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Biomedical subjects

G C Wagner

Publications and source records attributed to G C Wagner.

At least 109 records · Page 6Linked to original sources
PubMed1982

Neurochemical similarities between d,l-cathinone and d-amphetamine.

Cathinone, the principal alkaloid of Khat, was compared to the psychomotor stimulant d-amphetamine on a number of neurochemical measures. Like d-amphetamine, d,l-cathinone released and blocked the uptake of tritiated dopamine (DA) in synaptosomal preparations. In addition, repeated high doses of d,l-cathinone produced long-lasting DA depletions in various rat brain regions and decreased the number of synaptosomal DA uptake sites in a manner similar to that seen after repeated d-amphetamine administration. Importantly, this DA neurotoxic effect of d,l-cathinone, like that of d-amphetamine, is selective since regional brain levels of norepinephrine (NE) or serotonin (5-HT) are not altered on a long-term basis by repeated administration of d,l-cathinone. These findings are discussed with reference to the current practice of Khat leaf chewing by people in north-eastern Africa.

Alkaloids↗
PubMed1981

Apoprotein formation and heme reconstitution of cytochrome P-450cam.

Apoprotein suitable for heme reconstitution has been prepared by an acid/butanone extraction of cytochrome P-450cam at pH 2.5. Absorption spectra of apo-P-450cam indicate less than 2% residual holoenzyme. Four tryptophan residues per molecule were estimated from the aromatic absorbance region of denatured apoprotein. Heme-reconstituted holoprotein was purified in 30% yield to a specific activity equivalent to the native enzyme. Absorption and EPR spectra of 57Fe- and 54Fe-heme-enriched P-450cam reveal complete restoration of the native active site.

Apoproteins↗
PubMed1981

Cobalt-substituted cytochrome P-450cam.

Reconstitution of the apo-cytochrome with cobalt protoporphyrin provides a faithful P-450cam analogue as characterized by optical, ligand-binding, and enzymatic parameters. The thiol and cyanide complexes exhibit Soret "hyper" spectra, not previously observed in cobalt porphyrins. Substrate-induced spectral changes and limited stereospecific hydroxylation activity are retained in the cobalt P-450cam. The EPR (electron paramagnetic resonance) spectra of the reduced cobaltous protein indicate clearly an endogenous axial ligand other than a nitrogenous base and support an assignment of thiolate coordination. A thiolate ligand is also indicated by EPR measurements in the oxygenated cobaltous analogue. By analogy, these studies suggest that the native ferrous and oxygenated P-450cam states retain a thiolate axial ligand.

Apoproteins↗
PubMed1981

Dopamine depletion by 6-hydroxydopamine prevents conditioned taste aversion induced by methylamphetamine but not lithium chloride.

Specific lesions of the central dopaminergic system produced by intraventricular injections of 6-hydroxydopamine with pargyline and desmethylimipramine pretreatment significantly attenuated conditioned taste aversions to a sweetened-condensed milk solution induced by methylamphetamine. Identically treated rats formed an aversion to the milk solution when lithium chloride was utilized. These results suggest that the methylamphetamine-induced aversion is dependent upon intact dopaminergic neurons.

Animals↗
PubMed1981

Neurochemical consequences following administration of CNS stimulants to the neonatal rat.

The possible induction of long-lasting catecholamine depletions in discrete brain regions by psychomotor stimulant drugs was examined in neonatal rats. Three agents, methylamphetamine, d-amphetamine, and methylphenidate were administered to groups of rat pups from days 10 to 40 of life. Pups were killed 2 weeks beyond the last drug administration. Catecholamine levels of various brain regions from groups of rats receiving 12.5, 25 or 50 mg/kg/day of each drug were compared with levels of vehicle treated pups. Both methylamphetamine and d-amphetamine at the higher doses induced long-lasting dopamine depletions in the caudate of rat pups. Methylphenidate had no long-term effect on dopamine while norepinephrine levels were not altered by any treatment.

Animals↗
PubMed1981

Effects of a high-dose treatment of methamphetamine on caudate dopamine and anorexia in rats.

Dose-effect curves of d-methamphetamine (MA) on intake of sweetened condensed milk by rats were obtained before and after twice a day treatment for four days with either saline (control) or a high (50 mg/kg) dose of MA previously shown to decrease the dopamine levels of the caudate. The animals that were more sensitive to MA's anorexic effect during the before-treatment determination were found to be more sensitive to the lethal effects of the high-dose treatment. This treatment produced a six month decrease in brain dopamine but no change in the anorexic effect on milk intake or in the stereotypic behavior elicited by the drug. Subsequently, the daily administration of 2.5 mg/kg of MA, 15 min before presentation of the milk, to both control and treatment groups produced tolerance to the drug's anorexic effect. After 4 to 5 weeks of repeated administration of this dose there was a significant difference between the control group's intake of milk and treatment group's intake as well as body weight. These differences indicate an effect on the treatment upon the formation of tolerance to the anorexic effects of MA.

Animals↗
PubMed1981

The aversive stimulus properties of repeated infusions of cocaine.

When the presentation of a novel food to a rat is followed by the administration of certain compounds, including psychomotor stimulants, the animal consumes less of the food on subsequent presentations relative to an animal administered saline. This phenomenon has been termed gustatory avoidance conditioning. Conflicting results have been obtained when cocaine is used in this procedure. Therefore, the possibility that the weak efficacy of cocaine in this paradigm is due to its relatively short duration of action was investigated. Fluid intake was limited to a single 15 min presentation, seven days a week. Following the determination of baseline water in take sweetened milk was given during the session followed by a series of infusions of cocaine through chronic indwelling peritoneal catheters. Four infusions, spaced 15 min apart, of 9.0 mg/kg cocaine induced an avoidance response, while one infusion of 36 mg/kg cocaine followed by three saline infusions did not. This supports the hypothesis that the low efficacy of cocaine in this paradigm is due, at least in part, to its short duration of action.

