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T W Seale

Publications and source records attributed to T W Seale.

At least 37 records · Page 2Linked to original sources
PubMed1989

Differential seizure sensitivities to picrotoxinin in two inbred strains of mice (DBA/2J and BALB/c ByJ): parallel changes in GABA receptor-mediated chloride flux and receptor binding.

Two strains of mice were shown to possess a differential sensitivity to picrotoxinin-induced convulsions; picrotoxinin elicited both tonic and clonic seizures at lower doses in the DBA/2J (DBA) strain compared to the BALB/c ByJ (BALB) strain. Less protection of picrotoxinin-induced tonic seizures was afforded by pentobarbital in the DBA strain. Biochemical studies revealed that picrotoxin inhibited 36Cl- efflux from forebrain synaptoneurosomes only in the DBA strain. In addition, picrotoxin inhibited pentobarbital-induced 36Cl- efflux to a greater extent in the DBA strain. No differences were observed in the binding of [3H]muscimol or [35S]t-butylbicyclophosphorothionate (TBPS) to forebrain homogenates, while pentobarbital was a less potent inhibitor of [35S]TBPS binding in the DBA strain. These findings suggest a genetic basis for the behavioral differences in convulsant sensitivity as well as for the neurochemical differences in allosteric coupling between convulsant and depressant/anticonvulsant sites associated with the GABA receptor-gated Cl- channel.

Animals↗
PubMed1989

Familial gigantiform cementoma: classification and presentation of a large pedigree.

Very few cases of gigantiform cementoma have been reported, and those associated with a positive family history are especially rare. Confusion exists about the relationship of gigantiform cementoma to florid osseous dysplasia, cementifying fibroma, and diffuse chronic sclerosing osteomyelitis. It has been unclear whether gigantiform cementoma should be accorded the status of a separate entity. In this article, we report our findings on a family that, over five generations, has exhibited clinical, radiographic, and/or histologic findings consistent with the designation familial gigantiform cementoma. This pedigree consists of 55 members. Significant heterogeneity in expression of this trait was noted. The pattern of occurrence of the trait is consistent with an autosomal dominant mode of inheritance with variable expressivity of the phenotype. We suggest that familial gigantiform cementoma should be recognized as a separate entity.

Cementoma↗
PubMed1989

Behavioral interaction between cocaine and caffeine: a drug discrimination analysis in rats.

The effects of caffeine upon the discriminative and rate-altering effects of cocaine were examined in rats. Using a food-reinforced two-lever operant procedure, 12 Sprague-Dawley male rats were trained to discriminate between 10 mg/kg cocaine and saline. Stimulus generalization tests with both cocaine and amphetamine resulted in a dose-related increase in cocaine-appropriate responding. A variable response rate topography was produced by cocaine. Caffeine also engendered a dose-related increase in cocaine-appropriate responding and resulted in a potency ratio of 15:1 when compared to cocaine. In contrast, increasing doses of caffeine produced a biphasic response rate function (first increases and then decreases). Response choice data suggested a potency relationship of amphetamine greater than cocaine greater than caffeine. Caffeine potentiated the discriminative stimulus properties of cocaine. Isobolographic analysis characterized this interaction as simple additivity. However, caffeine's effects upon the rate-altering effects of cocaine resulted in a biphasic interaction pattern. With low doses of cocaine in combination with various doses of caffeine, the interaction for rate reduction is best categorized as "supra-additive," in contrast, increasing either the cocaine dose or caffeine dose could change the interaction to simple additivity and/or infra-additivity.

Animals↗
PubMed1989

Effects of caffeine, cocaine and their combination on fixed-interval behavior in rats.

The effects of the central nervous system stimulants, caffeine and cocaine, on schedule-controlled behavior were determined in rats trained to perform a fixed-interval (FI) 5-minute task. When given alone caffeine produced a doubling of FI response rate at a dose of 10 mg/kg and reduced responding at a dose of 32 mg/kg. Cocaine, which was also expected to increase FI responding, did not increase response rate at doses of 3.2 or 10 mg/kg and decreased the rate of responding at a dose of 32 mg/kg. Caffeine had minimal effects on quarter life and appeared to increase local rates of responding across the interval. Cocaine decreased quarter life dramatically at a dose that had no effect on overall response rate. Local rates of responding were increased early in the interval and decreased in the later segments. The effects of both drugs were found to be rate-dependent. When these compounds were given in combination the results obtained appeared to be related to the rate of responding that caffeine alone would produce.

