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Biomedical subjects

J B Richards

Publications and source records attributed to J B Richards.

At least 37 records · Page 2Linked to original sources
PubMed1993

A high-dose methamphetamine regimen results in long-lasting deficits on performance of a reaction-time task.

Rats were treated with a high-dose methamphetamine (METH) regimen (50 mg/kg 3 times at 8-h intervals). Three weeks after treatment, they were trained on a reaction-time task. METH-treated rats failed to improve over a 3-month test period, while controls demonstrated a gradual increase in reaction-time speed over the same test period. METH treatment resulted in a significant dopamine depletions in the caudate/putamen and nucleus accumbens/olfactory tubercle; significant serotonin depletions in caudate/putamen, nucleus accumbens/olfactory tubercle, somatosensory cortex, amygdala and hippocampus. In contrast to the decreases observed in other brain regions, serotonin levels were significantly greater than controls in the hypothalamus. It is suggested that the behavioral impairment in the METH-treated animals is due to (a) serotonin and/or dopamine depletions or (b) abnormal or hyper-innervation of serotonin to the hypothalamus.

Animals↗
PubMed1993

Effects of salbutamol upon performance on an operant screen for antidepressants.

The beta adrenergic (beta) agonist salbutamol increased reinforcement rates and decreased response rates on a differential-reinforcement-of-low-rate (DRL) 72-S schedule. These changes in DRL 72-S schedule performance are also produced by most clinically used antidepressants. The effects of salbutamol on a DRL 72-S schedule were dose-dependently antagonized by the beta antagonist metoprolol, but not changed by the 5HT antagonist methysergide. Additionally, neither salbutamol nor the antagonism of salbutamol by metoprolol caused disruption of DRL 72-S schedule performance. These results indicate that stimulation of beta receptors, and not of 5HT receptors, mediates salbutamol antidepressant-like effects on a DRL 72-S schedule.

Albuterol↗
PubMed1993

Effects of caffeine and PD 116,600 on the differential-reinforcement-of-low rate 72-S (DRL 72-S) schedule of reinforcement.

Caffeine and PD 116,600 were found to decrease the reinforcement rate and increase the response rate in rats performing under a differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule of reinforcement. In contrast, antidepressant drugs previously have been found to increase the reinforcement and decrease the response rate. Caffeine has been found to test similar to antidepressant drugs on at least one other behavioral screen, but caffeine does not possess clinical antidepressant properties. These results provide further support for the DRL 72-s schedule as a behavioral screen for antidepressant drugs.

Animals↗
PubMed1993

DRL interresponse-time distributions: quantification by peak deviation analysis.

Peak deviation analysis is a quantitative technique for characterizing interresponse-time distributions that result from training on differential-reinforcement-of-low-rate schedules of reinforcement. It compares each rat's obtained interresponse-time distribution to the corresponding negative exponential distribution that would have occurred if the rat had emitted the same number of responses randomly in time, at the same rate. The comparison of the obtained distributions with corresponding negative exponential distributions provides the basis for computing three standardized metrics (burst ratio, peak location, and peak area) that quantitatively characterize the profile of the obtained interresponse-time distributions. In Experiment 1 peak deviation analysis quantitatively described the difference between the interresponse-time distributions of rats trained on variable-interval 300-s and differential-reinforcement-of-low-rate 72-s schedules of reinforcement. In Experiment 2 peak deviation analysis differentiated between the effects of the psychomotor stimulant d-amphetamine, the anxiolytic compound chlordiazepoxide, and the antidepressant desipramine. The results suggest that peak deviation analysis of interresponse-time distributions may provide a useful behavioral assay system for characterizing the effects of drugs.

Animals↗
PubMed1993

Fluoxetine prevents the disruptive effects of fenfluramine on differential-reinforcement-of-low-rate 72-second schedule performance.