Animals↗
PubMed1980

Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine.

Repeated administration of high doses of methamphetamine produced long-term decreases in dopamine (DA) levels and in the number of DA uptake sites in the rat striatum. These two effects were dose-related and did not appear to be due to the continued presence of drug in striatal tissue. Long-lasting depletions induced by methamphetamine were selective for striatal DA neurons since norepinephrine (NE) levels in all of the rat brain regions examined were not changed on a long-term basis by methamphetamine treatments. Supersensitivity of DA receptors did not accompany the loss of striatal DA and its uptake sites.

Animals↗
PubMed1980

The effects of dopaminergic agents on the locomotor activity of rats after high doses of methylamphetamine.

Treatment of rats with 100 mg/kg/day of methylamphetamine for four days produced long lasting (16 week) depletions of central nervous system levels of dopamine but not of norepinephrine. This methylamphetamine treatment also attenuated the ability of methylamphetamine and apomorphine to produce increases in locomotor activity without shifting the dose-response curve to the right or left. These rats underwent significant decreases in activity after lower doses of haloperidol while the response to L-Dopa was virtually unchanged.

Animals↗
PubMed1980

Amphetamine induces depletion of dopamine and loss of dopamine uptake sites in caudate.

Long-lasting depletion of dopamine and concomitant loss of dopamine uptake sites follow repeated administration of methylamphetamine to rats. We found similar effects after similar treatment with d-amphetamine, but not after treatment with methylphenidate. Methylphenidate also failed to produce long-term depletion of regional catecholamine levels in rhesus monkeys. These long-lasting alterations of the dopaminergic system suggest that amphetamines or their metabolites have toxic interactions with dopaminergic neurons, which do not occur with methylphenidate.

Animals↗
PubMed1979

Methamphetamine-induced changes in brain catecholamines in rats and guinea pigs.

Repeated administration of methamphetamine was found to cause long-term changes in caudate dopamine levels in the rat and guinea pig. Methamphetamine was administered twice a day for thirty days. Two weeks following the last injection, the animals were killed and brains assayed for catecholamine content. These long-term depletions of dopamine, when combined with similar observations previously reported in rhesus monkeys, indicate a species generality of the effects of methamphetamine on caudate dopamine levels.

Animals↗
PubMed1978

Fast reactions in carbon monoxide binding to heme proteins.

Using fast flash photolysis, we have measured the binding of CO to carboxymethylated cytochrome c and to heme c octapeptide as a function of temperature (5 degrees-350 degreesK) over an extended time range (100 ns(-1) ks). Experiments used a microsecond dye laser (lambda = 540 nm), and a mode-locked frequency-doubled Nd-glass laser (lambda = 530 nm). At low temperatures (5 degrees-120 degreesK) the rebinding exhibits two components. The slower component (I) is nonexponential in time and has an optical spectrum corresponding to rebiding from an S = 2, CO-free deoxy state. The fast component (I*) is exponential in time with a lifetime shorter than 10 mus and an optical spectrum different from the slow component. In myoglobin and the separated alpha and beta chains of hemoglobin, only process I is visible. The optical absorption spectrum of I* and its time dependence suggest that it may correspond to recombination from an excited state in which the iron has not yet moved out of the heme plane. The temperature dependences of both processes have been measured. Both occur via quantum mechanical tunneling at the lowest temperatures and via over-the-barrier motion at higher temperatures.

Binding Sites↗
PubMed1975

The effect of temperature on the spectroscopic properties of the heme c octapeptide from cytochrome c.

The effect of temperature on the optical properties of the acetylated heme c octapeptide from cytochrome c was examined. At above ambient temperatures the observed optical spectrum with maxima at 549 and 424 nm was characteristic of high-spin ferrous hemeproteins. At below ambient temperatures the optical spectrum became characteristic of low-spin ferrous hemeproteins with maxima at 547, 518, and 410 nm. A thermodynamic characterization of this two component system yielded a deltaHO of -10.1 +/- 0.7 kcal/mol and a delta S0 of-37.6 +/- 2.5 e.u. for the temperature dependent process. Discussion of the spectroscopic and thermodynamic parameters was presented in terms of the consistent magnetic and structural properties of heme complexes.

Binding Sites↗
PubMed1975

Spectroscopic properties of ferrous heme complexes of sterically hindered ligands.

Mesoheme IX complexes of sterically hindered ligands 2-methylimidazole, tert-butylamine and 2-methylpyridine in aqueous glycerol solutions are characterized by broad visible absorption spectra at ambient temperature exhibiting close similarities to high-spin ferrous hemeproteins. Spectrophotometric titrations of mesoheme IX with these ligands indicate well-defined equilibria for 2-methylimidazole and tert-butylamine corresponding to the formation of penta-coordinate strong-field ligand complexes. Variable temperature spectra of these complexes from ambient to 77 degrees K exhibit a change to hemochrome spectra characteristic of the low-spin unhindered ligand complexes. Corresponding changes in the visible spectra are not observed for the high-spin hemeproteins deoxymyoglobin, horse-radish peroxidase and cytochrome ć. The appropriate utilization of these hindered ligand heme complexes as model systems for high-spin ferrous hemeproteins has been discussed.

Binding Sites↗