Animals↗
PubMed1989

Breast-milk composition in women with cystic fibrosis: report of two cases and a review of the literature.

Breast milk was collected from two women with cystic fibrosis (CF) and data from the literature was reviewed. The sodium concentration was within normal limits, 11-24 mmol/L in colostrum and 7-8 mmol/L in mature milk. Normal physiologic changes in milk composition after parturition (decreases in Na and increases in lactose) and during individual feeding periods (increases in fat and decreases in protein) were observed. Concentrations of milk protein, fat, and sugars were normal when the pulmonary disease of these patients was mild. During exacerbations of pulmonary disease, the concentrations of milk macronutrients were reduced. Milk secreted by women with CF appears to be physiologically normal, safe for the infant, and breast-feeding by mothers with CF should no longer be discouraged. Variations in the macronutrient content of CF milk warrants routine monitoring of the mother with CF and the breast-fed infant, especially during exacerbations in the pulmonary aspects of this disease.

Adult↗
PubMed1988

3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs.

3,7-Dimethyl-1-propargylxanthine (DMPX), a caffeine analog that exhibits in vitro selectivity for A2-adenosine receptors, compared to A1-adenosine receptors, has now been investigated with respect to in vivo potency and selectivity. DMPX potently and selectively blocked the actions of the potent A2 adenosine agonist, 5'-N-ethylcarboxamidoadenosine (NECA), in DBA/2 mice, compared to blockade of the same responses elicited by the selective A1-adenosine agonist, N6-cyclohexyladenosine (CHA). DMPX was 57-fold more potent versus NECA-induced hypothermia than versus CHA-induced hypothermia and 11-fold more potent versus NECA-induced behavioral depression than versus CHA-induced behavioral depression. The hypothermia is mediated by peripheral receptors, based on blockade by 8-(p-sulfophenyl)theophylline (PSPT), while the behavioral depression is centrally mediated, based on lack of blockade by PSPT. DMPX was 28- and 15-fold more potent than caffeine in blocking peripheral and central NECA-responses, respectively. DMPX was equipotent with caffeine versus CHA-induced hypothermia and 2.5-fold more potent than caffeine versus CHA-induced behavioral depression. The motor stimulating potency of DMPX (ED50 10 mumol/kg) was slightly greater than caffeine.

Adenosine↗
PubMed1988

Effects of chronic amphetamine in BALB/cBy mice, a strain that is not stimulated by acute administration of amphetamine.

The effects of d-amphetamine and methylphenidate on locomotor activity of BALB/cByJ mice were evaluated. d-Amphetamine had no effect or inhibited locomotor activity at acute doses of up to 10 mg/kg while methylphenidate stimulated locomotor activity at acute doses between 10 and 32 mg/kg. The dose-response curves for methylphenidate and d-amphetamine appeared to be quantal in nature. During a 21-day chronic treatment with 10 mg/kg d-amphetamine no evidence of tolerance to the depressant effects of relatively high doses of d-amphetamine was observed. However, a 3.2 mg/kg dose of d-amphetamine, which acutely inhibited locomotor activity, was found to stimulate locomotor activity following chronic amphetamine treatment. Doses of methylphenidate which acutely stimulated activity were without effect in mice chronically receiving amphetamine. Although the mechanism underlying these behavioral effects has yet to be established, our results indicate that inherent alterations can differentially affect both acute and chronic susceptibility to the behavioral effects of amphetamine and methylphenidate. Use of such altered strains of mice can be especially revealing of subtle behavioral effects brought about by chronic drug treatment which are not readily demonstrated following acute administration of amphetamine.

Animals↗
PubMed1988

Complexity of the cognitive phenotype of an inherited form of learning disability.

An extended kindred with familial reading and spelling disorder was evaluated in a detailed genetic study. Comprehensive evaluations of cognitive functioning, verbal and non-verbal information-processing and academic achievement were obtained in order to arrive at a detailed phenotypic characterization of 'affected' and 'unaffected' family members. The pattern of major deficiencies in reading and spelling in this family was consistent with an autosomal dominant genetic determinant which had variable expression and incomplete penetrance. Although similar phonemic segmentation and sequencing difficulty appeared to characterize many of the affected family members, there was a high degree of phenotypic variability within this kindred. Caution is advised in interpreting the results of studies of subtypes of dyslexia which fail to take etiology into account, and it is argued that rigorous within-kindred phenotypic studies of dyslexia should be done before generalizations are made to unrelated families.

