Biomedical subjects

P R Dodd

Publications and source records attributed to P R Dodd.

At least 55 records · Page 3Linked to original sources

PubMed1993

Transmitter amino acid neurochemistry in chronic alcoholism with and without cirrhosis of the liver.

Neurotransmitter receptor studies are beginning to be applied more widely to human brain tissue obtained at autopsy. By taking tissue from well-documented cases which have been extensively characterized on histological and morphometric criteria, it is becoming possible to make clinicopathological correlations in studies of the effects of chronic alcohol abuse. Recent findings of alterations in the nature and amounts of amino acid neurotransmitter receptors in alcoholism are summarized, with special emphasis on the effects of chronic severe liver disease. There are selective changes in receptors in the superior frontal cortex of alcoholics. There is a marked increase in the density of the GABA binding site, and a lesser change in the density of the 'central-type' benzodiazepine site, on the GABAA-benzodiazepine receptor complex. In contrast, glutamate receptors may be much less affected. Together with morphological and cognitive studies, the results suggest that the superior frontal cortex is preferentially damaged in chronic alcoholism. An increase in 'central-type' benzodiazepine sites in both superior frontal cortex and motor cortex in cirrhotic alcoholics may reflect a more global brain damage, as observed in morphological studies. However, it should be noted the changes in [3H]GABA/muscimol binding were less pronounced in cirrhotic alcoholics than in non-cirrhotic alcoholics.

Journal Article↗

PubMed1992

Amino acid neurotransmitter receptor changes in cerebral cortex in alcoholism: effect of cirrhosis of the liver.

Gamma-aminobutyric acidA/benzodiazepine receptor binding sites and the N-methyl-D-aspartate subclass of glutamate receptor sites were assessed in synaptic plasma membrane homogenates of cerebral cortex tissue obtained at autopsy from cirrhotic and noncirrhotic alcoholic patients and matched control subjects. The alcoholic patients consumed an average of greater than 80 g of ethanol/day, the control subjects less than 20 g/day. Postmortem delays up to approximately 100 h caused no significant loss of any of the binding sites; the patient and subject groups were closely matched for age. The affinities (KD) of the receptor sites did not differ between the patient and subject groups, nor between cortical regions. Using three different radioligands ([3H]muscimol, [3H]flunitrazepam, and [3H]diazepam), the gamma-aminobutyric acidA/benzodiazepine receptor complex was found to have greater density (Bmax) in superior frontal gyrus in alcoholic patients (which selectively shows morphological change in alcoholic patients), but was unchanged in motor cortex. Alcoholic patients with cirrhosis had much less pronounced changes. The density of the N-methyl-D-aspartate subclass of glutamate receptors, assessed with [3H]MK-801, did not vary across patient and subject groups.

Adult↗

PubMed1992

Glutamate and gamma-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves.

Cerebral cortex tissue was obtained at autopsy from neonatal Poll Hereford calves with clinically confirmed maple syrup urine disease (MSUD), neonatal Holstein-Friesian calves with clinically confirmed citrullinemia, and matched controls. From this, synaptosomes were prepared for studies of neurotransmitter amino acid uptake and stimulus-induced release, and synaptic plasma membranes were obtained for studies of associated postsynaptic receptor binding sites. As well as having abnormal brain tissue concentrations of the pathognomic plasma amino acids (markedly increased levels of the branched-chain compounds valine, isoleucine, and leucine in MSUD; marked elevation of citrulline levels in citrullinemia), both groups of diseased animals showed reduced brain tissue concentrations of each of the transmitter amino acids glutamate, aspartate, and gamma-aminobutyric acid (GABA). Nontransmitter amino acids were generally unaffected in either disease. Citrullinemic calves showed a marked increase in brain glutamine concentration; in calves with MSUD, the glutamine concentration was raised, but to a much lesser extent. The Na(+)-dependent synaptosomal uptake of both glutamate and GABA was markedly reduced (to less than 50% of control values in both cases) in citrullinemic calves but was unaltered in calves with MSUD. Whereas synaptosomes from normal calves showed the expected stimulus-coupled release of transmitter amino acids, especially glutamate and aspartate, and no response to stimulus of nontransmitter amino acids, there was no increased release of transmitter amino acids in response to depolarization in synaptosomes from citrullinemic calves.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Reaction↗

PubMed1991

[3H]MK-801 binding in immature and mature chicken forebrain.

