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H A Tilson

Publications and source records attributed to H A Tilson.

At least 19 recordsLinked to original sources
PubMed1979

Screening for neurobehavioral toxicity: the need for and examples of validation of testing procedures.

The need for a sensitive and reliable screen to assess environmental agents for potential behavioral and neurological toxicity is discussed. Factors involving strategy, choice of animals and doses, route of administration, duration of study and requirements for the selection of neurobehavioral tests are also evaluated. The primary emphasis concerns the need for standardization and validation of neurobehavioral tests to be used in neurotoxicology. It is suggested that test validation be accomplished by comparing the observed results of known neurotoxicants in animal models which are chosen to predict effects based on reported human symptomatology. As a means of demonstrating how test validation is used in our laboratory, data from a number of experiments concerning the effects of a variety of chemical agents on three measures of motor functioning were discussed. The neurobehavioral effects of acrylamide, and agent known to produce "dying-back" axonopathies, were assessed using separate techniques presumed to measure hindlimb and forelimb functioning and general motor activity. The prediction that acrylamide will first decrease hindlimb functioning, while decreasing forelimb grip strength and motor activity at higher doses, was confirmed. The validity of the hindlimb measurement was supported using a neurotoxicant, carbon disulfide, known to affect motor functioning in a manner similar to acrylamide. The validity of the forelimb technique was shown indirectly using normative data collected from rats of both sexes tested at various ages, i.e., males were stronger than females and grip scores changed as a function of age. The relative sensitivities of the fore- and hindlimb measurements were found to be approximately the same when used to assess the effects of known muscle relaxants, such as phenobarbital and chlordiazepoxide. Finally, it was predicted and confirmed that an environmental agent believed to affect behavior secondarily to effects on other organ systems would affect all measures of motor functioning at approximately the same dose.

Animals↗
PubMed1979

Effects of carbon disulfide on motor function and responsiveness to d-amphetamine in rats.

Male, albino rats of the Fisher strain were exposed to 2 mg carbon disulfide/l of air for 4 hours per day, 5 days per week for 6 weeks. Neurobehavioral effects were not observed after 3 weeks of dosing, but hindlimb extensor responses and performance on the inclined screen (motor coordination) were impaired after 6 weeks of exposure. Forelimb grip strength and exploratory locomotor activity were not affected. Three weeks after cessation of dosing, recovery of function was observed. Rats exposed to CS2 for 6 weeks were found to be stimulated less than air ventilated controls by 3 mg/kg of d-amphetamine. In addition, d-amphetamine-induced augmentation of an acoustic startle response was attenuated in CS2 exposed rats. These data suggest that repeated exposure to CS2 affects the availability of brain norepinephrine for release. Enhanced responsiveness to the stereotypic effects of a high dose of d-amphetamine (6 mg/kg) suggested changes in functioning of dopaminergic systems. Three weeks after cessation of dosing, there was no difference between groups in their response to d-amphetamine.

Animals↗
PubMed1979

A method for the routine assessment of fore- and hindlimb grip strength of rats and mice.

A technique to measure the fore-and hindlimb grip strength of rats (adult and preweanling) and mice is described. the procedure utilizes inexpensive equipment, is rapid and efficient, and provides continuous level data. As a means of validating the sensitivity of the test, the effects of phenobarbital and chlordiazepoxide on the grip strength of adult Fisher strain and Sprague-Dawley derived adult rats were investigated. Dose-related decreases in fore- and hindlimb grip scores were observed in both strain of rats. The interanimal variability in this test was less in Fisher rats than in Sprague-Dawleys. The technique appears to have a great deal of potential in studies concerning the neuromotor effects of environmental and psychopharmacological agents.

Animals↗
PubMed1979

Effects of selenium, alone and in combination with silver or arsenic, in rats.

In two experiments, Sprague-Dawley rats were administered elemental selenium (Se; 10 ppm), silver (Ag; 1000 ppm) and arsenic (As; 50 ppm), either alone or in combination (Ag+Se or As+Se). Administration was via drinking water. Body weight, fluid intake, and food consumption were monitored weekly and measures of forelimb and handlimb strength were taken. Se depressed body weights in both experiments, as did As+Se. Food consumption relative to body weight tended to be increased by Se alone; none of the other treatments affected body weight, except for As+Se. Water consumption was depressed in all cases, which was attributed to a palatability effect. Limb strength was not affected by any treatment. The addition of Ag to the drinking water containing Se appeared to reduce the toxic effect of Se. However, As appeared to interact in a potentiating fashion with Se. There was 1 death in the Se alone group, none in the As group, but 7 out of 10 animals receiving As+Se had died by the end of the 18 week dosing period.

