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J W Dailey

Publications and source records attributed to J W Dailey.

At least 19 recordsLinked to original sources
PubMed1992

Serotonergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats.

Seizure predisposition in Genetically Epilepsy-Prone Rats (GEPRs) is characterized by abnormal sensitivity to a number of seizure provoking stimuli. The GEPR model is composed of two independently derived colonies with each exhibiting a characteristic convulsive pattern. In response to a standardized sound stimulus, GEPR-3s exhibit moderate or clonic convulsions while GEPR-9s exhibit more severe tonic extensor convulsions. In order to further characterize the neurochemical abnormalities that underlie seizure predisposition in GEPRs, the current study examined serotonin concentrations in 14 discrete brain areas of controls, GEPR-3s and GEPR-9s. In all areas examined, serotonin concentrations were lower in either one or both GEPR types than in seizure resistant controls. In 6 of the 14 areas both GEPR-3s and GEPR-9s had levels significantly lower than controls. In an additional 7 areas GEPRs had serotonin concentrations of similar magnitude which were significantly lower than control when the GEPR values were combined. In cerebellum, GEPR-3s had significantly lower serotonin concentration than either controls of GEPR-9s while in the striatum, GEPR-9s had significantly lower serotonin levels than either GEPR-3s or controls. In summary, GEPRs have widespread deficits in serotonin concentration and that these abnormalities appear to contribute to the seizure predisposition that characterizes these animals.

Animals↗
PubMed1992

Evidence that carbamazepine and antiepilepsirine may produce a component of their anticonvulsant effects by activating serotonergic neurons in genetically epilepsy-prone rats.

In order to investigate the mechanism of action of anticonvulsant drugs, we examined the effects of carbamazepine (CBZ) and antiepilepsirine (AE) on convulsions and on brain biogenic amines in genetically epilepsy-prone rats (GEPR). AE was an effective anticonvulsant in moderate seizure GEPR (GEPR-3, ED50 = 65.5 mg/kg) and in severe seizure GEPR (GEPR-9, ED50 = 68.5 mg/kg). Because GEPR are known to have deficiencies in brain norepinephrine (NE) and serotonin (5-HT), which are of etiologic significance in their seizure predisposition, we evaluated the effects of anticonvulsant doses of CBZ and AE on dialyzable NE, 5-HT and their metabolites. Dialysis probes were stereotaxically inserted into hippocampi of awake and unrestrained GEPR-3 and GEPR-9. Either AE (100 mg/kg in GEPR-3; 100 mg/kg in GEPR-9) or CBZ (45 mg/kg in GEPR-3; 6 mg/kg in GEPR-9) was administered i.p. after establishing basal release. Significant increases in dialyzable 5-HT, but not NE, were seen at the approximate time to peak anticonvulsant effect for each drug in both strains. The changes in 5-HT release remained closely associated with the anticonvulsant actions after i.v. administration of either AE (40 mg/kg) or CBZ (25 mg/kg) in GEPR-3. Pretreatment of GEPR-9 with p-chlorophenylalanine depleted brain 5-HT and greatly diminished the anticonvulsant effectiveness of both drugs. We conclude that both CBZ and AE are effective anticonvulsants in GEPR and that enhancement of serotonergic transmission may contribute to the anticonvulsant effect of these drugs.

Animals↗
PubMed1992

Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study.

To test the hypothesis that plasma tryptophan and/or its transport ratio is decreased in primary fibromyalgia (PF), we measured plasma tryptophan and its transport ratio in 29 patients with PF and 30 healthy controls without significant pain, in a blinded manner. Twenty-one other amino acids were also similarly analyzed among these study subjects. Transport ratio of tryptophan was found to be significantly (p less than 0.01) decreased in PF compared with the control group (0.09 +/- 0.02 vs 0.10 +/- 0.02). Plasma tryptophan level was lower in PF (45 +/- 10 nmol/ml) than in healthy controls (51 +/- 15 nmol/ml), showing a trend towards significance (p less than 0.09). Additionally, plasma histidine and serine levels were found to be significantly (p less than 0.01) lower in patients with PF than in controls. Our results suggest that a decreased brain serotonin level, as possibly reflected by a decreased transport ratio of plasma tryptophan, may play a pathophysiologic role in PF.

