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Biomedical subjects

J L York

Publications and source records attributed to J L York.

At least 55 records · Page 3Linked to original sources
PubMed1982

Studies on the discriminative stimulus properties of ethanol in squirrel monkeys.

Eight male squirrel monkeys were trained to use the pharmacological effects of ethanol [orally via gastric intubation 1600 mg/kg (IG), in normal saline] versus those produced by equivolume saline as discriminative stimuli in an operant conditioning (bar pressing) procedure in which the availability of banana-flavored food pellets was made contingent upon the drug condition of the animal (ethanol SD, saline S delta for four monkeys; saline SD, ethanol S delta for the other four monkeys). Test doses of 7.5 mg/kg pentobarbital IG and 80 mg/kg barbital IG closely mimicked the cue properties of ethanol, while doses of morphine sulfate (5.0-20 mg/kg IG) failed to elicit ethanol-appropriate responding. Other ethanolic beverages containing 1600 mg/kg ethanol in the same volume as the training dose, and found to mimic the cue properties of pure ethanol were bourbon, gin, beer, vodka, and red wine. The single test dose of cognac, scotch, and tequila elicited responding different from that of the training dose of ethanol. Thus, the pharmacological effects of ethanolic beverages containing the same dose of ethanol (1600 mg/kg) may be noticeably different to some subjects. Blood levels of ethanol produced by the different beverages may be an important variable. There was no differential effect of the beverages upon free-feeding behavior of the monkeys at the time of testing. Ethanol preference tests conducted at the end of the study (i.e., after nearly 2 years of drug discrimination training) indicated that the assignment of ethanol as the condition under which food pellets were available (SD condition) moderately increased the ethanol preference of those subjects as compared to monkeys for whom ethanol had served as the S delta condition.

Alcoholic Beverages↗
PubMed1982

Conditioned and unconditioned influences on body temperature and ethanol hypothermia in laboratory rats.

Both a naive group and a group of chronically handled rats were observed to develop hyperthermia when their cages (rats in situ) were removed from their usual positions on cage rack shelving and placed upon the laboratory bench for a period of 60 minutes. That procedure apparently functioned as a stressful unconditioned stimulus for the naive group. The extent of hyperthermia was more pronounced in the chronic group, presumably owing to the classical conditioning of environmental cues to the stressful events that had repeatedly been associated in the past with placement of the cage onto the benchtop. Doses of naloxone (10 mg/kg) and of ethanol (1 g/kg) that normally produced negligible effects on body temperature were found to significantly reduce the hyperthermia that developed when cages were placed onto the benchtop. The hypothermic response to 2 g/kg of ethanol was lessened in both groups by placement of the cages onto the benchtop.

Animals↗
PubMed1982

Body water content, ethanol pharmacokinetics, and the responsiveness to ethanol in young and old rats.

Total body water was determined by desiccation of samples of 6 young (5-7 months) and 6 old (24-26 months) female CD strain rats and was observed to contribute 58.8 +/- 1.4 and 45.8 +/- 1.7% to the total body mass of the respective groups. The values obtained were used to construct an equation (linear regression: body weight vs. percent body water) with which to estimate the body water content of living subjects (n = 10 each) of the same populations, using body weight as the predictive variable. Doses of ethanol estimated to produce similar drug concentrations in the body water compartments were administered to old and young subjects and were observed to produce similar blood ethanol disappearance curves in both groups of rats. The regional brain concentrations of ethanol were found to be highest in the pons-medulla and lowest in the midbrain. On a region-by-region basis the values obtained for young rats were observed to more closely approximate the concentrations of ethanol in the neck blood than were the values obtained from the analysis of brain tissue from old rats. Old and young subjects dosed on the basis of predicted equivalent dilution of ethanol in body water did not differ noticeably in their response to ethanol hypothermia.

Aging↗
PubMed1981

The ethanol stimulus in rats with differing ethanol preferences.

Alcohol-accepting (AA) and alcohol-nonaccepting (ANA) rats (Alko, Finland) were tested for their ability to master a shock-motivated (0.6 mA scrambled AC current) T-maze discrimination in which IP injections of ethanol (1.0 g/kg, 10% w/v in saline, 20-min latency) and, on alternate days, equivolume saline were employed as a discriminative stimuli signalling the safety of right or left goal compartments. ANA rats reached the criterion level of performance (eight of ten correct first-trial responses) more quickly than did AA rats (12.3 +/- 2.3 versus 31.4 +/- 7.7 sessions, P less than 0.01) and also maintained a superior level of performance through-out the course of the experiment, suggesting that ethanol may have been a more salient cue for ANA rats than for AA rats. Injections of acetaldehyde (0.1-0.25 g/kg, 1.0-2.5% w/v in saline) produced ethanol-appropriate responding to a greater extent in ANA rats than in AA rats, indicating that the actions of acetaldehyde may contribute importantly to the stimulus condition produced by the injection of ethanol in ANA rats. Sodium pentobarbital (10.0 g/kg) was equally effective in mimicking the action of ethanol in both AA and ANA rats. AA and ANA rats did not differ significantly in the impairment of motor performance produced by a range of ethanol doses, suggesting that differences in stimuli related to motor impairment do not contribute to the differences observed in the cue value of ethanol for AA and ANA rats.

