mechanism of this reduction (direct or prolongation of early inhibition) cannot be determined.

Animals↗
PubMed1987

Effects of two isomers of hexachlorocyclohexane (HCH) on cortical beta-adrenoceptors in rat brain.

Two isomers of hexachlorocyclohexane (HCH) have profound effects on the acquisition of kindled seizures. The gamma-isomer (lindane, gamma-HCH) increases the rate of acquisition in a dose-related manner whereas the beta-isomer (beta-HCH) has the opposite effect, retarding the rate in a dose-related manner. There is evidence that adrenergic influences may play a role in seizure generalization and in this study we examined the effect of these two isomers of HCH on the binding of a ligand to beta-adrenoceptors. Tritiated dihydroalprenolol was used as the ligand in an assay using cortical tissue from rats after 10 days of treatment with 10 mg/kg, p.o. of isomers or corn oil. Results showed a statistically significant decrease in the number of beta-adrenoceptors in cortical tissue taken from gamma-HCH-treated rats. In contrast, there was a statistically significant increase in the number of beta-adrenoceptors cortical tissue taken from beta-HCH-treated rats. Neither treatment produced a significant change in KD. We concluded that the beta-adrenoceptor system in rat cortex is differentially affected by the isomers of HCH. Because the kindling model of epilepsy is sensitive to modulations in adrenergic function, this system may be involved in the pro- and anticonvulsant effects of these HCH isomers on kindling acquisition.

Animals↗
PubMed1987

Effects of lindane upon transmitter release and end-plate responsiveness in the neuromuscular junction of the frog.

Studies were carried out to determine whether the insecticide, lindane, influenced calcium-mediated electrical activity or release of neurotransmitter in vitro. In neuroblastoma cells, lindane (1-100 microM) did not appreciably modify action potentials elicited in normal or sodium-free solutions nor did it have a significant effect upon either transient or sustained-type calcium channels. Exposure of cutaneous pectoris neuromuscular junctions of the frog to 100 microM lindane increased spontaneous release of transmitter. In neuromuscular junctions perfused with 0.5 mM Ca++/6 mM Mg++ Ringer (low quantal release conditions), lindane increased evoked release of transmitter. The absolute increase amounted to just less than one quanta and the extent of the increase was inversely proportional to the mean number of quanta released by the nerve terminal before exposure to lindane. No effect on release of transmitter could be demonstrated when neuromuscular junctions were perfused in normal Ringer. Exposure of neuromuscular junctions to 100 microM lindane also decreased the amplitudes of miniature end-plate potentials. Amplitudes of responses to iontophoretically-applied acetylcholine (ACh) were similarly affected, suggesting that the decrease in amplitudes of miniature end-plate potentials was a reflection of decreased sensitivity of the end-plate to ACh. At neuromuscular junctions of the cutaneous pectoris of the frog, lindane appeared to produce two major effects. Presynaptically, it produced changes in spontaneous and evoked release of transmitter that were consistent with a small increase in free intracellular concentration of Ca++. Postsynaptically, it reduced the sensitivity of the end-plate to ACh.

Acetylcholine↗
PubMed1987

Factors responsible for increased excitability of dentate gyrus granule cells during exposure to lindane.

Rats were anesthetized with urethane, implanted with stimulating and recording electrodes in the perforant path and dentate gyrus, and exposed to different doses of lindane. Analysis of evoked field potential responses indicated that lindane exposure resulted in consistent, dose-dependent changes. Two separable effects were observed. First, lindane produced a small increase in the field excitatory postsynaptic potential (EPSP). Second, lindane produced much more significant effects upon granule cell excitability as evidenced by decreased threshold for evoking the field population spike (PS), increased amplitude of the PS and decreased latencies to PS onset and to peak. An analysis of these data suggests that presynaptic actions, e.g., increased transmitter release from perforant path terminals, do not appear to play an important role in the increased responsivity of granule cells. The most important factor appears to be a dose-dependent increase in the excitability of the granule cell due to other causes. In comparable studies, other subjects were prepared similarly and tested with other convulsive agents. Comparison of lindane to other convulsants revealed that lindane mimicked the changes produced in dentate gyrus responses by GABA antagonist drugs including picrotoxin, pentylenetetrazol and bicuculline. The glycine antagonist, strychnine, produced a different spectrum of effects. The data lend support to the hypothesis that an interaction of lindane with the GABA receptor-chloride channel complex is an important mechanism underlying both subconvulsant and convulsant actions. A reduction in tonic, GABA-mediated inhibition may be the basis for the increase in intrinsic granule cell excitability.

