Biomedical subjects

G C Haggerty

Publications and source records attributed to G C Haggerty.

10 recordsLinked to original sources

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: III. Results of proficiency studies. Steering Group.

The goal of the IPCS Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The first phase of the Collaborative Study involved training the participants: evidence of training was then evaluated using positive-control compounds. The positive-control studies required the laboratories to identify, using the FOB, specific neurotoxic syndromes produced by acute exposure to p,p'-DDT, parathion, and by short-term repeated dosing with acrylamide. For the sake of expediency, only one dose of each chemical was used instead of collecting dose-response data. Motor activity test chambers were not of uniform design. The laboratories were therefore required to demonstrate adequate sensitivity by the ability to detect statistically-significant activity increases and decreases produced by triadimefon and chlorpromazine, respectively, following acute administration of a range of doses. The resulting FOB and motor activity data showed variability in the magnitude of effects obtained: some of these differences were attributed to miscommunications, difficulties with the techniques or protocol, or the limitations of having only one dose. All laboratories, however, successfully met the criteria set forth by the Study Steering Committee.

Animals↗

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: IV. Control data. Steering Group.

The goal of the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories worldwide. The control data were crucial to the outcome of the studies in terms of sensitivity and reliability of the test measures, which in turn impact on the between-laboratory comparisons of chemical effects. In addition, analyses of control data can aid in determining endpoints that may require modification to improve their sensitivity and reliability. The control data from the eight laboratories were examined in terms of the following parameters: 1) control variability within studies for each laboratory; 2) within-laboratory replicability of control values across studies; 3) within-laboratory stability of control values over the course of testing for a given study; and 4) between-laboratory comparisons of parameters (1), (2), and (3). The analyses indicated considerable differences across endpoints, wherein some measures showed high variability and little replicability, while others were extremely reproducible. Generally, there were similar ranges of variability and replicability of control data across laboratories, although in some cases one or two laboratories were markedly different from the others. The physiological (weight, body temperature) and neuromuscular (grip strength, landing foot splay) endpoints exhibited the least variability, whereas the subjective assessments of reactivity varied the most. These data indicate a reasonable degree of comparability in the data generated in the participating laboratories.

Animals↗

PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: V. Results of chemical testing. Steering Group.

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. Following the training phase and the conduct of proficiency studies in all laboratories, participants proceeded to test the effects of seven chemicals in both single dose and four-week repeated dosing scenarios. The chemicals studied were acrylamide, bisacrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples from a common source. In order to judge the general utility of these procedures in a diversity of testing situations, laboratories conducted the studies under their standard conditions, using their choice of rat strain and test equipment. Chemical does and time of peak effect for acute testing were determined by each laboratory: these parameters were quite similar for some chemicals, but varied greatly for others. The results of the chemical tests indicated that while there was some variability in the data on specific endpoints, all laboratories detected and characterized the effects of all but one of the known neurotoxicants. The one exception (toluene) was probably due to other factors (e.g., dose level, route of administration) rather than lack of sensitivity of the test methods. This study provides extensive data regarding the use of neurobehavioral screening methods over a range of laboratory conditions as well as the reliability, sensitivity, and robustness of the tests to detect neurotoxic potential of chemicals.

Animals↗

PubMed1986

The pharmacological activity of the fatty acid conjugate 11-palmitoyloxy-delta 9-tetrahydrocannabinol.

A long-retained cannabinoid metabolite has been detected in rat tissue after intravenous administration of delta 9-tetrahydrocannabinol (THC) and has been identified as a fatty acid conjugate of psychoactive 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-delta 9-THC) and palmitic acid. The objective of these studies was to determine if this compound, 11-palmitoyloxy-delta 9-tetrahydrocannabinol (11-palm-delta 9-THC) is pharmacologically active. Intravenously injected 11-palm-delta 9-THC decreased thermal sensitivity and induced catalepsy in rats, responses similar to those produced by 11-OH-delta 9-THC, but less pronounced and more delayed. To further characterize the response, animals were intracisternally injected with 11-OH-delta 9-THC or 11-palm-delta 9-THC. Catalepsy and decreased thermal sensitivity were seen in the 11-OH-delta 9-THC and 11-palm-delta 9-THC groups, and again, 11-OH-delta 9-THC appeared to be the more potent of the two cannabinoids. In contrast to the intravenous study, 11-palm-delta 9-THC-induced effects were seen soon after treatment and appeared to be fully developed by the first test time (15 min). The intracisternal results suggest that 11-palm-delta 9-THC itself is active; however, since it is known that the fatty acid conjugate is hydrolyzed in vivo to 11-OH-delta 9-THC in the rat, the possibility remains that the effects of 11-palm-delta 9-THC are due to metabolic conversion to 11-OH-delta 9-THC.

