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Biomedical subjects

J W Dailey

Publications and source records attributed to J W Dailey.

At least 55 records · Page 3Linked to original sources
PubMed1994

A microdialysis study of amino acid concentrations in the extracellular fluid of the substantia nigra of freely behaving GEPR-9s: relationship to seizure predisposition.

Substantia nigra (SN) is known to play an important role in seizure generalization. Both excitatory and inhibitory neurotransmitters can modulate this role of SN. Previous studies have shown that GABA as well as aspartate and glutamate participate in seizure regulation through this site. Evidence for such a role comes from studies on the genetically epilepsy-prone rat (GEPR) and other seizure models. In the GEPR, bilateral microinjections of NMDA receptor antagonists in SN block or reduce seizure severity. In order to further evaluate which neurotransmitters are specifically involved at the SN level of seizure regulation in the GEPR, we undertook a microdialysis study of K+ stimulated release of amino acids in the SN of GEPR-9s- and non-epileptic controls. A 1 mm loop-type microdialysis probe was inserted through pre-implanted guides into the SN of awake and freely moving rats (seven GEPR-9s and four non-epileptic controls), and used to perfuse a 100 mM K+ (high K+) solution for 2 h. Four 30 microliters samples were collected prior to high K+ stimulation (basal release), during high K+ perfusion, and after high K+ infusion. After precolumn derivatization with phenylisothiocyanate, levels of aspartic (ASP) and glutamic (GLU) acids, glycine (GLY), taurine (TAU) and GABA were measured by reversed phase high performance liquid chromatography. Two hours after the initiation of high K+ infusion, the increases relative to basal were, for non-epileptic controls, 35%, 74%, 68%, 847% and 283% respectively for ASP, GLU, GLY, TAU and GABA. Corresponding increases for GEPR-9s were 14%, 10%, 41%, 505% and 123% respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1994

Noradrenergic terminal fields as determinants of seizure predisposition in GEPR-3s: a neuroanatomic assessment with intracerebral microinjections of 6-hydroxydopamine.

The genetically epilepsy-prone rat (GEPR) and other mammals with genetically based epilepsy are characterized by an innate predisposition to seizures evoked by a wide variety of stimuli (including those of endogenous origin). The present investigation was undertaken to identify the anatomical location of the noradrenergic terminal fields responsible for regulation of seizure predisposition. In this study, audiogenic seizure severity was used as the index of seizure predisposition. The effect of widespread destruction of noradrenergic terminal fields was compared with the effect of destroying regionally distinct terminal fields. These lesions were produced by microinfusion of 6-hydroxydopamine (6-OHDA) into the locus ceruleus, the A1 noradrenergic area, the noradrenergic dorsal bundle, the cerebellar peduncles and spinal intrathecal space. Selective depletion of norepinephrine in the forebrain, the cerebellum, or the spinal cord failed to alter audiogenic seizure severity. An increase in seizure severity was always associated with marked depletion of norepinephrine in the midbrain excluding the inferior colliculus. Also a significant correlation existed between the seizure intensification and reduction of norepinephrine in this structure in all instances where a seizure intensification was observed. An association of seizure intensification also existed in all cases except one with depletion in the pons/medulla. The present findings support the hypothesis that the noradrenergic terminal fields of the midbrain excluding the inferior colliculus are determinants of seizure predisposition. Inasmuch as audiogenic seizures are a type of brainstem seizure, the present findings do not a priori pertain to the noradrenergic regulation of forebrain seizures.

Acoustic Stimulation↗
PubMed1993

Noradrenergic mechanisms for the anticonvulsant effects of desipramine and yohimbine in genetically epilepsy-prone rats: studies with microdialysis.