Animals↗
PubMed1987

Interactions of lindane with synaptically mediated inhibition and facilitation in the dentate gyrus.

Rats were anesthetized with urethane and prepared with electrodes to stimulate the perforant path and to record extracellular field potentials from the dentate gyrus of the hippocampus. Pairs of stimuli were presented to the perforant path both at different stimulus intensities and at different time separations to evaluate the effects of exposure to lindane on inhibition and facilitation. Lindane appeared to produce a selective effect on early, GABA-mediated inhibition. The magnitude of effect was dose-dependent. Exposure had no effect on synaptically mediated facilitation or on late inhibition which is presumably associated with calcium-activated increases in potassium conductance. The effect of lindane on GABA-mediated inhibition was measurable at exposures that are subconvulsant in unanesthetized subjects. It is concluded that an antagonism of GABA-mediated inhibition is probably an important mechanism by which lindane produces neuronal hyperexcitability and convulsions. These findings clearly support in vitro data which indicate that lindane binds to the chloride channel and acts to inhibit GABA-mediated chloride flux.

Animals↗
PubMed1986

Modification of excitation and inhibition evoked in dentate gyrus by perforant path stimulation: effects of aminophylline and kindling.

Rats were implanted with chronic electrodes to stimulate the perforant path and record the elicited monosynaptic evoked potentials from the dentate gyrus of the hippocampal formation. Dentate responses were examined in awake and anesthetized animals after exposure to saline and aminophylline (100 mg/kg, IP). In the awake animal, aminophylline treatment did not significantly alter the threshold or elicited amplitude of either the excitatory post-synaptic potential (EPSP) or the population spike (PS). Aminophylline pretreatment markedly enhanced the length and severity of elicited seizures from hippocampal (dentate gyrus) or perforant pathway stimulation. After daily perforant pathway stimulations which established "kindled" seizures, aminophylline significantly increased only the amplitude of the evoked PS in awake animals. In animals anesthetized with chloropent, aminophylline increased significantly before kindling the amplitude of both the EPSP and PS without effecting thresholds for each. After perforant pathway kindling, only the PS amplitude was increased significantly by aminophylline. Inhibition, thought to be from GABA-mediated recurrent collaterals, was found to be increased rather than decreased by kindling. Further, aminophylline treatment did not result in reduction of this inhibition before or after kindling. These data suggest that at this dose of aminophylline neither enhanced transmitter release at this synapse as measured by the amplitude of the EPSP, nor reduced recurrent collateral inhibition significantly contributed to the prolongation of elicited seizure afterdischarge. The increase in PS amplitude reflecting an increased number of granule cells excited to discharge with perforant path stimulation after aminophylline was noted in awake animals but was greatest in the anesthetized animals. Although the number of granule cells excited to discharge was increased by aminophylline, the small increase in amplitude seen compared to the effects of other neurotoxins on this synapse makes this an unlikely explanation for the profound increased seizure response seen after aminophylline.

Aminophylline↗
PubMed1986

The acquisition of a kindled response in developing rats using 24-h intertrial intervals.

The purpose of this study was to evaluate a methodology which would permit serial EEG recordings and daily amygdaloid kindling stimulations in young rats (16-26 days old). The preparation was sufficient to maintain the developing rats for 26 consecutive days of stimulation and recording and to permit the acquisition of kindled seizures. Developing rats required a slightly greater number of trials to acquire the kindled response than did adult rats in previous studies using a 24-h intertrial interval.

Age Factors↗
PubMed1985

Comparative pharmacological effects on visual cortical neurons in monocularly deprived cats.

Monocularly deprived (MD) cats show a loss of responsiveness to visual stimulation of the deprived eye among visual cortical neurons. Several lines of evidence suggest that this effect involves, at least in part, a suppression of deprived eye input, possibly mediated by GABA inhibition. In order to better understand the nature of this suppression we have evaluated the effectiveness of different types of disinhibitory and excitatory agents to reverse the effects of MD. We investigated bicuculline (a GABA antagonist); picrotoxin (a GABA antagonist with a different mechanism of action from bicuculline); strychnine (a glycine antagonist); ammonium ion (a blocker of membrane chloride channels); physostigmine (a cholinesterase inhibitor); and naloxone (an opiate antagonist and also a GABA antagonist). All drugs were given intravenously. Bicuculline restored binocularity to 50% of the visual cortical neurons tested and naloxone to 36%. With both drugs, receptive fields of the normal eye tended to lose specificity. The emergent deprived eye receptive fields were usually similar to those of the normal eye after drug administration. Ammonium ion produced binocular responses in 27% of neurons tested, but receptive fields were grossly abnormal; moreover, ammonium infusion tended to depress neuronal responsiveness. All other drugs tested failed to restore binocularity. These experiments lend further credence to the hypothesis that GABA inhibition contributes to the cortical effects of MD, since only drugs with GABA antagonistic action were effective in restoring neuronal responsiveness to the deprived eye.

