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Biomedical subjects

L M Dixon

Publications and source records attributed to L M Dixon.

At least 19 recordsLinked to original sources
PubMed1998

Derivatives of WAY 100635 as potential imaging agents for 5-HT1A receptors: syntheses, radiosyntheses, and in vitro and in vivo evaluation.

Analogues of the potent and selective 5-HT1A ligand, WAY 100635, were synthesized and examined as potential candidates for imaging 5-HT1A receptors by positron emission tomography (PET). Several of the analogues displayed nanomolar affinity for the 5-HT1A receptor, comparable to WAY 100635. Three of these were examined in a model of human liver metabolism vis-à-vis WAY 100635. All showed a markedly lower propensity for amide hydrolysis than WAY 100635. Radiolabelling of these three potential PET radiotracers with carbon-11 was readily achieved from [11C]-iodomethane, and the newly synthesized radioligands were tested in vivo in rats for binding to 5-HT1A receptors. Whereas two of the ligands failed to bind to 5-HT1A receptors in vivo, one was successful. The latter, [11C]-7 [4-(2'-methoxyphenyl)-1-[2'-[N-(2'-pyridinyl)-2-bicyclo[2.2.2]octanec arboxamido]ethyl]-piperazine], showed good brain penetration, hippocampal:cerebellar ratios of 10:1 at 45 min postinjection. Blocking studies with a variety of drugs demonstrated that the binding of [11C]-7 in vivo was selective for 5-HT1A receptors. [11C]-7 is a promising candidate as a ligand for imaging 5-HT1A receptors by PET.

Animals↗
PubMed1996

Cloning of a G protein-activated inwardly rectifying potassium channel from human cerebellum.

Based on sequence homology with the rat atrial G protein-coupled muscarinic potassium channel (GIRK1 or KGA1/KGB1), a human cDNA encoding a G protein-activated inwardly rectifying K+ channel (HGIRK1) was isolated. The cDNA encodes a protein of 501 amino acids and shares 99% identity to rat GIRK1 in its total amino acid sequence. Southern blot analysis of genomic DNA indicates a high degree of conservation among various species. In the human population a useful NlaIII restriction fragment length polymorphism was found in the coding sequence of HGIRK1. Co-expression of HGIRK1 and the 5-HT1A receptor in Xenopus oocytes resulted in opening of the channel upon treatment with serotonin. HGIRK1 currents showed strong inward rectification and could be blocked by extracellular Ba2+. Northern blot analysis shows that HGIRK1 expression in human is most abundant in the brain, while lower levels are round in kidney and heart.

Amino Acid Sequence↗
PubMed1994

Cerebellar glutamate metabolizing enzymes in spinocerebellar ataxia type I.

We measured the levels of three glutamate metabolizing enzymes, namely, glutamate dehydrogenase (GDH), aspartate aminotransferase (AAT), and glutamine synthetase (GS) in cerebellar and occipital cortices of nine patients with dominantly-inherited olivopontocerebellar atrophy (OPCA; spinocerebellar ataxia type I). As compared with the controls, mean GDH activities in cerebellar cortex of the OPCA patients were normal whereas levels of AAT (-17%) and the glial enzyme GS (-27%) were significantly reduced. No statistically significant changes were observed in occipital cortex, a morphologically unaffected brain area. We suggest that the decreased GS levels could reflect impaired capacity of astrocytes to metabolize glutamate which might contribute to the degenerative processes in OPCA cerebellum.

Adult↗
PubMed1994

Regional thyroid hormone levels in rat brain.

Levels of T4 and T3 were measured in half-brain and seven brain regions. Although thyroid hormones were distributed throughout the brain, T4 levels were highest in cerebellum and thalamus. The highest T3 levels were observed in the thalamus and lowest levels were found in olfactory bulb, hypothalamus, and amygdala.

Animals↗
PubMed1994

Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self-administration.