Acetaldehyde↗
PubMed1981

Consumption of intoxicating beverages by rats and mice exhibiting high and low preferences for ethanol.

Lines of rats selectively bred for alcohol consumption or avoidance (AA and ANA, ALKO, Finland) as well as inbred strains of mice (C57BL/6J and DBA/2J) and common female Wistar rats (Charles River) exhibiting high and low preferences for ethanol were tested under free-choice conditions for their consumption of solutions of ethanol (5, 10, or 15 g/100 ml tap water), sodium pentobarbital (0.19, 0.038, 0.076 g/100 ml tap water), and different beverages containing ethanol in the range of 8.1--9.6% (red and white wine, Scotch, ethanol in Hawaiian Punch). The Wistar rats and the mice classified as alcohol-preferring also tended to consume more of the pentobarbital solution than did alcohol-avoiding animals. Alcohol-nonaccepting (ANA) rats, however, consumed considerably more of all three pentobarbital solutions than did the alcohol-accepting (AA) rats. The intake of pentobarbital by the ANA rats and C57/BL/6J mice was in the range of 25--40 mg/kg/day, quantities that might be expected to produce pharmacological effects discriminable by those animals. The intake of ethanol by ANA rats was markedly elevated when the ethanol was contained in white wine or in punch.

Alcohol Drinking↗
PubMed1980

Proton magnetic resonance study of the histidines in hemerythrin and chemical identification of the nonligand histidines.

Three non-iron-liganded histidines have been studied in methemerythrin azide monomers from Pascolopsis gouldii by 250-MHz proton correlation nuclear magnetic resonance (NMR) spectroscopy. Four of the seven histidines in the protein are not observed because of paramagnetic broadening by the coordinated iron; neither are they observed as contact or pseudocontact shifted resonances. The NMR titration of the three free histidines establishes them as normal histidines with pK' values of 7.00 +/- 0.03 and Hill coefficients of 0.90, 0.81, and 0.81 +/- 0.03. The chemical shift of the protonated and neutral histidines is normal, and the bandwidth of the resonance absorption is 5 Hz. A pH-dependent reversible transition in the chemical shift of the histidine C(2)H occurs at pH 6.5; above this pH the three protons occur as a singlet but break into three singlets of different chemical shift at acid pH values. Two of the three "free" histidines have been identified by their susceptibility to photooxidation as His-82 and His-34.

Animals↗
PubMed1980

Mechanism for the potentiation of oxygen toxicity by disulfiram.

Rats given disulfiram (200 mg/kg) or diethyldithiocarbamate (200 mg/kg) by intraperitoneal injection were exposed to 2 atmospheres absolute oxygen in a hyperbaric chamber or kept in normoxia. By 12 hr of hyperoxia exposure, none of the control but 30% of the disulfiram-treated and 87% of the diethyldithiocarbamate-treated rats had died. Both disulfiram and diethyldithiocarbamate administration decreased lung cytosolic superoxide dismutase activity, but the pharmacokinetics were different. At 1 hr postinjection of diethyldithiocarbamate superoxide dismutase activity was 40% decreased but returned to control activity within 13 hr (4 hr, 18% inhibited). In contrast, disulfiram administration produced a greater decrease at 4 hr (31%) than at 1 hr (16%) and was still effective at 13 hr (28% less than control). Although disulfiram did not produce as great a decrease at 1 hr as did diethyldithiocarbamate, it's effect was more persistent. In vitro, diethyldithiocarbamate inactivated superoxide dismutase at 10(-4) M, although 10(-3) M disulfiram did not cause any reduction in enzymatic activity. The contrast between the inhibition by disulfiram of lung superoxide dismutase activity in vivo and its lack of effect in vitro suggests metabolism of disulfiram to diethyldithiocarbamate. It is likely that disulfiram administration potentiates oxygen toxicity via in vivo reduction to diethyldithiocarbamate and subsequent inhibition of superoxide dismutase.

Animals↗
PubMed1979

The sites of the lactoperoxidase-catalyzed iodination of human fibrinogen.

A study of those tyrosines in fibrinogen which are surface-oriented and which may be involved in polymerization has been investigated using as a probe iodination catalyzed by lactoperoxidase. The iodine distribution in the major cyanogen bromide fragments was studied. A fragment of the B beta chain extending beyond residue 118 had the highest specific activity. Tyrosine 119 was identified as the residue most susceptible to iodination. There was no difference in susceptibility to iodination of N-DSK (A alpha 1-51, B beta 1-118, gamma 1-78)2, Ho1-DSK (first hydrophobic disulfide knot), and Hi2-DSK (second hydrophobic disulfide knot). Tyrosines 18 and 32 of the gamma chain of N-DSK were not significantly iodinated in fibrinogen, but tyrosines 1 and 68 were labeled, as was the tyrosine of the A alpha chain. The data indicate that there are regions of the hydrophobic disulfide knot, Ho1-DSK, which are surface-oriented. The distribution of iodine as mono- and diiodotyrosine in N-DSK and Ho1-DSK reflected the percentage (83 and 17, respectively) found in iodinated fibrinogen from which these fragments were prepared. In contrast the segments of the B beta chain extending beyond Met118 contained 46% of the iodine in diiodotyrosine, while the A alpha chain fragment, Hi2-DSK, contained 28% as diiodotyrosine. No significant iodination of histidine was detected.