Previous studies have shown that the rate of calcium uptake stimulated by N-methyl-D-aspartate (NMDA) increased during the maturation phase of synapse development in chicken forebrain. To investigate whether this change in function is due to a change in the properties of NMDA receptor associated ion channels, we measured the binding of [3H]MK-801 (a ligand which binds to the NMDA receptor associated ion channel) to membranes from immature and mature chicken brain. The binding properties of MK-801 in chicken brain were similar to those in mammalian brain. There was no significant difference in any of the binding parameters measured at the two ages, i.e. KD, Bmax and optimal glutamate concentration for and maximal enhancement by glutamate of MK-801 binding. These results suggest that there is no change in the NMDA operated ion-channels during maturation. Thus the maturational change in NMDA receptor function could be due to: a change in the agonist portion of the NMDA receptor, a change in the regulation of the receptor/ionophore complex, perhaps by the postsynaptic density whose structure and composition changes during the same period, or a change in the number of voltage-sensitive calcium channels recruited as a result of NMDA receptor activation.

Adenosine Triphosphate↗

PubMed1991

The interaction of a Huntington disease factor with receptors for the neurotoxin kainic acid.

A factor from mammalian and human brain, which inhibits the rate of migration of leukocytes obtained from sufferers from Huntington disease (Walls and Ruwoldt, 1984), inhibited the specific binding of the neurotoxin [3H]kainic acid to rat brain synaptic membranes. The factor was present in sucrose-particulate but not in soluble fractions from rat sub-cortical tissue, and was destroyed by tryptic digestion. Whereas an ammonium sulfate fraction of direct saline extracts of brain (Walls and Ruwoldt, 1984) gave poor chromatography on HPLC, prior separation of a sucrose-particulate fraction resulted in much improved chromatography. There was a good concordance between leukocyte migration inhibitory activity and [3H]kainic acid binding inhibitory activity. The factor may be an endogenous modulator of the kainic acid subset of receptors for the excitatory neurotransmitter glutamic acid.

Animals↗

PubMed1991

Mechanisms of synaptic plasticity. Changes in postsynaptic densities and glutamate receptors in chicken forebrain during maturation.

We have shown that the synapse maturation phase of synaptogenesis is a model for synaptic plasticity that can be particularly well-studied in chicken forebrain because for most forebrain synapses, the maturation changes occur slowly and are temporally well-separated from the synapse formation phase. We have used the synapse maturation phase of neuronal development in chicken forebrain to investigate the possible link between changes in the morphology and biochemical composition of the postsynaptic density (PSD) and the functional properties of glutamate receptors overlying the PSD. Morphometric studies of PSDs in forebrains and superior cervical ganglia of chickens and rats have shown that the morphological features of synapse maturation are characteristic of a synaptic type, but that the rate at which these changes occur can vary between types of synapses within one animal and between synapses of the same type in different species. We have investigated, during maturation in the chicken forebrain, the properties of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptors, which are concentrated in the junctional membranes overlying thick PSDs in the adult. There was no change in the number of NMDA receptors during maturation, but there was an increase in the rate of NMDA-stimulated uptake of 45Ca2+ into brain prisms. This functional change was not seen with the other ionotropic subtypes of the glutamate receptor and was NMDA receptor-mediated. The functional change also correlated with the increase in thickness of the PSD during maturation that has previously been shown to be due to an increase in the amount of PSD associated Ca(2+)-calmodulin stimulated protein kinase II (CaM-PK II). Our results provide strong circumstantial evidence for the regulation of NMDA receptors by the PSD and implicate changing local concentrations of CaM-PK II in this process. The results also indicate some of the ways in which properties of existing synapses can be modified by changes at the molecular level.

Animals↗

PubMed1991

Alterations in cortical [3H]kainate and alpha-[3H]amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding in a spontaneous canine model of chronic hepatic encephalopathy.