We examined the influence of chronic cocaine exposure, in an unlimited access self-administration paradigm, on density of the dopamine transporter (3H-WIN 35,428 and 3H-GBR 12,935 binding) and concentration of monoamine (dopamine, serotonin, noradrenaline and metabolites) neurotransmitters in rat brain. In normal rodent striatum 3H-WIN 35,428 and 3H-GBR 12,935 binding to the dopamine transporter, although generally similar, showed different subregional rostrocaudal and mediolateral gradients, suggesting that the two ligands might bind to different subtypes or states of the dopamine transporter. Following chronic, unlimited access cocaine self-administration, binding of 3H-WIN 35,428 was significantly elevated in whole nucleus accumbens (+69%, p < 0.001) and striatum (+65%, p < 0.001) on the last day of cocaine exposure ("on-cocaine group"); whereas in the 3 week withdrawn animals ("cocaine-withdrawn group"), levels were either normal (striatum) or reduced (-30%, p < 0.05, nucleus accumbens). Although similar changes in 3H-GBR 12,935 binding were observed, this dopamine transporter ligand showed a smaller and highly subregionally dependent increase in binding in striatal subdivision of the on-cocaine group, but a more marked binding reduction in the cocaine-withdrawn animals. As compared with the controls, mean dopamine levels were reduced in striatum (-15%, p < 0.05) of the on-cocaine group and in nucleus accumbens (-40%, p < 0.05) of the cocaine-withdrawn group. These data provide additional support to the hypothesis that some of the long-term effects of cocaine exposure (drug craving, depression) could be consequent to reduced nucleus accumbens dopamine function. Our data also suggest that dopamine transporter concentration, and perhaps function, might undergo up- or downregulation, either as a direct effect of cocaine, or indirectly as part of a homeostatic response to altered synaptic dopamine levels, and therefore might participate in the neuronal events underlying cocaine-induced behavioral changes.

Animals↗
PubMed1993

Brain cytochrome oxidase activity after kindled seizures: a quantitative histochemical mapping study.

Quantitative histochemistry was used to analyze changes in cytochrome oxidase (CO) activity in 93 brain regions after entorhinal cortex kindling. Rats were kindled to at least six stage-5 seizures and sacrificed either 24 h or 28 days after the last convulsion. Regional brain CO activity was quantitated in histological sections using calibrated densitometric standards. No statistically significant differences in regional CO activity between kindled and control brains were seen either 24 h or 28 days after the last convulsion. These results suggest that the brain changes underlying the kindling state are not reflected in localized alterations in mitochondrial respiratory capacity. They also indicate that long-lasting changes in regional brain CO activity recently found after electroconvulsive shock are not common to all types of seizures.

Animals↗
PubMed1992

Brain neurotransmitter changes in human narcolepsy.

We measured the concentrations of the three major monoamine neurotransmitters noradrenaline, dopamine, and serotonin, their metabolites, and receptor binding sites in autopsied brain of three patients with narcolepsy. As compared with the controls, concentrations of the noradrenaline and serotonin metabolites MHPG and 5-HIAA, respectively, were markedly elevated in cerebral cortical subdivisions of the narcolepsy patients together with a trend for above-normal neurotransmitter/metabolite "turnover" ratio. A moderately reduced number of alpha 1-adrenoceptors, as judged by the reduced levels of 3H-prazosin binding, was observed in cerebral cortex of two of the three patients with narcolepsy. Mean striatal levels of dopamine and its metabolite homovanillic acid were normal, whereas the concentration of dopamine's second metabolite, dihydroxyphenylacetic acid, was markedly reduced by 50% or greater. This was accompanied by a marked increase (+125%) in mean 3H-spiperone binding to the D2 dopamine receptor in both caudate and putamen; in contrast, the levels of 3H-SCH 23390 binding to the striatal D1 dopamine receptor were in the normal range. Our data provide evidence for altered brain monoaminergic neurotransmitter function in human narcolepsy.

Adult↗
PubMed1989

Effects of chronic haloperidol on stress-induced oral behaviour in rats.

Rats received daily injections of haloperidol (HAL, 5 mg/kg SC, or IP) or tartaric acid vehicle for 14-21 days. Four to six days after discontinuation of the daily injections, rats were given a single 5-min tail pinch (TP) test. HAL-treated rats showed significantly shorter latencies to display oral behaviours (OB: licking, gnawing, or drinking) compared to controls in five separate replications. Food consumption per se was not consistently affected. Shorter OB latencies were significantly correlated both with increased striatal 3H-spiperone binding and with apomorphine stereotypy scores. In a final experiment, this effect of HAL on OB latencies was blocked by a systemic injection of naloxone (2 mg/kg IP) prior to the TP test. Naloxone did not affect OB latency in control rats, suggesting the possibility of endogenous opiate involvement in the chronic HAL effects. The overall results suggest that OB latencies following mildly activating stimulation may provide a useful behavioural assay for neuroleptic-induced oral abnormalities as well as a functional index of striatal dopamine D-2 receptor sensitivity.