Amino Acids↗
PubMed1992

Plasma and urinary catecholamines in primary fibromyalgia: a controlled study.

Plasma and urinary catecholamines were measured in a blinded manner among 30 patients with primary fibromyalgia (PF) and 30 healthy controls without significant pain to determine possible elevations of catecholamines in PF, as well as their correlations with psychological and clinical variables in this syndrome. Results showed no significant differences between fibromyalgia and control groups in any of the catecholamines measured, nor was there a correlation between catecholamine levels and any of the clinical features or psychologic measures.

Adult↗
PubMed1992

Effects of fluoxetine on convulsions and on brain serotonin as detected by microdialysis in genetically epilepsy-prone rats.

Fluoxetine, an antidepressant and inhibitor of serotonin reuptake, was evaluated as an anticonvulsant in genetically epilepsy-prone rats (GEPRs) because seizure predisposition in GEPRs is partially dependent on deficits in brain serotonin. Fluoxetine produced dose-dependent reductions in sound-induced convulsion intensity in both moderate seizure GEPRs and severe seizure GEPRs with the peak anticonvulsant effect occurring 4 hr after i.p. administration. A subchronic study in severe seizure GEPRs demonstrated that the ED50 after 28 days of dosing (8.2 mg/kg) was lower than the acute ED50 (15.9 mg/kg) so that there was no apparent development of tolerance. The lower ED50 after subchronic administration apparently resulted from accumulation of fluoxetine and its metabolite norfluoxetine in brain. Brain microdialysis studies showed that acute fluoxetine administration resulted in a significant increase in extracellular serotonin concentration in the thalamus. The increase in serotonin concentration in the dialysate corresponded temporally with the anticonvulsant effect produced by fluoxetine. Intrathalamic administration of fluoxetine via the dialysis probe caused an increase in serotonin concentration in the dialysate, suggesting that the effect of fluoxetine was on nerve terminals. Fluoxetine could be dialyzed from thalamus after its i.p. administration. Fluoxetine concentration in the thalamic dialysate was similar to the concentration found in plasma. We conclude that fluoxetine is an effective anticonvulsant in GEPRs and that the microdialysis results strongly suggest a relationship between the effects of fluoxetine on serotonergic neurons and the anticonvulsant effect produced by this drug.

Animals↗
PubMed1991

Amino acids, monoamines and audiogenic seizures in genetically epilepsy-prone rats: effects of aspartame.

It has been suggested that aspartame facilitates seizures in man and animals because phenylalanine, one of its major metabolites, interferes with brain transport of neurotransmitter precursors and alters the synthesis of monoamine neurotransmitters such as norepinephrine, dopamine and/or serotonin. This facilitation is purportedly more likely in subjects predisposed to seizures. One test of this hypothesis would be to administer a wide range of aspartame doses to subjects whose seizure predisposition is dependent on abnormalities in monoaminergic function. Genetically epilepsy-prone rats (GEPRs) have a broadly based seizure predisposition that is based, in part, on widespread central nervous system noradrenergic and serotonergic deficits. Further reductions in the functional state of these neurotransmitters increases seizure severity in GEPRs. Thus, GEPRs appear ideally suited for testing the hypothesis that aspartame facilitates seizures by interfering with central nervous system monoamines. Oral administration of acute (50-2000 mg/kg) or sub-chronic (up to 863 mg/kg/day for 28 days) doses of aspartame did not alter seizure severity in either of two types of GEPRs. Not surprisingly, acute aspartame doses produced dramatic changes in plasma and brain amino acid concentrations. Hypothesized alterations in monoamine neurotransmitter systems were largely absent. Indeed, increases in norepinephrine concentration, rather than the hypothesized decreases, were the most evident alterations in these neurotransmitter systems. We conclude that aspartame does not facilitate seizures in GEPRs and that convincing evidence of seizure facilitation in any species is lacking.

Acoustic Stimulation↗
PubMed1991

Scope and contribution of genetic models to an understanding of the epilepsies.