Excitatory amino acid receptor binding parameters were investigated in a spontaneous dog model of chronic hepatic encephalopathy. L-[3H]Glutamate, (+)-[3H]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine maleate ([3H]MK-801), [3H]kainate, and alpha-[3H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding experiments were performed using crude cerebrocortical synaptosomal membrane preparations from dogs with congenital portosystemic encephalopathy (PSE) and control dogs. There was no change in the affinity or density of L-[3H]-glutamate or [3H]MK-801 binding sites in dogs with congenital PSE compared with control dogs. However, in the PSE dogs there was a significant reduction in the density of [3H]kainate binding sites compared with control dogs and abolition of the low-affinity [3H]AMPA binding site. The relative binding capacity of PSE synaptosomal membranes for [3H]kainate and [3H]AMPA was expressed as the ratio Bmax/KD. There was a significant inverse correlation between the Bmax/KD ratio for [3H]AMPA binding and the worst grade of encephalopathy experienced by each dog. These results suggest that there is a significant perturbation of cerebrocortical non-N-methyl-D-aspartate receptor binding in dogs with congenital PSE which may have relevance to the pathogenesis of hepatic encephalopathy.

Animals↗

PubMed1990

Plasma GABA-like activity in rats with hepatic encephalopathy is due to GABA and taurine.

Significant discrepancy exists between radioreceptor and high-performance liquid chromatographic estimates of plasma GABA concentrations in animal models of hepatic encephalopathy. A possible explanation for this discrepancy is the presence in plasma of a substance that can inhibit [3H]-GABA binding but is not GABA itself. The aim of this study was to determine whether any of the amino acids that are increased in the plasma of animal models of acute and chronic hepatic encephalopathy (glutamine, glutamate, phenylalanine, tyrosine, citrulline and taurine) can significantly inhibit [3H]-GABA binding and contribute to the GABA-like activity of plasma aliquots. At final assay concentrations equivalent to plasma concentrations found in hepatic encephalopathy, only taurine was found to significantly inhibit [3H]-GABA binding to whole rat brain synaptosomal membranes (36% inhibition at 30 mumol/L final assay concentration). The concentration of taurine that resulted in 50% inhibition (final assay concentration) was 158 mumol/L, corresponding to a plasma concentration of 1.58 mmol/L. Taurine inhibition of [3H]-GABA binding was competitive because the receptor density was unaltered, but the receptor affinity decreased with increasing concentration of taurine. Plasma GABA-like activity (determined by radioreceptor assay) and plasma GABA and taurine concentrations (determined by high-performance liquid chromatography) were measured in 18 rats with acute or chronic hepatic encephalopathy and 9 control rats. Plasma GABA-like activity and plasma GABA and taurine concentrations were significantly increased in rats with hepatic encephalopathy compared with control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Increased gamma-aminobutyric acid receptor function in the cerebral cortex of myoclonic calves with an hereditary deficit in glycine/strychnine receptors.

Inherited congenital myoclonus (ICM) of Poll Hereford cattle is a neurological disease in which there are severe alterations in spinal cord glycine-mediated neurotransmission. There is a specific and marked decrease, or defect, in glycine receptors and a significant increase in neuronal (synaptosomal) glycine uptake. Here we have examined the characteristics of the cerebral gamma-aminobutyric acid (GABA) receptor complex, and demonstrate that the malfunction of the spinal cord inhibitory system is accompanied by a change in the major inhibitory system in the cerebral cortex. In synaptic membrane preparations from ICM calves, both high-and low-affinity binding sites for the GABA agonist [3H]muscimol were found (KD = 9.3 +/- 1.5 and 227 +/- 41 nM, respectively), whereas only the high-affinity site was detectable in controls (KD = 14.0 +/- 3.1 nM). The density and affinity of benzodiazepine agonist binding sites labelled by [3H]diazepam were unchanged, but there was an increase in GABA-stimulated benzodiazepine binding. The affinity for t-[3H]butylbicyclo-o-benzoate, a ligand that binds to the GABA-activated chloride channel, was significantly increased in ICM brain membranes (KD = 148 +/- 14 nM) compared with controls (KD = 245 +/- 33 nM). Muscimol-stimulated 36Cl- uptake was 12% greater in microsacs prepared from ICM calf cerebral cortex, and the uptake was more sensitive to block by the GABA antagonist picrotoxin. The results show that the characteristics of the GABA receptor complex in ICM calf cortex differ from those in cortex from unaffected calves, a difference that is particularly apparent for the low-affinity, physiologically relevant GABA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Uptake of gamma-aminobutyric acid and L-glutamic acid by synaptosomes from postmortem human cerebral cortex: multiple sites, sodium dependence and effect of tissue preparation.