Adolescent↗
PubMed1987

Ontogeny of susceptibility to the convulsant, Ro 5-4864, and its relationship to audiogenic seizure susceptibility in inbred mice.

The postnatal development of susceptibility to the convulsant effects of Ro5-4864 (4'-chlorodiazepam) was characterized in two inbred mouse strains (DBA/2J and BALB/c ByJ) which as adults differ markedly in their response to this convulsant. Onset of susceptibility to a dose of Ro5-4864 which caused a high frequency of clonic seizures in adults was observed at 10 days of age in DBA/2 mice, but not until 35 days in BALB/c By mice. At 14 days of age an abrupt increase in susceptibility to Ro5-4864-induced tonic seizures was found in DBA/2 but not BALB/c By mice. Both the peak of tonic seizure susceptibility (21 days) and the time course of its subsequent age-dependent decline closely paralleled the change in audiogenic seizure susceptibility in the DBA/2 strain. PK11195 (40 mg/kg) blocked Ro5-4864 (25 mg/kg)-induced, age-dependent tonic seizures but had no effect on clonic seizure induction in the same mice. These observations establish that both the susceptibility to Ro5-4864 in adult mice and the postnatal time course for development of susceptibility to this convulsant are inherently different in these two strains of mice. The lack of coincidence between the developmental onset of susceptibility to Ro5-4864-induced seizures and the onset of supersensitivity to Ro5-4864-induced tonic seizures during the period of peak audiogenic seizure susceptibility in DBA/2 mice implies that more than one neurochemical mechanism is involved in the ability of Ro5-4864 to induce seizures in this strain. However, the blockade of Ro5-4864-induced tonic seizures by PK11195 suggests that peripheral type benzodiazepine receptors may mediate this effect.

Acoustic Stimulation↗
PubMed1987

Coincidence of seizure susceptibility to caffeine and to the benzodiazepine inverse agonist, DMCM, in SWR and CBA inbred mice.

Several lines of evidence suggest that the convulsant actions of caffeine are mediated through benzodiazepine receptors. A pharmacogenetic approach has been used to further explore the relationship of these receptors to caffeine-induced seizures. The susceptibility of two inbred strains of mice (CBA and SWR) to the convulsant actions of picrotoxinin, strychnine, Ro 5-4864 and DMCM was examined. Previous studies have demonstrated these two strains differ in their susceptibilities to the convulsant action of caffeine. While no differences were observed between these two strains in susceptibility to tonic seizures induced by picrotoxinin, RO 5-4864 or strychnine, SWR mice were significantly less sensitive to tonic seizures induced by DMCM compared to CBA mice (CD50 values in CBA and SWR mice were 6 and 12 mg/kg IP). Both clonazepam and the benzodiazepine receptor antagonist, Ro 15-1788, significantly blocked caffeine-induced seizures. Further, when subconvulsant doses of caffeine and DMCM were combined, a synergistic action was observed. Taken together, these findings support the hypothesis that the convulsant actions of caffeine result from an action at benzodiazepine receptors, and that the hyporesponsiveness of the SWR strain to both caffeine- and DMCM-induced seizures could result from an inherited abnormality in these sites.

Animals↗
PubMed1987

Different genes specify hyporesponsiveness to seizures induced by caffeine and the benzodiazepine inverse agonist, DMCM.

Two strains of inbred mice differed significantly in their susceptibility to tonic seizures induced by caffeine and the benzodiazepine inverse agonist, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). The hyporesponsive strain, SWR, was not less susceptible to the convulsant action of other chemical convulsants, an observation which indicated that the response differences between the strains were pharmacologically specific. These observations and drug interaction studies suggested that caffeine-induced seizures might be mediated through an "inverse" agonist-like action of caffeine on benzodiazepine receptors associated with GABA receptor-benzodiazepine receptor-chloride ionophore complex. To determine whether the coincident alteration in susceptibility to DMCM and caffeine resulted from a single mutational change or was the result of two different genetic changes occurring coincidentally between these two strains of mice, progeny from conventional Mendelian crosses (F1, F2 and reciprocal backcrosses) were analyzed for the co-segregation of susceptibility to DMCM and caffeine. The inheritance of DMCM sensitivity was consistent with a single autosomal gene determinant in which the allele specifying increased responsiveness was dominant to the allele determining hyporesponsiveness. The frequent occurrence of recombinant phenotypes (e.g., caffeine hyporesponsive but DMCM sensitive mice) among F2 and backcross progeny established that different genetic determinants encode DMCM susceptibility and caffeine susceptibility in these two strains of mice. Thus, while these data establish a simply inherited difference in benzodiazepine responsiveness between the two mouse strains, they also indicate that this pair of strains is inappropriate for a genetic analysis aimed at probing the relationship between caffeine-induced seizures and the benzodiazepine receptor.