Animals↗
PubMed1988

Graded increases in brain GABA: differential effects on feeding and other behaviours in rats.

Elevations of brain gamma-aminobutyric acid (GABA) induced by inhibitors of GABA transaminase (GABA-T) are known to induce a number of functional effects including depression of food intake. The aim of the present study was to determine the brain GABA elevation threshold for changes in feeding and several other behaviours, in an effort to clarify whether feeding changes might be secondary to other functional deficits. To this end, various doses of the GABA-T inhibitors ethanolamine-o-sulfate (EOS) and gamma-vinyl GABA (GVG) were injected intracisternally and effects on whole brain GABA, food and water intake, open field activity, catalepsy indices, pain sensitivity, and core temperature were assessed 24 h later. Progressive increases in brain GABA levels were found to differentially affect the responses studied. At the low end of the continuum, significant decreases in feeding behaviour were associated with relatively modest increases in brain GABA (40-60%). At higher levels of GABA elevation (greater than 100%), changes in motoric functions and rectal temperature became apparent. At still higher levels (greater than 200% increases in brain GABA), significant antinociceptive effects were detected. These results support the notion that feeding decreases induced by low doses of GABA-T inhibitors may reflect a fairly specific effect on appetite mechanisms, but also indicate that with increasingly higher doses several other deficits are likely to contribute to the overall decrease in food intake.

4-Aminobutyrate Transaminase↗
PubMed1988

Brain neurotransmitters in glycine encephalopathy.

We measured neurotransmitter markers in autopsied brain of infants with glycine encephalopathy (GE). Because patients with GE develop intractable seizures, special attention was devoted to those neurotransmitter systems implicated in human epilepsy. Mean levels of glycine in the frontal cortex of GE patients were three times higher than control values. No abnormalities were observed for concentrations of gamma-aminobutyric acid (and related receptors), other major neurotransmitter amino compounds, or activities of cholineacetyltransferase and aspartate aminotransferase. Mean acetylcholinesterase activity was significantly elevated by 46%. As experimental data suggest, glycine markedly potentiates the action of the excitatory neurotransmitter glutamic acid. To the extent that the brain seizures in patients with GE can be explained by this mechanism, pharmacotherapy with excitatory amino acid antagonists may represent a new approach to the treatment of GE.

Amino Acid Metabolism, Inborn Errors↗
PubMed1988

Aspartic acid aminotransferase activity is increased in actively spiking compared with non-spiking human epileptic cortex.

Increased concentration of the excitatory neurotransmitter aspartic acid in actively spiking human epileptic cerebral cortex was recently described. In order to further characterise changes in the aspartergic system in epileptic brain, the behaviour of aspartic acid aminotransferase (AAT), a key enzyme involved in aspartic acid metabolism has now been examined. Electrocorticography performed during surgery was employed to identify cortical epileptic spike foci in 16 patients undergoing temporal lobectomy for intractable seizures. Patients with spontaneously spiking lateral temporal cortex (n = 8) were compared with a non-spiking control group (n = 8) of patients in whom the epileptic lesions were confined to the hippocampus sparing the temporal convexity. Mean activity of AAT in spiking cortex was significantly elevated by 16-18%, with aspartic acid concentration increased by 28%. Possible explanations for the enhanced AAT activity include increased proliferation of cortical AAT-containing astrocytes at the spiking focus and/or a generalised increase in neuronal or extraneuronal metabolism consequent to the ongoing epileptic discharge. It is suggested that the data provide additional support for a disturbance of central excitatory aspartic acid mechanisms in human epileptic brain.

Adolescent↗
PubMed1986

Learning is improved by a soybean oil diet in rats.