Animals↗
PubMed1978

Effect of imipramine on serotonin turnover in the lateral hypothalamus.

One hour following an infusion of 3H-5-hydroxytryptamine, animals were injected with either 15 mg/kg imipramine hydrochloride or 0.9% NaCl and then the lateral hypothalamus was perfused for 40 min. Samples of perfusate were analyzed by thin layer chromatography for estimation of 3H-labelled 5-hydroxytryptamine and metabolites. The results indicate that impramine hydrochloride 15 mg/kg decreases serotonin release and turnover in the lateral hypothalamus.

Animals↗
PubMed1978

Synthesis and turnover of 3H-5-hydroxytryptamine in the later cerebroventricle.

The lateral cerebroventricle was perfused using two different labelling procedures in three separate experiments on 5-hydroxytryptamine metabolism. The sensitivity of 5-hydroxytryptamine metabolism to various drugs was subsequently determined. The results demonstrate that two serotonin reuptake blockers, imipramine and fluoxetine, increase the efflux of 3h-5-hydroxytryptamine into the ventricle without affecting the efflux of 3H-5-hydroxyindoleacetic acid. BL-3912 A, a drug with weak serotonin agonist activity, also increased the efflux of 3H-5-hydroxytryptamine into the ventricle.

Animals↗
PubMed1978

Behavioral and neurological toxicity of polybrominated biphenyls in rats and mice.

Male, albino rats of the F-344/N strain and mice of the B6C3F1 strain were dosed by gavage, 5 days per week for a toal of 22 doses with 0.03--30 mg/kg of FireMaster FF-1, 0.168-16.8 Mg/kg of 2,4,5,2',4',5'-hexabromobiphenyl (HBB), or corn oil vehicle. A battery of tests was administered at the end of repeated dosing (30 day examination) and 30 days after dosing ceased (60 day test). FF-1 and, to a much lesser extent, HBB decreased body weight and performance on a variety of tests designed to detect neuromuscular dysfunction. Included in these tests were activity in the open field, forelimb grip strength, and muscular reflexes. Visual placement responses were also decreased in some animals, while hypothermia was observed in others. Emotionally, as measured by the number of defecations and urinations in the open field, was not affected by exposure to either compound. At the end of 30 day test, mice were less affected by exposure to these polybrominated biphenyls (PBBs) than rats; rats tended to worsen during the 30 days of no dosing, while mice tended to improve. These experiments indicate that oral dosing with levels of PBBs below those required to produce signs of acute toxicity produced behavioral or neurological toxicity when given repeatedly.

Animals↗
PubMed1978

Strategy for the assessment of neurobehavioral consequences of environmental factors.

One of the critical issues confronting the evolving discipline of behavioral and neurological toxicology is the general lack of test validation in animal models. This paper seeks to provide a strategy aimed at resolving this important problem. It is proposed that test validation be accomplished by evaluating known neurotoxins in a battery of tests chosen to assess in animal models a wide range of effects on the basis of reported human toxicosis symptomatology. We propose to measure ongoing home cage motor activity, food consumption, water consumption, clay consumption (and the diurnal cycling of these), neurological/physiological indices (reflexes, autonomic signs, equilibrium/gait, balance, tremor, reactivity, and muscular strength), and aspects of cognitive and associative behavior involving both endogenous and exogenous (sensory) control of responding. An integrated, time-efficient scheme, covering 90 days of chemical treatment and 30 days of post-dosing recovery will be used. Chemical substances to be evaluated were chosen with the view of representing classes of neurotoxic effects. For initial study, triethyltin was chosen as an agent producing demyelination of nerves, acrylamide as an agent producing "dying-back" neuropathy, and methylmercury as an agent producing mixed central and peripheral neuropathies. Agents which attack specific loci in the nervous system and those producing anoxia will not be assessed in the first stages of this research due to lack of species generality of known effects, present lack of appropriate exposure facilities, or other problems. In addition, two drugs (amphetamine and sodium salicylate) will be investigated to support the generality of the testing procedures. By comparing the observed results of the neurotoxins in the animal models with the predicted effects based on reported human symptomatology, some decision concerning the validity of each procedure will be made. It is expected that the validation of tests to be used in behavioral and neurological toxicology will permit the meaningful assessment of more complex issues, such as the mechanisms by which neurotoxins act.