Animals↗
PubMed1986

Inherent hyporesponsiveness to methylxanthine-induced behavioral changes associated with supersensitivity to 5'-N-ethylcarboxamidoadenosine (NECA).

Two inbred mouse strains, SWR and CBA, differed significantly in their susceptibility to acute dose dependent theophylline- and caffeine-induced stimulation of locomotor activity. The efficacy of both methylxanthines was reduced in the SWR strain compared to the CBA strain. When brain levels of theophylline were determined at a dose (32 mg/kg IP) which gave maximal behavioral separation of the two strains, no significant differences were found between them (SWR levels 12.5 +/- 1.9, CBA levels 14.3 +/- 1.7 micrograms/g wet weight brain). The dose dependent ability of several adenosine agonists (N6-cyclohexyladenosine, (-)-N6-phenylisopropyladenosine, 5'-N-ethylcarboxamidoadenosine) to depress locomotor activity was investigated. SWR mice were found to be significantly more sensitive to NECA-induced depression of locomotor activity and the NECA-induced hypothermia than were CBA mice (respective ED50 values for inhibition of activity, 11.6 and 30.5 nmoles/kg IP). No differences were found in brain [3H]-NECA levels at doses which produced marked differences in behavioral effects between the two strains. The differences in adenosine agonist sensitivity between the strains were both agonist- and behavior-specific. These data indicate that an inherited alteration in behavioral responsiveness to methylxanthine administration can be inversely associated with inherent alterations in susceptibility to the action of specific adenosine analogs. An adenosine A-2 receptor sub-class may be involved in these changes in in vivo pharmacological susceptibility to the action of both methylxanthines and adenosine agonists on locomotor activity.

Adenosine↗
PubMed1986

Inherent differences in sensitivity to methylxanthines among inbred mice.

The behavioral effects of caffeine, theophylline, paraxanthine, and theobromine on locomotor activity were analyzed in four strains of inbred mice that were previously shown to differ in their acute toxic responses to caffeine administered at high dosages. Dose response curves for the effects of caffeine, theophylline, paraxanthine and theobromine on locomotor activity were established in CBA/J, C57BL/6J, DBA/2J and SWR/J strains of inbred mice. Paraxanthine was the maximally effective methylxanthine in the CBA/J, DBA/2J and SWR/J strains, while in the C57BL/6J strain, caffeine was the maximally effective methylxanthine. Theophylline failed to stimulate locomotor activity in the C57BL/6J strain and theobromine failed to stimulate activity in all of the strains tested. Decreases in locomotor activity were seen at the 100 mg/kg dose of caffeine in the C57BL/6J mice and at the 100 mg/kg dose of theophylline in the C57BL/6J, DBA/2J and SWR/J strains. Theobromine produced decreases in locomotor activity in the C57BL/6J, DBA/2J and SWR/J strains of mice. In contrast to the other methylxanthines, paraxanthine failed to decrease activity across the range of doses tested (1.0-150 mg/kg). These data suggest that the methylxanthines have genetically specified multiple modes of action upon locomotor activity and that the use of genetically distinct strains of mice may have important value in the neurochemical and pharmacological dissection of methylxanthine-induced behavioral effects.

Animals↗
PubMed1986

Complex genetic determinants of susceptibility to methylxanthine-induced locomotor activity changes.