Studies of the genetic models of the epilepsies emphasize that some seizure disorders result from an aberrant "wiring diagram" coupled with abnormal activity of individual neurons. These defects cause the unique seizer-triggering mechanisms operative within the epileptic nervous system but which are inactive or do not exist in normal subjects. Moreover, causes of epilepsy reside not only within the brain area, wherein initial appearance of epileptic EEG discharge occurs, but also outside that region. Etiologically significant neurochemical dysfunctions may be common features of the epileptic condition in genetic models across species. Accordingly, genetically determined convulsive epileptogenesis in rats, baboons, and humans may result partially from noradrenergic and GABAergic deficits. In contrast, genetically derived absence seizures in the rat and perhaps also humans may occur in response to GABAergic excess. The unique features of the genetically epileptic animals emphasize their usefulness in developing novel drugs that selectively ameliorate seizure predisposition.

Animals↗
PubMed1989

Aspartame fails to facilitate pentylenetetrazol-induced convulsions in CD-1 mice.

Concentrations of plasma amino acids and brain monoamines as well as pentylenetetrazol-induced seizures were monitored in CD-1 mice treated with aspartame in acute oral doses from 0 to 2500 mg/kg. One hour after administration aspartame produced increases in plasma concentrations of phenylalanine and tyrosine and modest reductions in concentrations of brain serotonin and 5-hydroxyindole acetic acid. However, these effects of the sweetener had no influence on the convulsive dose fifty (CD50) of pentylenetetrazol. Moreover, aspartame failed to alter the percentage of mice exhibiting seizures when exposed to an approximate CD50 of pentylenetetrazol. Finally, aspartame had no effect on brain norepinephrine or dopamine concentrations. In sharp contrast to previously reported studies, these observations suggest that aspartame, given in heroic doses, does not alter the propensity to seizure activity in CD-1 mice. We conclude that changes in plasma amino acids and brain serotonin produced by large oral bolus doses of aspartame are insufficient to result in functional deficits which might have the capacity to facilitate pentylenetetrazol-induced seizures.

Amino Acids↗
PubMed1986

Cerebral cortical GABA and benzodiazepine binding sites in genetically seizure prone rats.

Adult male and female genetically seizure-prone rats were assessed for sound-induced seizures. Heterozygous control groups were compared with mild seizure (designated GEPR 3) and severe seizure animals (GEPR 9). Groups of animals were killed and crude synaptosome fractions (P2) prepared from freshly dissected cerebral cortices. Binding sites for gamma-aminobutyric acid (GABA) were assessed by [3H]-muscimol in the absence or presence of excess GABA and/or pentobarbital. Binding sites for benzodiazepines were assessed by [3H]-flunitrazepam in the presence or absence of clonazepam. Compared to controls, GEPR 3 animals had a modest increase and GEPR 9 animals a larger increase in Bmax for both high and low affinity GABA sites, with no change in Kd. Chloride-dependent, barbiturate-enhanced GABA binding (increased Bmax) was observed in all conditions and groups. Likewise benzodiazepine binding (Bmax) increased slightly in GEPR 9 animals. There were no observed changes in binding sites for a survey of biogenic amines. Seizure-prone animals appear to have compensatory denervation-like supersensitivity for their most prominent inhibitory receptor, which may or may not be linked to the seizure event.

Animals↗
PubMed1978

Effects of adrenalectomy and adrenal steroids on norepinephrine synthesis and monamine oxidase activity.

Rat heart norepinephrine (NE) tunover was increased 6--10 days after bilateral adrenalectomy. This increase was prevented by administration of deoxycorticosterone acetate (DOCA) but not by either hydrocortisone or corticosterone. Blood pressure decreased following adrenalectomy. This decrease was prevented by DOCA, hydrocortisone and corticosterone. Monoamine oxidase (MAO) activity increased in the heart but not in the liver following adrenalectomy. DOCA prevented the increase in heart MAO activity whereas hydrocortisone and corticosterone were ineffective. In intact animals, heart and liver MAO activity were not changed by 5 days of cold exposure, a procedure which increases NE turnover. It is suggested that the increase in heart NE turnover may be related to the increase in MAO activity seen after adrenalectomy.