This study compared the effects of fenfluramine and fluoxetine on the differential-reinforcement-of-low-rate 72-s schedule of reinforcement. Fluoxetine, a clinically effective antidepressant, increases extracellular serotonin (5-HT) by blocking the uptake of 5-HT after release. Fenfluramine increases extracellular 5-HT through transporter-mediated release (although it also blocks 5-HT uptake). The following characteristics were identified. First, fenfluramine and fluoxetine had two different effects on the differential-reinforcement-of-low-rate 72-s schedule. Fluoxetine had an antidepressant-like effect by increasing reinforcement rate without disrupting the interresponse time distribution. Fenfluramine's effect on the differential-reinforcement-of-low-rate 72-s schedule was not antidepressant-like: it did not increase the reinforcement rate, whereas it did disrupt the interresponse time distribution. Second, when fluoxetine and fenfluramine were given in combination, fluoxetine prevented the disruptive effects of fenfluramine. This result is consistent with fluoxetine's ability to block fenfluramine-induced 5-HT release, and supports the argument that the uptake transporter mediates fenfluramine's effects on both 5-HT release and behavior. Putative behavioral mechanisms (waiting capacity and temporal discrimination) which may mediate the acute effects of fluoxetine are discussed.

Animals↗
PubMed1992

Fluoxetine attenuates the DL-fenfluramine-induced increase in extracellular serotonin as measured by in vivo dialysis.

Rats with hippocampal dialysis probes were treated with DL-fenfluramine (FEN), fluoxetine, or FEN with fluoxetine pre-treatment. FEN (12.5 mg/kg) increased extracellular serotonin (5-HT) from 0.4 +/- 0.04 to 25.2 +/- 4.16 pg/10 microliters. Fluoxetine (10.0 mg/kg) increased extracellular 5-HT levels from 0.4 +/- 0.05 to 2.4 +/- 0.33 pg/10 microliters. FEN-induced increases in extracellular 5-HT were attenuated by 66% with fluoxetine pre-treatment. This result supports the view that the 5-HT releasing properties of FEN are mediated by the 5-HT uptake transporter.

Animals↗
PubMed1992

The NMDA receptor antagonist MK-801 does not protect against serotonin depletions caused by high doses of DL-fenfluramine.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain. DL-Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.

Animals↗
PubMed1992

Fenfluramine-induced increases in extracellular hippocampal serotonin are progressively attenuated in vivo during a four-day fenfluramine regimen in rats.

Rats were administered 8 injections of 12.5 mg/kg fenfluramine over a 4-day period. Extracellular hippocampal serotonin levels were monitored in vivo during the 4-day treatment period. Predrug baseline serotonin levels were 0.6 +/- 0.17 pg/5 microliters; 60 min after the first fenfluramine injection extracellular serotonin levels were increased to 28.06 +/- 5.2 pg/5 microliters. Fenfluramine-induced increases in serotonin were substantially reduced on the 2nd through 4th days of the regimen. Baseline serotonin levels were increased on days 2 through 4 of the treatment regimen. In a separate group of animals post-mortem tissue concentrations of serotonin were measured 2 weeks after 1,2,4, or 8 injections of 12.5 mg/kg fenfluramine. There were decreases in serotonin tissue concentrations which were related to the number of fenfluramine injections administered. The in vivo dialysis and post-mortem tissue assay results are consistent with the view that fenfluramine is neurotoxic.

Animals↗
PubMed1991

A quantitative interresponse-time analysis of DRL performance differentiates similar effects of the antidepressant desipramine and the novel anxiolytic gepirone.

We describe an interresponse-time analysis of performance on a differential-reinforcement-of-low-rate 72-s schedule. This analysis compares the obtained interresponse-time distribution of individual rats to a corresponding random interresponse-time distribution. The random interresponse-time distribution is a negative exponential probability function; it predicts the relative distribution of interresponse times if the rat emitted the same number of responses randomly (i.e., with a constant probability) with respect to time. The analysis provides quantitative measures of peak location and dispersion of the interresponse times toward random performance. In Experiment 1, an unexpected outcome of this analysis was that the rats would have obtained more reinforcers had they responded at the same rate but randomly. Based on the interresponse-time analysis in Experiment 1, it was shown that rats trained on the differential-reinforcement-of-low-rate 72-s schedule could increase the number of reinforcers obtained in two ways: first, by a coherent shift of the interresponse-time distribution toward longer durations and, second, by dispersal of the interresponse times toward a random interresponse-time distribution. Experiment 2 applied the analysis described in Experiment 1 to the effects of desipramine and gepirone. Both drugs decreased response rate and increased reinforcement rate, but their effects on the distribution of interresponse times were different. The increase in reinforcement rate observed with desipramine was accompanied by a coherent shift of the reinforcement rate observed with gepirone was accompanied by dispersal of the interresponse-time distribution toward the random negative exponential prediction.