The intent of this study was to investigate the role of inheritance in the determination of susceptibility to methylxanthine-induced behavioral changes. Two strains of inbred mice, SWR and CBA, which differ significantly in their response to caffeine- and theophylline-induced stimulation of locomotor activity, were used in classical genetic crosses to produce reciprocal F1 hybrids, reciprocal backcross progeny F2 progeny. Theophylline dose response curves in the reciprocal F1 hybrid strains were identical to each other and to their methylxanthine-responsive (CBA) parent. These results indicated that theophylline responsiveness behaved as a simple autosomal dominant trait. Behavioral responses of these F1 hybrid strains to caffeine showed the same maximal enhancement of locomotor activity as their CBA progenitor at a dose 10 mg/kg IP, but locomotor activity stimulation also occurred at 32 mg/kg IP, a dose which inhibited their CBA parent. These data suggest that the genes specifying caffeine responsiveness differ from those encoding theophylline responsiveness. For both caffeine and theophylline, behavioral phenotypes and their expected frequencies of occurrence among backcross and F2 progeny differed significantly from the segregation ratios expected for a trait determined by a single gene. These non-Mendelian segregation ratios suggest that locomotor activity stimulation by both of these methylxanthines is polygenically determined. It was anticipated that the same genetically encoded neurochemical mechanism would underlie the difference in behavioral response to the two methylxanthines. However, no significant correlation between caffeine-induced and theophylline-induced stimulation of locomotor activity was observed among progeny derived from backcrosses of F1 self-crosses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Differential antagonism of the behavioral depressant and hypothermic effects of 5'-(N-ethylcarboxamide) adenosine by theobromine.

The methylxanthine, theobromine (3,7-dimethylxanthine), was tested in mice, to determine whether theobromine could function in vivo as an adenosine receptor antagonist, in keeping with its reported in vitro effects as a blocker of agonist binding to the adenosine A-1 receptor. Theobromine doses, which themselves had no direct effects on spontaneous locomotor activity, completely blocked N6-cyclohexyladenosine-induced suppression of locomotor activity but were without effect on 5'-N-ethylcarboxamide adenosine (NECA)-induced decreases in motor activity. In contrast to the specific antagonism, theobromine blocked the hypothermia induced by both of these adenosine analogs. These results demonstrate that theobromine is an active in vivo adenosine receptor antagonist and that the antagonism of N6-cyclohexyladenosine sensitive systems occurs even though theobromine does not stimulate spontaneous locomotor activity. Thus, the behavioral stimulant effects of methylxanthines may be more related to effects on NECA-sensitive systems, which are not blocked by theobromine. The use of in vivo differences in the effects xanthine may provide a useful tool in the development of compounds to probe the mechanisms of caffeine induced CNS effects.

Adenosine↗
PubMed1986

Phenyl isopropyl adenosine alters fetal electrocorticogram, breathing and heart rate.

Six fetal sheep were equipped with intratracheal, amniotic and vascular catheters and electrocorticogram electrodes to study the effect of phenyl isopropyl adenosine (PIA) on electrocorticogram and fetal breathing movements. Three animals had functioning electrocardiogram electrodes. During 1,000-min control periods, low-voltage high-frequency (LVHF) electrocorticogram predominated 60 +/- 1% (mean +/- SEM) of total time. Fetal breathing movements occurred 34 +/- 1% of total time and only during LVHF electrocorticogram. PIA 0.125 mg was given intravenously to the fetus during established LVHF electrocorticogram and fetal breathing movements. LVHF electrocorticogram converted in 58 +/- 16 s to high-voltage low-frequency (HVLF) electrocorticogram which persisted for 10 +/- 3 min. This was followed by a third electrocorticogram pattern for 119 +/- 12 min. Fetal breathing movements ceased in 47 +/- 25 s and did not recur for 150 +/- 20 min. An increase in fetal breathing movements (59 +/- 2% of total time) occurred between 300 and 800 min (control 34 +/- 1%, p less than 0.05). Electrocardiogram demonstrated a decrease in heart rate from 170 +/- 6 to 90 +/- 6 beats per min with return to baseline in 113 +/- 49 min. No significant changes occurred in blood gases. We conclude that fetal electrocorticogram, fetal breathing movements and heart rate are influenced by adenosine.

Adenosine↗
PubMed1985

Sensitivity of inbred mice to methylxanthines is not determined by plasma xanthine concentration.

Male CBA/J and SWR/J mice were tested with doses of caffeine, theophylline and 8-p-sulfophenyltheophylline (xanthine). Caffeine produced dose-related decreases in locomotor activity and colonic temperatures in SWR/J mice. However, caffeine produced increases in locomotor activity and failed to lower the body temperature of CBA/J mice. Theophylline produced a decrease in body temperature of SWR/J mice. Comparison of brain caffeine levels demonstrated no difference in brain pharmacokinetics. The peripherally active xanthine failed to alter body temperature at the same molar dose as that of theophylline. These data clearly demonstrate that genetic differences in the effects of methylxanthine are due to inherent differences in the central nervous system sensitivity of the two strains. The data further indicate that while differences in xanthine metabolism may occur in inbred mice, these differences are not a major factor in the acute, peak plasma level, effects of xanthines.

Animals↗