The uptake of gamma-aminobutyric acid (GABA) and L-glutamic acid by synaptosomes prepared from frozen postmortem human brain was shown to be effected via distinct high and low affinity sites. At approximately 17 h postmortem delay, the kinetic parameters for GABA uptake were: high affinity site, Km 7.1 +/- 2.5 microM, Vmax 18.7 +/- 4.8 nmol.min-1 per 100 mg protein; low affinity site, Km 2 +/- 1 mM, Vmax 425 +/- 250 nmol.min-1 per 100 mg protein (means +/- S.E.M., n = 13). Kinetic parameters for L-glutamate uptake were: high affinity site, Km 7.5 +/- 1.0 microM, Vmax 85 +/- 8 nmol.min-1 per 100 mg protein; low affinity site, Km 1.8 +/- 1.2 mM. Vmax 780 +/- 175 nmol.min-1 per 100 mg protein (n = 11). A detailed kinetic analysis of high affinity GABA uptake was performed over a range of sodium ion concentrations. The results were consistent with a coupling ratio of one Na+ ion to one GABA molecule; a similar result was found with rat brain synaptosomes. However, rat and human synaptosomes differed in the degree to which the substrate affinity of the high affinity GABA uptake site varied with decreasing Na+ ion concentration. High affinity GABA uptake was markedly affected by the method used to freeze and divide the tissue, but did not vary greatly in different cortical regions. There was some decline of high affinity GABA uptake activity with postmortem delay, apparently due to a loss of sites rather than a change in site affinity.

Adult↗

PubMed1989

Cortical dihydropyridine binding sites are unaltered in human alcoholic brain.

The density and affinity of sites labeled by the 1,4-dihydropyridines, [3H]nitrendipine and (+) [3H]PN 200-110, were not significantly different in superior frontal and parietal cortical membranes from alcoholic patients and nonalcoholic control patients. This is in contrast to the increased number of dihydropyridine receptors and increased functional activity of calcium channels reported in brain from rats treated chronically with ethanol and in neural cell lines grown in the presence of ethanol. These results indicate that 1,4-dihydropyridine-sensitive calcium channels (L type) in the brain, despite possible acute changes, are unaltered following long-term ethanol exposure in humans.

Alcoholism↗

PubMed1989

Neurochemical studies on quinolone antibiotics: effects on glutamate, GABA and adenosine systems in mammalian CNS.

Quinolone antibiotics, which can be proconvulsant in susceptible patients, were found to inhibit the specific binding of the adenosine receptor ligands L-3H-N6-phenylisopropyladenosine (L-3H-PIA) and 3H-N-ethylcarboxamidoadenosine (3H-NECA) to rat brain synaptic membranes. The inhibitions were concentration dependent, and for both ligands the order of potency was rosoxacin greater than nalidixic acid greater than oxolinic acid greater than or equal to ciprofloxacin greater than norfloxacin greater than enoxacin: IC20 values (concentrations causing a 20% inhibition of specific binding) ranged from 30-35 microM to 1-3 mM. Hill coefficients were approximately 0.5, suggesting that the compounds are probably antagonists at these sites. Most of the compounds did not alter 3H-diazepam binding directly, although rosoxacin showed relatively strong, and enoxacin weak, concentration-dependent inhibition. At 50 microM the compounds enhanced the maximal gamma-aminobutyric acid (GABA) activation of 3H-diazepam binding to varying degrees, without altering the EC50 of activation, whereas at 200 microM they tended to reduce GABA activation. Most noteworthy was the large increase in GABA-stimulated 3H-diazepam binding caused by 50 microM nalidixic acid. The compounds did not alter the Ca2+/Cl- -dependent binding of 3H-glutamate, nor of the binding of the glutamate site-selective ligands 3H-kainate and alpha-3H-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (3H-AMPA); the uptake of the non-metabolized glutamate analogue D-3H-aspartate by cortical homogenates was also unaffected. The CNS side effects of these antibiotics may result, in part, from interaction with sites which mediate the inhibitory neurotransmission of adenosine and, possibly, GABA.