Animals↗
PubMed1990

Conditioned rotation: a behavioral analysis.

Rats trained to turn in circles have been used by a number of investigators to study brain dopamine metabolism. We report the results of a behavioral analysis of conditioned rotation and describe the apparatus used in our laboratory to train rats and monitor their performance. A novel discrimination procedure was used which required each rat to turn left in one training chamber with one set of stimulus conditions and right in a different chamber. Water-deprived animals were trained to circle for a water reward. Initial acquisition of this task required 11 days of training. At the end of acquisition, a discrimination test indicated that turning in the left and right directions was under stimulus control of the chamber environment. We found that trained turning had a highly stereotyped temporal organization with a rapid movement component during which the rat executed the turn, and a longer pause time component during which the rat consumed the water reinforcer.

Animals↗
PubMed1990

In vivo dialysis measurements of dopamine and DOPAC in rats trained to turn on a circular treadmill.

In vivo dialysis was used to measure extracellular fluid concentrations of dopamine and dihydroxyphenylacetic acid (DOPAC) in rats which were trained to run on a circular disk treadmill for water reinforcement. Turning resulted in bilateral increases in DOPAC in lateral striatum as well as nucleus accumbens/medial striatum. Dopamine release showed small but not significant increases at both sites. Changes in DOPAC release were not lateralized. Free drinking without circling also resulted in significant increases in DOPAC in these two brain areas. During free drinking, dopamine release was significantly increased in lateral striatum but not in nucleus/medial striatum. These experiments indicate that dopamine metabolism is increased in rat striatum and nucleus accumbens in animals running on circular treadmills as well as by free drinking.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Unilateral dopamine depletion causes bilateral deficits in conditioned rotation in rats.

Rats were trained to rotate for a water reward using a procedure which required each rat to turn in both the left and right directions. The rats were then lesioned with unilateral injections of 6-hydroxydopamine in the nigrostriatal bundle to produce unilateral dopamine depletion. Rats which had greater than 95% depletion had significant deficits in turning both ipsilateral and contralateral to the depleted side. Circling contralateral to the lesion was more impaired than circling ipsilateral to the lesion. All animals showed deficits in both the initiation of movement and in speed of turning. In addition, the rats displayed a chronic turning bias in the ipsilateral direction 16 weeks postlesion. These results indicate that unilateral dopamine depletion causes a variety of impairments in trained circling behavior. Although contralateral circling is most impaired, there is a significant decrease in ipsilateral performance. We conclude that normal conditioned circling behavior requires bilateral dopamine innervation.

Animals↗
PubMed1981

Electron microscopy of network structures in thermally-induced globular protein gels.

Thin sections of heat-set proteins gels formed from bovine serum albumin, insulin, lysozyme, ribonuclease, and alpha-chymotrypsin, have been studied by transmission electron microscopy. Micrographs have been interpreted as showing protein networks with strands between one and two times as thick as the native protein diameters. Considerable differences in the persistence characteristics, and frequencies of cross-linking, of the strands are observed, and there are variations in network homogeneity over long distances which correlate well with changes in gel opacity caused by alterations in pH and ionic strength. Evidence that artefacts are unlikely to have influenced these interpretations has been obtained in the BSA case in particular, by studying the aggregation process in solution, using alternative microscope approaches such as heavy-metal shadowing and negative staining. assuming that artefacts are absent, gel section micrographs have been simulated by a computer procedure, and the results suggest that, in most cases, the simplest interpretation of the microscope data is in terms of a "string of beads" model for the aggregation process, involving only moderately unfolded, and still globular, protein molecules. Other structural interpretations cannot be ruled out, however, as the degree of protein unfolding, and the exact mode of incorporation of the monomers into the network filaments, cannot be established by the microscope technique alone.

Chymotrypsin↗
PubMed1972

Dolichols, ubiquinones, geranylgeraniol and farnesol as the major metabolites of mevalonate in Phytophthora cactorum.