A semi-synthetic diet containing 20% polyunsaturated fat (soybean) oil was fed to young male hooded rats for 21 days. These animals exhibited improved performance on an environmentally-cued testing paradigm which is thought to reflect cognitive learning skills (i.e., Place Navigation Water Task). Other rats fed the same base diet but containing 20% saturated fat (lard) showed no such improvement compared to chow-fed (4.5% mixed fat) controls. The animals fed soybean oil also exhibited a transient resistance to extinguish this learning. This improved learning could not be explained by changes in general motor activity, basal body temperature, energy consumption, body weight, or in the brain activity of choline acetyltransferase, the marker enzyme for cholinergic neurons. These findings constitute the first evidence that short-term variations in the quality of dietary fat can enhance mammalian learning.

Animals↗
PubMed1986

Effects of dietary fat on pain threshold, thermoregulation and motor activity in rats.

Groups of young male Sprague-Dawley (albino) or Long-Evans (hooded) rats were fed the same semi-purified diets containing 20% (w/w) fat in the form of soybean oil vs. lard, or a reference diet of standard Purina Chow (4.5% mixed fats) for 21 days. Behavioral testing after this time revealed that albino rats fed the diet containing soybean oil had increased paw-lick latencies on a 58 degrees C hot plate compared to chow-fed rats. In addition, both strains fed the diet containing soybean oil were protected from hypothermia induced by placing animals in a 4 degrees C cold room for 60 min following systemic injection of 10-15 mg/kg d-amphetamine. Rats of both strains fed the lard diet displayed paw-lick latencies similar to those shown by rats fed chow and hypothermic changes intermediary to those shown by rats fed soybean oil vs. chow diets. Horizontal crossings as well as rearings in a 15 min test of open field activity were the same for all diet groups within strains. No substantial differences were observed in the number of calories consumed, amount of body weight gained or basal colonic temperatures across diet conditions. The results suggest that a soybean oil-based diet can alter physiological mechanisms which mediate these indices of pain perception and thermoregulation. More generally, they indicate that qualitative changes in dietary fat content may be capable of altering certain behavioral states.

Amphetamine↗
PubMed1985

Catamenial hemoptysis. New methods of diagnosis and therapy.

Bronchopulmonary endometriosis is a rare cause of hemoptysis. We describe a woman with catamenial hemoptysis which was localized with chest CAT scanning and treated successfully with danazol. The proposed pathogenesis and manifestations of thoracic endometriosis are reviewed, and the use of new diagnostic and therapeutic modalities in its management are discussed.

Adult↗
PubMed1978

The diagnostic potential of rheoencephalography in psychiatry.

A 33 electrode monopolar rheoencephalograph was employed to produce a 15 min record of electrical impedance plethysmographic pulse-volume waves in 139 healthy sujects and 782 patients belonging to 15 psychiatric syndromes. Parameters of amplitude, percent rise time and average inflow angle were hand-measured and their means obtained for 30 waveforms throughout each record. Results obtained depended significantly upon chronological age and in some cases on gender. Mental health was found clearly distinguishable from psychiatric disability, but psychiatric syndromes could not be differentiated from one another. A low percent rise time coupled with a high average inflow angle were typical of youth and mental health.

Adolescent↗
PubMed1977

Infectious mononucleosis and fatal myocarditis.

Mycocarditis is an uncommon manifestation and, very rarely, a lethal complication of infectious mononucleosis. A 14-year-old girl initially had exudative pharyngitis and splenomegaly and developed refractory ventricular fibrillation. The diagnosis of infectious mononucleosis was confirmed by both a strongly positive heterophil antibody test and a high titer of Epstein-Barr virus. Pathologic studies demonstrated extensive histiocytic and lypmhocytic infiltration of the myocardium.

Adolescent↗
PubMed1976

Carotid-vertebral artery blood transit time: results in healthy subjects and patients with schizophrenia and brain disease.

Estimation of blood transit time in the neck and the extension of this into the head was made by a method of electrical impedance, over a wide age range, in 159 healthy subjects, 160 schizophrenic patients, and 199 patients with organic brain disease. In each case, the distance between the electrocardiogram and the next succeeding pulse-volume impedance wave was measured and averaged over 30 serial wave forms. Chronological age proved a significant variable, transit times lengthening progressively with the age, but only for measurements extending into the head. Sex and hemispheric laterality played no significant role. With age held constant, mean transit times into the head were significantly prolonged in both groups of patients as compared with controls. No significant differences were found however between means of psychiatric andneurological patients. It is suggested that these results reinforce the organic etiology of schizophrenia.

Adolescent↗