4-Quinolones↗

PubMed1988

Deficit of spinal cord glycine/strychnine receptors in inherited myoclonus of Poll Hereford calves.

Inherited myoclonus of Poll Hereford calves is characterized by hyperesthesia and myoclonic jerks of the skeletal musculature, which occur spontaneously and in response to sensory stimuli. The disease shows autosomal recessive inheritance, and significant proportions of the Poll Hereford herds in many countries are thought to be carriers of the mutant gene. Studies revealed a specific and marked (90 to 95 percent) deficit in [3H]strychnine binding sites in spinal cord membranes from myoclonic animals compared to controls, reflecting a loss of, or defect in, glycine/strychnine receptors. Spinal cord synaptosomes prepared from affected animals showed a significantly increased ability to accumulate [3H]glycine, indicating an increased capacity of the high-affinity neuronal uptake system for glycine. In contrast, stimulus-induced glycine release and spinal cord glycine concentrations were unaltered.

Amino Acids↗

PubMed1988

A comparison of methodologies for the study of functional transmitter neurochemistry in human brain.

A number of different approaches to the study of functional neurochemistry in human brain are discussed. The advantages and disadvantages of three main techniques are contrasted: (i) using animal tissue preparations as models of the human brain; (ii) using human peripheral tissue preparations as models of dynamic CNS processes; and (iii) studying human tissue, obtained postmortem, directly. Animal models are often readily obtained and reliable, and the high degree of inbreeding of common laboratory animals ensures that they usually yield consistent results. However, there are a number of human disorders for which animal models are either poor or unavailable, and species differences make extrapolation from the animal to the human case difficult. Human peripheral tissue models rely on a degree of homology between peripheral and CNS processes; in most cases, the evidence for such homologies derives from animal, rather than human, studies. Moreover, several examples are known where a peripheral process mimics the equivalent glial cell activity more closely than the neuronal, which can be a serious drawback for studies of neurotransmission. The use of postmortem human brain tissue presents a number of obvious difficulties, resulting from variations in the patient's age, agonal state, sex, preterminal medication, postmortem delay, etc. Human beings are genetically and nutritionally heterogeneous, so that data variability is usually greater here than when using tissue from laboratory animals. However, it is possible to control for a number of these factors, for example, by matching samples for basal metabolic rate and tissue integrity, and recently developed tissue freezing and storage techniques permit the use of within-subject experimental designs to help reduce experimental variation. A range of neurotransmitter functions are well retained in such tissue samples, so that regional variations, differential transmitter activities, drug effects, etc., can be studied in normal tissue samples, as well as in samples taken from cases of neurological and psychiatric disease. This allows, for example, changes in neuroanatomical indices to be correlated with localised alterations in a specific neurotransmitter function. A systematic approach to the analysis and matching of tissue samples is advocated. The three approaches should be considered to be complementary, especially for the study of human brain diseases.

Animals↗

PubMed1988

Necropsy study of GABA/benzodiazepine receptor binding sites in brain tissue from chronic alcoholic patients.

Neurological and cognitive deficits occur in many chronic alcoholic patients. Quantitative studies reveal a significant reduction in the number of neurons in the superior frontal gyrus of chronic alcoholics, with no change in the motor cortex. Our studies are aimed at delineating which neurotransmitter systems are altered in alcoholics and to correlate these alterations with morphometry and, where possible, clinical signs. Much evidence suggests both short- and long-term effects of ethanol on GABA-mediated neurotransmission. GABA and benzodiazepines bind to distinct, but allosterically linked, sites on the GABA/benzodiazepine receptor complex. In the absence of any detected difference in the number of benzodiazepine receptors in both the frontal and motor cortex from alcoholic and control patients, a significant increase in the amount of GABA enhancement of [3H]diazepam binding was measured in frontal cortex membranes from patients with Wernicke's encephalopathy relative to non-alcoholic controls. This finding suggests an increased coupling of the GABA and benzodiazepine recognition sites in this area, which may be due to ethanol-induced conformational changes in the receptor complex.