Animals↗
PubMed1977

Behavioral suppressant effects of clonidine in strains of normotensive and hypertensive rats.

The behavioral effects of orally administered clonidine were investigated in Long--Evans (LE), Sprague--Dawley (SD) or Kyoto Wistar (KW) rats assumed to be normotensive and in NIH spontaneously hypertensive (SH) rats. Although clonidine (0.05-1 mg/kg) resulted in the same qualitative effect, i.e., depression of motor activity, the dose of clonidine required to depress motor activity to 50% of control levels (ED50) tended to vary according to strain. An analysis of variance of the dose response curves for the four strains of rats indicated a significant strain effect. When the effects of clonidine on food-reinforced operant responding were investigated it was observed that SD and SH rats differed with regard to rate and temporal pattering of IRT greater than 20 sec responding. Although oral administration of clonidine (0.006-0.1 mg/kg) produced similar percentage decreases from control in SH and SD rats, and analysis of the temporal patterning of responding indicated differences in responsiveness to the behavioral effects of clonidine. These studies demonstrate strain-related differences in responsiveness to the behavioral suppressant effects of clonidine. Marked differences between genetically hypertensive rats and rats assumed to be normotensive were not evident.

Animals↗
PubMed1977

Behavioral comparisons of R-2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane (BL-3912A) with R-DOM and S-amphetamine.

The behavioral effects of R-2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane or BL-3912A were compared with those of S-Amphetamine and R-DOM. BL-3912A facilitated acquisition of shuttle box responding by rats without increasing noncontingent intertrial (ITI) activity, while S-Amphetamine increased both avoidance and ITI responding. R-DOM had a biphasic effect on avoidance responding, increasing it at low doses and disrupting at higher doses. At doses that facilitated shuttle box responding, BL-3912A had no effect on unacclimated motor activity of rats nor on the rate of continuous avoidance responding by rats. S-Amphetamine increased the frequency of both motor activity and operant avoidance responding, while R-DOM decreased motor activity and increased operant avoidance responding. By facilitating avoidance behavior without increasing othermeasures of psychomotor activity, BL-3912A represents a unique psychopharmacological agent clearly different from R-DOM and S-Amphetamine.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1977

Turnover of 3H-5-hydroxytryptamine to 3H-5-hydroxyindoleacetic acid and the 3H-5-methoxyindoles in nondeprived and 24 hr food deprived rats.

Serotonin turnover in the lateral in hypothalamus (LH) was determined in nondeprived and 24 hr food deprived rats. The LH was infused with 0.5 muCi of 3H-5-hydroxytrptamine 1 hr prior to push-pull perfusion. The percentage of nCi/muCi of radioactivity was analyzed by thin layer chromatography and liquid scintillation spectrometry. There was significantly more 5-hydroxyindoleacetic acid and 5-methoxytryptamine formed in the 24 hr food deprived rats. These results indicate a faster 5-hydroxytryptamine turnover rate in the LH of 24 hr food deprived rats than in nondeprived rats.

5-Methoxytryptamine↗
PubMed1977

Further studies on BL-3912A: effects on avoidance behavior of rats with low baselines and on reaction thresholds to electric footshock.

Rats selected for their low performance baselines in an active avoidance shuttle box task were given various doses of R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane (BL-3912A), S-amphetamine or piracetam. BL-3912A at 1 mg/kg IP had no significant behavioral effects, while 5 and 10 mg/kg significantly increased the number of avoidance responses without affecting responses during the intertrial interval (ITI). Statistically reliable effects on behavior were not observed following 20 mg/kg of BL-3912A. S-Amphetamine at 0.5 and 1 mg/kg IP also facilitated avoidance responding, but could be differentiated from BL-3912A in that the S-amphetamine significantly increased shuttles during the ITI. S-Amphetamine at 0.1 mg/kg was not effective, while 2 mg/kg increased ITI activity. Piracetam (50 or 200 mg/kg) had no significant effects on avoidance or shuttles during ITI. Using an electric shock titration procedure, BL-3912A at 10 and 20 mg/kg IP had no significant effect on reaction thresholds. Animals receiving 100 mg/kg of p-chlorophenylalanine po for 3 days and tested 2 days later showed hyperalgesia to the electric shock. In summary, BL-3912A facilitated shuttle box avoidance responding of rats with low performance baselines. Behavioral facilitation occurred without concomitant increases in noncontingent activity or apparent changes in reactivity to electric footshock.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