Animals↗

PubMed1985

The effect of prenatal procarbazine treatment on brain development in the rat.

Groups of pregnant Sprague-Dawley rats were treated orally with procarbazine, an antineoplastic drug, at dose levels of 0, 1.0, 2.5, 5.0, 7.5, and 10.0 mg/kg/day from days 12 through 15 of gestation. Following normal delivery, offspring were raised until day 21 and sacrificed, and their brains removed and weighed. A dose-dependent micrencephaly, characterized by hypoplasia of the cerebral hemispheres, was seen starting at 2.5 mg/kg/day. In a second study, groups of pregnant female rats were given a single dose of 10 mg/kg procarbazine on gestation day 12, 13, 14, or 15. Micrencephaly occurred in 21-day-old offspring from all groups, with the greatest effect induced on days 13, 14 and 15. Analysis of brain region weights revealed a maximum reduction in neocortex weight in offspring from groups treated on days 13 and 14. The hippocampus, cerebellum, and diencephalon-midbrain were also reduced in size, depending on the day of treatment, while the corpus striatum and pons-medulla were spared. In a final study, embryos from females treated on gestation days 12 through 15 were removed, fixed, and sectioned at 24-hour intervals starting on gestation days 13. Necrosis and cellular degeneration were observed with decreasing severity in the telencephalon, diencephalon, mesencephalon, and medulla. The neocortex of 20-day treated fetuses was characterized by a thickening of the ventricular zone and reduced cellularity of the cortical plate.

Aging↗

PubMed1984

The effect of a single administration of phencyclidine on behavior in the rat over a 21-day period.

The effects of phencyclidine (PCP) (7.0, 11.7, 19.5, 32.6, and 54.4 mg/kg) on locomotor activity, stereotyped behavior (circling, backing up, and weaving frequency), and rotarod performance were evaluated. In addition, the frequency of other PCP-induced abnormal behaviors (head in corner, arched back, and cataleptic freeze) was determined. All doses of PCP produced a significant increase in locomotor activity and stereotyped behavior as well as an impairment of rotarod performance. Both the duration and the time to peak effects (with the exception of rotarod performance) of these PCP-induced behavioral changes appeared to be dose dependent. The delay in attaining peak effects for locomotor activity and stereotypy was attributed to PCP-induced gross motor ataxia, which became more severe and long lasting with increasing dose. Although the longest period of time that significant changes were seen in locomotor activity, stereotyped behavior, and rotarod performance was 12 hr, sporadic recurrences of stereotypy and a significant increase in cataleptic freeze were observed in the high-dose groups (19.5, 32.6, and 54.4 mg/kg) up to 21 days postadministration. These persistent behaviors (stereotypy and cataleptic freeze) are not unlike certain of the prolonged behaviors seen in man with PCP overdose (catatonic stupor along with repetitive orofacial and limb movements).

Animals↗

PubMed1984

The neuroteratogenicity of procarbazine in the rat: behavioral, morphological, and neurochemical aspects.

Pregnant female Sprague-Dawley rats were treated from day 12 through day 15 of gestation with procarbazine, an antineoplastic drug, and their offspring were subjected to tests of locomotor development and behavior. Treatment levels ranged from 0.5 mg/kg/day, a dose that produced no abnormalities, to 10 mg/kg/day, a dose that caused a marked micrencephaly in the absence of other teratological changes. Despite marked morphological brain changes, preweaning locomotor development, as assessed by open-field swimming activity and vertical grid climbing, was normal in all offspring. Post-weaning passive avoidance learning and retention were also normal. Groups that had been treated prenatally with teratogenic doses (5.0 and 10.0 mg/kg/day) displayed less rearing behavior in the open field, while ambulation in the periphery of the open field arena was unaffected. Groups treated with subteratogenic doses (0.5 and 1.0 mg/kg/day) did not differ from control. In addition to the behavioral studies, sodium-dependent high-affinity choline uptake and choline acetyltransferase activity (CAT) were measured (per mg protein) in the cortex and hippocampus of animals that had been exposed prenatally to either teratogenic or subteratogenic doses of procarbazine. In spite of a substantial reduction in size of both brain structures in the group receiving a teratogenic dose, choline uptake and CAT did not differ from control.

Abnormalities, Drug-Induced↗

PubMed1983

The effects of an in vivo administration of phencyclidine on sodium-dependent high affinity choline uptake in rat hippocampus and striatum in vitro.