Amino Acid Sequence↗
PubMed1978

A comparison of the discriminative stimulus effects of ethanol, barbital, and phenobarbital in rats.

Five different groups of rats were trained in a food-motivated, bar-pressing task to discriminate from the nondrug condition (physiologic saline, i.p.) the effects produced by i.p. injections of ethanol (330, 660, or 990 mg/kg), sodium barbital (80 mg/kg), or sodium phenobarbital (25 mg/kg). The establishment of highly effective discriminations required 20--40 training sessions for all drugs, with the exception that rats trained with 330 mg/kg of ethanol required 80--100 training sessions. After the drug-nondrug discriminations were well established, cross tests revealed that ethanol did not elicit drug-appropriate responding in the groups trained with sodium barbital or sodium phenobarbital. However, both barbiturates elicited drug-approppriate responding to some extent in rats trained with ethanol as the discriminative stimulus. With barbital, the greatest generalization was observed in rats trained with the low dose of ethanol (330 mg/kg). The findings emphasize the need for the use of several training doses and for transfer tests in both directions when the stimulus effects of drugs are compared.

Animals↗
PubMed1976

The iron and subunit binding sites of hemerythrin. The role of histidine, tyrosine and tryptophan.

Of the three tyrosine residues available for nitration by tetranitromethane in hemerythrin, nitration of tyrosine residue 70 has no effect on dissociation of octomers to monomers, but nitration of tyrosines 18 and/or 67 results in dissociation to monomers. The latter data suggests these residues are important for subunit association. The reactive sulfhydryl, the modification of which produces dissociation, was protected as a mixed disulfide during the nitration but was regenerated for analysis of the state of association. Residue 70 can be selectively modified because of its exposed position and perhaps because of its slightly lower pk of 6.9, compared to 7.3 as an average of all nitrotyrosines in a completely nitrated hemerythrin. Solvent perturbation studies in 20% Me2SO indicate that 3 tyrosines, in agreement with the nitration results, and 2 tryptophan residues are exposed; however, oxidation at a 2-fold molar excess of N-bromosuccinimide oxidizes three tryptophan whereas a 3.5-fold excess oxidizes all four, but results in a rapid active site destruction. Photo-oxidation with methylene blue results in oxidation of only two tryptophan residues. These data have been interpreted to indicate that two tryptophans are free and two are involved in subunit association. Photo-oxidation with methylene blue results in the destruction of three histidines but no decrease in active site absorption. Histidine modification with diethyloxydiformate shows that three histidines react with no change in active site absorption. These results indicate that four histidines are unreactive toward these modifying agents and are therefore either buried or are ligands to the iron.

Binding Sites↗
PubMed1975

Assessment of tolerance to barbital by means of drug discrimination procedures.

This study was designed to determine the relative development of tolerance to the discriminative-stimulus and hypnotic properties of barbital. By selectively reinforcing lever presses only in the presence of one of the drug stated, rats were trained in a Skinner Box to discriminate the effect of sodium barbital (80 mg/kg) injection from that of saline injection. After the rats were well trained, the administration of daily hypnotic doses of barbital (240 mg/kg) for 8 days produced marked tolerance to the hypnotic effect of the barviturate in all animals. The ability of the 80 mg/kg dose to serve as a discriminative stimulus was not impaired in animals which had been trained with the drug as the condition during which bar presses had been reinforced (SD condition). Animals for which bar presses had gone unrewarded under barbital (Sdelta condition) displayed a tendency to develop tolerance to the stimulus properties of barbital. These findings are interpreted in the light of dose-effect studies, and it is suggested that the acquired polarity of the drug condition determined by its assignment as Sd or Sdelta may influence the discriminability of the drug in future exposures.

Animals↗
PubMed1975

Long-term effects of barbital on spontaneous activity of rats trained to use the drug as a discriminative stimulus.

This investigation sought to determine if the discriminative stimulus properties of barbital are reflected in the pattern of spontaneous motor activity induced by the drug. Rats were trained in a Skinner box to discriminate the effects of sodium barbital (80 mg/kg), injected 60 min prior to training, from those of saline. Half of the animals (Group I) were taught the drug discrimination by rewarding them for bar pressing only when they were in the drug condition. The other half of the animals (Group II) were rewarded only in the absence of the effects of barbital. Spontaneous motor activity was monitored during the 20 min period from 40--60 min after injection of the drug or saline. After several months of drug discrimination training, the patterns of spontaneous activity displayed by all animals suggested that the treatments had become conditioned to signal the forthcoming availability or non-availability of food in the Skinner box. The data also suggested that chronic exposure to barbital may induced adaptations which allowed the drug to increase spontaneous motor activity.

Animals↗