Alcoholism↗

PubMed1987

Brain gamma-aminobutyric acid receptor binding is normal in rats with thioacetamide-induced hepatic encephalopathy despite elevated plasma gamma-aminobutyric acid-like activity.

Brain gamma-aminobutyric acid (GABA) receptor density, affinity, and function, and plasma GABA-like activity were determined in rats with acute hepatic encephalopathy induced by an intraperitoneal injection of thioacetamide. In addition, the effect of various stress factors on brain GABA binding was assessed. Plasma GABA-like activity was significantly increased in rats with thioacetamide-induced hepatic encephalopathy compared with rats injected with vehicle alone (1506 +/- 993 nM, n = 7 vs. 367 +/- 97 nM, n = 9, mean +/- SD; p less than 0.001). In contrast, there were no alterations in either brain GABA receptor binding or in GABA-enhanced benzodiazepine binding in rats with hepatic encephalopathy when compared with relevant controls. However, rats that had received intraperitoneal injections of thioacetamide or vehicle (0.15 M NaCl) had significantly more low-affinity GABA receptors than rats that had neither been injected nor handled before killing (8769 +/- 1101 vs. 2710 +/- 757 fmol/mg protein, mean +/- SEM, p less than 0.001). We concluded that stress factors appear to be important causes of altered brain GABA binding. Brain GABA receptor binding and function, however, are unaltered in rats with thioacetamide-induced hepatic encephalopathy despite elevated plasma GABA-like activity.

Animals↗

PubMed1986

Optimization of freezing, storage, and thawing conditions for the preparation of metabolically active synaptosomes from frozen rat and human brain.

Samples of rat and human cerebral cortex were frozen, stored, and thawed under a variety of conditions to define further the optimal procedure for storing human brain samples for subsequent metabolic and functional studies that use incubated synaptosomes. Tissue samples were best preserved by immersing them in isotonic sucrose prior to slow freezing, but there was no advantage in first chopping up the material. High concentrations of sucrose, rather than exerting a cryoprotective effect, were detrimental to subsequent synaptosomal performance (oxygen uptake, K+ accumulation, stimulus-induced release of amino acid neurotransmitters). However, good activity was observed in preparations from rat brain frozen in the absence of fluid. This result was confirmed by studies on the uptake of gamma-aminobutyrate (GABA) into an osmotically sensitive compartment in synaptosomes prepared from frozen human autopsy material transshipped from the brain tissue collection ("brain bank") at Harvard Medical School, MA, USA, to Sydney, Australia. Although activity was slowly lost over a 3-mo period in rat tissue samples stored at -20 degrees C, there was little or no such loss at -70 degrees C.

Animals↗

PubMed1986

Adenosine receptors in post-mortem human cerebral cortex and the effect of carbamazepine.

Representative A1 site- and A2 site-selective ligands for adenosine receptors were found to bind to a single class of non-co-operative sites in synaptic membranes prepared from pieces of normal human temporal lobe cerebral cortex obtained at autopsies performed within 24 h post-mortem. The known adenosine antagonists theophylline and 1-isobutyl-3-methylxanthine also bound to these sites and could completely displace either ligand. Computer analysis combining data from 21 separate experiments which used membranes prepared from seven different autopsy cases gave the following kinetic parameters for the site: equilibrium dissociation constants (KD) for L-PIA, 4.1 +/- 0.9 nmol/l; KD for NECA, 26 +/- 4 nmol/l; KD for theophylline, 28 +/- 5 mumol/l; receptor number (Bmax), 510 +/- 77 fmol/mg protein. Carbamazepine could also displace either radioligand from the sites, although solubility limits for this drug were reached at 50% receptor occupancy. The KD for carbamazepine was 138 +/- 18 mumol/l. Other anticonvulsants tested were generally ineffective at their therapeutic concentrations, although phenytoin showed a small amount of ligand binding inhibition. The results are in line with earlier studies in rodent tissue preparations, and suggest a possible purinergic component in the anticonvulsant activity of carbamazepine in a man.

1-Methyl-3-isobutylxanthine↗