A large body of evidence suggests that the seizure-prone state of genetically epilepsy-prone rats (GEPRs) results, in part, from deficits in central nervous system noradrenergic function. In order to link the synaptic concentration of norepinephrine (NE) to seizure behavior, we evaluated the effects of both desipramine and yohimbine on convulsions and on extracellular NE and serotonin (5-HT) concentrations in the thalamus of severe seizure GEPRs (GEPR-9s). Under anesthesia, guide cannulae were stereotaxically placed over thalami. After recovery from surgery, dialysis probes were inserted and the animals were placed individually into a plexiglass chamber where they were allowed to move about freely. Artificial CSF was perfused and samples were collected for analysis on HPLC with electrochemical detection. Either desipramine (10 and 20 mg/kg) or yohimbine (10 mg/kg) was administered i.p. after a stable baseline of NE or 5-HT was established. Significant increases in the extracellular NE concentration were seen after injection of both drugs. Temporal linkage exists between the maximum NE increase and the maximum decrease in audiogenic response score (ARS) for these two agents. No significant increases in the extracellular 5-HT concentration occurred after administration of either desipramine or yohimbine at a dose of 10 mg/kg. We conclude that these two drugs are effective anticonvulsants in GEPRs at least partially because they enhance noradrenergic transmission.

Animals↗
PubMed1993

Anticonvulsant effects of intracerebroventricularly administered norepinephrine are potentiated in the presence of monoamine oxidase inhibition in severe seizure genetically epilepsy-prone rats (GEPR-9s).

Pharmacological and neurochemical evidence indicates that brain noradrenergic systems play an important role in the determination of audiogenic seizure severity in genetically epilepsy-prone rats (GEPRs). In earlier studies, intracerebroventricular (ICV) injections of norepinephrine suppressed convulsions in a now extinct moderate seizure GEPR colony. Also, ICV noradrenergic agonists are known to produce dose-related anticonvulsant effects in the extant moderate seizure GEPRs (GEPR-3s). The present experiments were undertaken to determine whether ICV norepinephrine also suppresses audiogenic seizures in the extant GEPR-3s and in the severe seizure genetically epilepsy-prone rats (GEPR-9s). Injections of norepinephrine or vehicle were made into the lateral ventricle through implanted guides. GEPR-9s were pretreated systemically either with the monoamine oxidase inhibitor pargyline or with saline. GEPR-3s received no pretreatment. In pargyline pretreated GEPR-9s, seizure severity fell and the fraction of animals exhibiting an anticonvulsant response increased progressively as the dose of norepinephrine was increased. In saline pretreated GEPR-9s, the anticonvulsant dose response curve for norepinephrine was shifted to a higher dose range. Accordingly, the anticonvulsant dose50 for norepinephrine was significantly greater in saline pretreated GEPR-9s than in pargyline pretreated animals. Moreover, the dose required to produce the anticonvulsant effect in GEPR-9s was approximately 10 fold greater than in the earlier studies in the extinct moderate seizure GEPRs. Also, the current experiment with extent GEPR-3s, showed that ICV norepinephrine was anticonvulsant in the same dose that was effective in the extinct colony of moderate seizure GEPRs. In general terms, these observations provide additional evidence that noradrenergic influences are anticonvulsant in the GEPR. The neurobiological factors responsible for reduced responsiveness of the GEPR-9 are presently unknown.

Animals↗
PubMed1993

Thalamic deficiency in norepinephrine release detected via intracerebral microdialysis: a synaptic determinant of seizure predisposition in the genetically epilepsy-prone rat.

Seizure predisposition in the genetically epilepsy-prone rat (GEPR) is caused by a combination of central nervous system abnormalities including deficiencies in the number of noradrenergic terminals and in the amount of norepinephrine (NE) released per terminal. Heretofore, estimates of a synaptic deficiency in NE concentration have been obtained from indirect indices. The present study uses intracerebral microdialysis to provide a direct demonstration of deficiency in extracellular NE levels in the GEPR brain. Under anesthesia, guide cannulae were stereotaxically placed over thalami of severe seizure GEPRs (GEPR-9s) and non-epileptic control rats. After recovery from surgery, dialysis probes were inserted intrathalamically and the animals were allowed to move about freely. Artificial cerebrospinal fluid (ACSF) was perfused at 1 microliter/min and 30-min samples were collected for analysis on HPLC with electrochemical detection. Desipramine (5 microM in ACSF for 2 h), yohimbine (5 microM in ACSF for 2 h) or KCl (100 mM in ACSF for 1 h) was administered through the dialysis fiber after a stable NE baseline was established. Significantly diminished in vivo NE release from the thalamus was seen in response to all treatments in GEPR-9s when compared with non-epileptic controls. These observations coupled with earlier findings of deficits in postsynaptic receptor density and signal transduction support the hypothesis that noradrenergic transmission in the GEPR contributes to seizure predisposition through a failure to provide a normal level of protection against seizure initiation and spread.