Adrenal Cortex Hormones↗
PubMed1978

Effects of maternally administered reserpine on the development of the cold stress response and its possible relation to adrenergic nervous system function.

Maternal administration of reserpine (100 microgram/kg/day) from day 8 of pregnancy until weaning of the pups produced no change in litter size, birth weight or weaning weight. At 70 to 80 days of age the offspring of reserpine treated dams were less able to maintain body temperature in response to cold stress with physical restraint. Similarly treated offspring exhibited a smaller rise in urinary free norepinephrine levels during the initial stages of cold exposure and they incorporated significantly less 14C from tyrosine into heart norepinephrine during acute cold exposure. No differences in incorporation of 14C into norepinephrine from tyrosine were evident when the animals were not subjected to cold stress. These data are consistent with the hypothesis that maternal administration of reserpine produces a permanent alteration in the ability of the offspring to respond to cold stress and that this deficit is related to an alteration in adrenergic nervous system development.

Animals↗
PubMed1977

The role of oxygen diffusivity in biochemical reactions.

It has been shown that increasing protein concentrations can decrease oxygen diffusion in 3 in vitro systems. We postulate that it is possible, and in some circumstances probable, that diffusion might be a rate limiting step in both in vitro and in vivo biological systems.

Animals↗
PubMedDate not supplied

Audiogenic convulsions in moderate seizure genetically epilepsy-prone rats (GEPR-3s).

The moderate seizure genetically epilepsy-prone rat (GEPR-3) typically exhibits a generalized clonic convulsion upon acoustical stimulation. The purpose of this report is to document sex-specific distinctions in the seizure characteristics as well as the effect of prior seizure experience on sensitivity to acoustically induced seizures in members of the GEPR-3 colony. Convulsive behavior was evaluated in approximately 3300 GEPR-3s. Each of these animals was stimulated with sound 3 times at weekly intervals. Audiogenic response score (ARS), latency to the onset of wild running and latency to convulsion were recorded for each animal in each of 3 tests given at 1 week intervals. Statistical analysis revealed that compared to their male littermates, females exhibited significantly shorter latencies to onset of running and convulsion for the last of the 3 weekly tests. Also, in both sexes, a significantly higher incidence of clonic convulsions, an increase in audiogenic response scores and a reduction in latencies to running and convulsion were observed in each succeeding audiogenic stimulation test. The mechanism of this increased seizure facilitation with prior seizure experience may have at least some similarity to that of kindling. The factors responsible for sex-specific distinctions in seizure severity are unknown at the present time.

Acoustic Stimulation↗
PubMedDate not supplied

Ontogeny of sound-induced seizures in the genetically epilepsy-prone rat.

Seizure responsiveness of the adult genetically epilepsy-prone rat (GEPR) is well documented. Much less is known about the ontogeny to seizure activity in the GEPR. In the present study, members of the moderate seizure (GEPR-3) and severe seizure (GEPR-9) colonies were tested for susceptibility to sound-induced seizures at 11 different ages ranging from 13 to 45 days post partum. Running episodes first appeared in GEPR-3s at 15 days post partum. Clonic seizures first appeared in GEPR-3s and GEPR-9s at 15 and 16 days post partum, respectively. Seizure incidence reached 100% by post partum day 21 in both colonies. GEPR-3s exhibited a 100% incidence of their characteristic clonic seizure at day 21. GEPR-9s exhibited a 77.3% incidence of clonic seizure and a 22.7% incidence of their adult characteristic tonic seizure at day 21. Tonic seizures first appeared in GEPR-9s at day 18 and increased in incidence over time reaching 100% by day 45. Two unexpected findings occurred in GEPR-3s. First, secondary rearing seizures were detected in all GEPR-3s exhibiting clonic seizures between day 16 and 21. Second, GEPR-3s exhibited a transient susceptibility between 19 and 27 days post partum to the more severe tonic seizures characteristic of adult GEPR-9s. Peak incidence of tonic seizures in GEPR-3s was 70%, occurring at day 23. The adult GEPR-3 pattern of 100% incidence of clonic seizures was restored by day 45.

Acoustic Stimulation↗