Acetates↗
PubMed1985

Facilitation of kindling in adult rats following neonatal exposure to lindane.

Neonatal male rats were exposed to lindane or corn oil directly by gavage or indirectly by maternal exposure. All surviving offspring were implanted with amygdaloid electrodes 90 days after weaning. Amygdaloid kindling began 10 days later using standard procedures. Neonatal lindane-exposed rats kindled significantly faster (9.9 +/- 0.5 days) than control groups (11.2 +/- 0.5 days). Lindane-exposed rats tended to have longer and more severe seizures than did non-exposed rats on each trial during kindling acquisition. These findings demonstrate that high exposures of lindane during development can lead to enduring changes in the nervous system that facilitate adult kindling.

Amygdala↗
PubMed1985

The effects of neurotoxicants on kindling and kindled seizures.

The application of a constant-amplitude electrical stimulation to many parts of the brain leads to the expression of progressively more severe epileptiform responses. The process of acquisition is termed kindling, and the acquired response is termed the kindled seizure. This state has been used in a number of important ways including the modeling of human epilepsy and behavioral disorders, the testing of drugs for anticonvulsant effects, and, more recently, the examination of hyperexcitability states induced by pesticides and other environmental chemicals. This report discusses attributes of kindling and kindled seizures, examines possible mechanisms responsible for them, and summarizes drug and chemical effects on them. Kindling is powerfully accelerated by exposures to only a few substances, among the most effective of which are the chlorinated hydrocarbon insecticides, lindane and dieldrin. An analysis of the acceleration of kindling produced by lindane suggests that the threshold concentration in the nervous system for kindling enhancement is approximately 0.4 microgram/g (1.4 X 10(-9) mol/g).

Acetylcholine↗
PubMed1984

An analysis of the actions of progabide, a specific GABA receptor agonist, on kindling and kindled seizures.

The anticonvulsant properties of the specific GABA receptor agonist, progabide, were evaluated in the kindled amygdaloid seizure model in rats. Progabide attenuated afterdischarge durations and the severity of the accompanying convulsive responses in previously kindled rats. This effect occurred only at doses that also produced sedation and ataxia. When administered daily during kindling acquisition, progabide increased the number of trials necessary to complete kindling. The duration and severity of responses induced by stimulations during the acquisition period were reduced in a dose-dependent manner. In spite of these changes during the acquisition period, all subjects exhibited kindled behavior comparable to that of controls when they had accrued the same total afterdischarge experience. In light of these and other data regarding the GABA system and its influences on kindling, we conclude that GABA acts nonspecifically to attenuate various seizure states. It appears that GABA plays no major role in the mechanisms actually responsible for kindling development.

Amygdala↗
PubMed1984

The effect of a glycine derivative (CP 1552-S) on kindled seizures in rats.

The effects of the glycine derivative, CP 1552-S (2-N-pentylaminoacetamide hydrochloride) were evaluated for potential anticonvulsant activity in rats which were cortically- or amygdaloid-kindled. Large doses (300-600 mg/kg, i.p.) of CP 1552 given 30 min before stimulation resulted in significant reductions in duration of afterdischarge after both partially-developed and fully-developed cortically-kindled seizures. The largest dose tested (600 mg/kg, i.p.) markedly reduced the duration of the elicited afterdischarge and the severity of seizure. This dose was associated with prestimulation sedation and a 50% incidence of post-afterdischarge spontaneous, electrical seizure activity. Against kindled amygdaloid seizures, CP 1552-S significantly reduced the duration of afterdischarge at 300 mg/kg (i.p.) without modifying the seizure and without prestimulation behavioral or electrical effects. The largest dose tested (600 mg/kg, i.p.) resulted in a significant reduction of the elicited duration of afterdischarge but was associated with a 25% incidence of prestimulation spontaneous electrical seizure activity and a 45% incidence of post-afterdischarge electrical seizure activity. When CP 1552-S (30-300 mg/kg, i.p.) was administered daily, prior to the amygdaloid kindling stimulus, no difference was noted in the rate of acquisition of the kindled amygdaloid response. It is concluded that the glycine derivative CP 1552-S, has little anticonvulsant activity against the acquisition or development of kindled amygdaloid seizures. It appears to have significant anticonvulsant effects against both cortically- and amygdaloid-kindled afterdischarges with little effect on the behavioral severity of the seizure. Further, large doses of CP 1552-S appeared to result in paradoxical post-afterdischarge and possibly prestimulation electrical seizure activity.