Farnesol, geranylgeraniol, dolichols and ubiquinones were the main radioactive components of the unsaponifiable lipid recovered from Phytophthora cactorum grown in aerated cultures containing [2-(14)C]mevalonate. The (14)C recovered in each of these components was in the approximate proportion 2:4:3:5. When the culture was not aerated no radioactive ubiquinone was recovered. Most of the (14)C recovered in the dolichols was found in dolichol-15 (37%), with decreasing amounts in dolichol-14 (30%) and -13 (14%) and only a little (5%) in dolichol-16, whereas the major components, by weight, of the mixture (13mug/g of damp-dry tissue) were dolichol-14, -15 and -16 in the approximate proportion of 1:3:1. Radioautography of appropriate chromatograms indicated the presence also of traces of radioactivity in dolichol-9, -10, -11, -12 and -17. Most (80%) of the (14)C recovered in the ubiquinones was associated with ubiquinone-9, the rest being in ubiquinone-8. Most (80%) of the weight of ubiquinones (19mug/g of damp-dry tissue) was also ubiquinone-9. The identification of these compounds was by chromatographic methods and, for the ubiquinones and dolichols, was confirmed by mass spectrometry. In addition, the incorporation of 4R- and/or 4S-(3)H from [4-(3)H]-mevalonates showed the expected stereochemistry of biosynthesis, namely that farnesol, geranylgeraniol and ubiquinones were biogenetically all trans and the dolichols each contained three biogenetically trans isoprene residues, the remaining residues being biogenetically cis. The distribution of (14)C in the components of the whole lipid of the fungus was consistent with 97% of both the farnesol and geranylgeraniol being present as the fatty acid ester. The corresponding value for dolichols was 37%. The observation by other workers, that this fungus does not form either squalene or sterol, was confirmed.

Alcohols↗
PubMed1972

The transfer of mannose from guanosine diphosphate mannose to dolichol phosphate and protein by pig liver endoplasmic reticulum.

When pig liver microsomal preparations were incubated with GDP-[(14)C]mannose, 10-40% of the (14)C was transferred to mannolipid and 1-3% to mannoprotein. The transfer to mannolipid was readily reversible and GDP was one of the products of the reaction. It was possible to reverse the reaction by adding excess of GDP and to show the incorporation of [(14)C]GDP into GDP-mannose. When excess of unlabelled GDP-mannose was added to a partially completed incubation there was a rapid transfer back of [(14)C]mannose from the mannolipid to GDP-mannose. The other product of the reaction, the mannolipid, had the properties of a prenol phosphate mannose. This was illustrated by its lability to dilute acid but stability to dilute alkali, and by its chromatographic properties. Dolichol phosphate stimulated the incorporation of [(14)C]mannose into both mannolipid and into protein, although the former effect was larger and more consistent than the latter. The incorporation of exogenous [(3)H]dolichol phosphate into the mannolipid, and its release, accompanied by mannose, on treatment of the mannolipid with dilute acid, confirmed that exogenous dolichol phosphate can act as an acceptor of mannose in this system. It was shown that other exogenous polyprenol phosphates (but not farnesol phosphate or cetyl phosphate) can substitute for dolichol phosphate in this respect but that they are much less efficient than dolichol phosphate in stimulating the transfer of mannose to protein. Since pig liver contained substances with the chromatographic properties of both dolichol phosphate and dolichol phosphate mannose, which caused an increase in transfer of [(14)C]mannose from GDP-[(14)C]mannose to mannolipid, it was concluded that endogenous dolichol phosphate acts as an acceptor of mannose in the microsomal preparation. The results indicate that the mannolipid is an intermediate in the transfer of mannose from GDP-mannose to protein. Some 4% of the mannose of a sample of mannolipid added to an incubation was transferred to protein. A scheme is proposed to explain the variations with time in the production of radioactive mannolipid, mannoprotein, mannose 1-phosphate and mannose from GDP-[(14)C]mannose that takes account of the above observations. ATP, ADP, UTP, GDP, ADP-glucose and UDP-glucose markedly inhibited the transfer of mannose to the mannolipid.

Animals↗