The effect of phencyclidine and other drugs on sodium-dependent high-affinity uptake of choline in the rat hippocampus and/or striatum was investigated and related to the behavioral changes induced by these agents. In contrast to atropine (40.0 mg/kg), which increased the uptake of choline in synaptosomes from both the rat hippocampus and striatum, the administration of phencyclidine (54.4 mg/kg), 30 min prior to sacrifice, caused a significant decrease in the uptake of choline in synaptosomes from rat striatum (but not hippocampus). This effect of phencyclidine could be seen up to 1 hr after administration of drug, but by 3.5 hr the uptake of choline was essentially back to normal. The inhibition of striatal uptake of choline occurred at a time when brain levels of phencyclidine and its metabolites were at their highest, and the animals were essentially immobile; it did not appear to correlate with behavioral changes (including stereotypy and catalepsy) seen at later times after this dose of phencyclidine (54.4 mg/kg), or at earlier times after smaller doses. Amphetamine (6.0 mg/kg) also decreased the uptake of choline in the striatum. Haloperidol (2.0 and 3.0 mg/kg) blocked both the phencyclidine and amphetamine-induced inhibition of the uptake of choline but only the behavioral effects of amphetamine. The data suggest that phencyclidine may be exerting an indirect effect on the uptake of choline in the striatum via its interaction with the dopaminergic system. However, this neurochemical effect of phencyclidine could not be related in any simple way to the immobility, stereotypy or catalepsy caused by this drug.

Amphetamine↗

PubMedDate not supplied

Duration and intensity of behavioral change after sublethal exposure to soman in rats.

The behavioral effects produced by acute exposure to sublethal doses of pinacolyl methylphosphonofluoridate (soman) were examined in the Sprague Dawley rat. Two hours after exposure to soman (100-150 micrograms/kg IM), dose-related decreases in spontaneous motor activity (SMA), fore- and hindlimb grip strength, thermal sensitivity, and rectal temperature were observed. In addition, acoustic startle response amplitude decreased, while response latency increased. Soman also depressed the percentage of conditioned avoidance and escape responses and increased response latency. In both the 103 and 116 micrograms/kg dose groups, effects on hindlimb grip strength persisted up to 14 days after exposure, while effects on hot plate response lasted for 7 days. A biphasic change in motor activity was seen in the 103 and 116 mg/kg soman groups: Initial SMA depression during the first 24 hours after exposure was followed by SMA increases which persisted up to 21 days. Animals that showed delayed hyperactivity often exhibited seizures and increased excitability when handled. The results of these studies demonstrate that sublethal doses of soman can cause marked and often long-lasting changes in behavior in the rat.

Animals↗

PubMedDate not supplied

Neurobehavioral profile of subcutaneously administered MK-801 in the rat.

MK-801 (dizocilpine) is an NMDA antagonist known to cause vacuolization and necrosis in susceptible cortical neurons. The objectives of the present work were to characterize the behavioral effects produced by a single administration of MK-801 and to determine how these effects may relate to the morphological changes seen in the central nervous system. Female rats (8/ group), approximately 9 weeks of age, received one of three doses of (+)MK-801 (0.1, 0.25, and 0.5 mg/kg) subcutaneously. Behavioral evaluation, using detailed clinical observations or a functional observational battery, was conducted every 15 minutes from 15-120 minutes post dosing and on Days 2, 3 and 7. Locomotor activity was assessed on Days 1,3,7 and 14. Stereotypy and ataxia were seen in all MK-801 groups soon after dosing, and continued to be observed in the two lower dose groups out to 2 hours. By 45 minutes post dosing, most of the rats from the 0.5 mg/kg group were completely immobile and did not show recovery for several hours. At 24 hours post dosing when all animals from the 0.5 mg/kg group were mobile, stereotypy and ataxia were evident. A differential dose effect was observed on locomotor activity on Day 1. Markedly increased locomotor activity was seen in the 0.1 mg/kg group, whereas activity was decreased in the 0.5 mg/kg group. This decrease at the highest dose level continued to be seen up to 3 days post dosing. In conclusion, acute dosing with MK-801 produced a behavioral pattern that was markedly affected by the increasing severity of ataxia with increasing dose and that was similar, in many aspects, to the profile that has been seen with single dose administration of phencylidine in the rat. Comparison of the temporal pattern of behavioral change (at the 0.5 mg/kg dose level) with that of necrosis development did not suggest a direct mechanistic relationship.

Animals↗