Acetamides↗
PubMed1984

A pharmacological study in the kindling model of epilepsy.

The anticonvulsant properties of carbamazepine were evaluated in the kindled amygdaloid seizure model in rats. Carbamazepine significantly raised the threshold for seizures, reduced the duration of elicited afterdischarges and attenuated the severity of seizures in previously-kindled rats, at doses that did not cause sedation or ataxia. A similar reduction in the duration of elicited afterdischarges and severity of seizures was seen after suprathreshold stimulation (400 mu A) with doses of carbamazepine that were without obvious sedative or ataxic effects. After acute intraperitoneal injections (solvent = 2% Tween-80 and 70% propylene glycol), the maximum anticonvulsant effectiveness against suprathreshold stimulation was seen at 30 min. When administered daily (13 days) during acquisition or development of kindling, carbamazepine (25 and 50 mg/kg, i.p.) had variable effects on kindling. Neither dose consistently reduced the duration of elicited afterdischarges during the acquisition phase. Both groups tended to reduce the developing seizure, with the smaller dose of carbamazepine (25 mg/kg) resulting in a more consistent and significant reduction in severity of seizures. No significant differences in number of daily stimulations needed to reach fully kindled seizures were found. Previous studies have reported variable results with carbamazepine and the kindled amygdaloid seizure in rats. The present study provides a comprehensive evaluation of carbamazepine in this model of epilepsy and discusses the results with regard to the finding reported previously.

Amygdala↗
PubMed1984

Anticonvulsant action of fluzinamide (AHR-8559) on kindled amygdaloid seizures.

The anticonvulsant properties of fluzinamide (AHR-8559) were evaluated in the kindled amygdaloid seizure model in rats. Fluzinamide significantly attenuated afterdischarge durations and the severity of the accompanying convulsive responses in previously kindled rats at doses that did not cause sedation or ataxia. After acute intraperitoneal injections, the maximum anticonvulsant effectiveness against suprathreshold (400 microA) stimulation was seen at 30 min. Fluzinamide (10-80 mg/kg i.p.) was also evaluated in previously kindled rats using threshold (20-microA increments) seizures. Low doses of fluzinamide significantly elevated seizure threshold and reduced both elicited afterdischarge durations and seizure severity. When administered daily during kindling acquisition, fluzinamide (20 and 40 mg/kg i.p.) significantly increased the number of trials necessary to complete kindling. The duration and the severity of the responses induced by stimulations during the acquisition period were reduced. Previous studies have shown that the anticonvulsant profile for fluzinamide, as determined by traditional electrical and clinical models of epilepsies, most closely resembled phenobarbital and valproic acid, and differed from phenytoin and ethosuximide. The current study is consistent with this profile, with fluzinamide--like phenobarbital and valproic acid--significantly modifying both acquisition of kindling and the fully kindled amygdaloid seizure.

Amygdala↗
PubMed1984

Modification of kindled amygdaloid seizures by opiate agonists and antagonists.

The effects of 19 opiate agonists and antagonists on kindled amygdaloid seizures in the rat were studied. The mu agonists tended to reduce the length of elicited afterdischarges and behavioral ranks, while markedly increasing postictal electroencephalogram spikes and behavioral arrest time. These effects were reversed by naloxone. The kappa agonists reduced behavioral rank and variably reduced afterdischarge length with a concomitant lengthening of postictal behavioral arrest time and number of electroencephalogram spikes. The putative sigma agonist, SKF 10,047, reduced afterdischarge durations only at the higher doses tested. The decreases found after the sigma agonists in postictal electroencephalogram spiking and time of behavioral arrest were not reversed by naloxone. Only the lower doses of normeperidine were found to decrease seizure thresholds. The mixed agonist/antagonists (MAA) cyclazocine and cyclorphan markedly increased seizure threshold and reduced afterdischarge duration and behavioral rank. Only the MAA pentazocine tended to increase threshold but not suprathreshold afterdischarge durations. The order of ability to modify the ictal events was MAA (selected) greater than kappa agonists greater than mu agonists greater than sigma agonists. The increase in postictal events (behavior arrest and spikes) was caused most effectively by pretreatment with mu agonist greater than kappa agonist greater than selected MAA greater than sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