Analysis of Variance↗
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↗
PubMed1988

Responsiveness of genetically epilepsy-prone rats to intracerebroventricular morphine-induced convulsions.

The sensitivity to intracerebroventricular morphine-induced convulsions was determined in members of the severe seizure (GEPR-9) and moderate seizure (GEPR-3) colonies of genetically epilepsy-prone rats as well as in non-epileptic control rats. GEPR-9s were more sensitive to morphine-induced wet-dog shakes, rearing with bilateral forelimb clonus and generalized clonus than controls of GEPR-3s. GEPR-3s were less sensitive to morphine-induced wet-dog shakes and rearing with bilateral forelimb clonus than controls. Both high and extremely low doses of morphine in GEPR-9s elicited tonic extensor convulsions resembling the characteristic sound-induced convulsion of GEPR-9s. The results suggest that opiotergic systems may contribute to the pathophysiology of the seizure-prone condition in GEPR-9s. Further, differences in responsiveness of opiotergic systems in GEPR-3s and GEPR-9s may partially account for differences in seizure severity in the characteristic sound-induced seizures of these two types of GEPRs.

Animals↗
PubMed1988

Brain norepinephrine and convulsions in the genetically epilepsy-prone rat: sex-dependent responses to Ro 4-1284 treatment.

Seizure predisposition in the Genetically Epilepsy-Prone Rat (GEPR) is at least partially dependent on central nervous system noradrenergic deficits. We have previously shown that moderate seizure GEPRs (GEPR-3) experience an increase in seizure severity after receiving Ro 4-1284, a monoamine vesicle inactivating drug. We are now reporting the effect of this drug on severe seizure GEPRs (GEPR-9). Motives for this study were: (a) to determine the effects of further depletion of innately deficient monoaminergic stores on seizure latencies and (b) to investigate whether a previously documented seizure severity difference between the sexes is related to the defective monoaminergic system in these subjects. GEPR-9s with known seizure history were tested for latency to onset of running phase and convulsion 45 minutes after Ro 4-1284 or saline administration. Brain norepinephrine levels were also determined. Ro 4-1284 caused severe depletion of monoamines in all brain areas assayed in both sexes of GEPR-9s and also caused a reduction in the latencies for onset of running and convulsion. The drug-induced norepinephrine depletion across the brain areas surveyed was significantly greater in females than in their male littermates. These observations prompt us to postulate that noradrenergic neurons in female GEPR-9s are functionally different from those in males and that this difference is detected in the differential effectiveness of Ro 4-1284 between the two sexes. Also, the influence of gonadal hormones on seizure predisposition and on the neurochemical actions of Ro 4-1284 may be different in GEPR-9 males and females.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1988

Psychotropic effects of caffeine.

Chronic, heavy caffeine ingestion may cause or exacerbate anxiety and may be associated with depression and increased use of antianxiety drugs. Caffeine may cause anxiety and panic in panic disorder patients and may aggravate the symptoms of premenstrual syndrome. Chronic users who are caffeine-sensitive may have symptoms of caffeinism at relatively low doses. Individuals who regularly consume moderate to heavy amounts of caffeine may develop caffeinism, or they may show signs of caffeine withdrawal syndrome after abstaining from the drug.

Affect↗
PubMed1986

The genetically epilepsy-prone rat: an overview of seizure-prone characteristics and responsiveness to anticonvulsant drugs.

The Genetically Epilepsy-Prone Rat (GEPR) is rapidly gaining support as a model of epilepsy. In addition to a marked sensitivity to both sound-induced and hyperthermic seizures, GEPRs exhibit unusual sensitivity to a number of seizure-provoking modalities, including various forms of electrical and chemical stimulation. The existence of a moderate seizure colony (GEPR-3) and a severe seizure colony (GEPR-9) allows pathophysiological studies of seizure susceptibility and severity. The consistency of seizures within each colony allows for comparisons in seizure naive GEPRs and seizure experienced GEPRs. The consistent seizure responses of the GEPR are also ideal for the testing of anticonvulsant drugs. Further, the relative potencies of anticonvulsant drugs between the two colonies of GEPRs predict the clinical efficacies of traditional antiepileptic drugs and may be able to predict novel anticonvulsants.

Acoustic Stimulation↗