Phospholipid composition of fat-bodies of Sarcophaga bullata.
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Animals↗
Biomedical subjects
R R Allen
Publications and source records attributed to R R Allen.
Acute effects of methylenedioxymethamphetamine (MDMA) on several complex brain functions in monkeys.
The effects of MDMA were assessed in rhesus macaques using behavior in an operant test battery (OTB) consisting of five food-reinforced tasks designed to model aspects of time estimation, short-term memory, and attention, motivation, learning, and color and position discrimination. Testing occurred 30 min after intramuscular, injections of MDMA (0.0, 0.1, 0.3, and 1.0 mg/kg). The behavioral endpoints monitored included percent task completed, response rate or latency, and response accuracy. Percent task completed was significantly decreased in the time estimation, learning, and motivation tasks at 1.0 mg/kg as compared to saline controls. Response accuracies in the time estimation and learning tasks were also decreased at 1.0 mg/kg. Response rate was decreased at 1.0 mg/kg in the motivation task but was not significantly affected in any other tasks. No behavioral endpoints were significantly affected in the short-term memory and attention and color and position discrimination tasks at any dose tested. Results indicate that time estimation, motivation, and learning are more sensitive to the acute effects of MDMA than are short-term memory and attention and color and position discrimination.
Animals↗
Repeated measures designs in behavioral toxicology: application to chronic marijuana smoke exposure.
This paper discusses the application of repeated measures methods in the statistical analysis of an experiment in behavioral toxicology. The chronic marijuana smoke exposure study conducted at the National Center for Toxicological Research is used for an example of the types of problems that one encounters in analyzing these types of studies. In particular, the standard univariate analysis most frequently used for repeated measures analyses has some very restrictive assumptions on the form of the covariance matrices. These assumptions are not met in the example discussed and are rarely met in many other problems. Other possible models for analyzing repeated measures when these assumptions are not met are presented and discussed. Other problems specific to the chronic marijuana smoke exposure study that may occur in similar type studies are presented. These include pooling the experimental units into groups with comparable baselines, choosing a function of the measures to be analyzed, dealing with a large data set with many observation times and missing data, unequal group sizes and different designs for different subsets of the experimental animals. The standard univariate repeated measures analysis was chosen to analyze the data even though the violations of the covariance assumptions may lead to finding differences that do not exist (Type I or false-positive errors), since the other methods presented also had covariance assumptions that were not met or had low power. Use of Bonferroni-type multiple comparisons on the single degree of freedom contrasts of interest hopefully reduced the chances of these false-positive results.
Analysis of Variance↗
Monkey versus human performance in the NCTR Operant Test Battery.
A battery of operant behavioral tasks, designed to monitor complex "cognitive" functions in monkeys, was adapted for use in children. Adaptations were then incorporated into the monkey battery so that monkeys and children performed exactly the same tasks. Food pellets served as reinforcers for monkeys; nickels for children. Correct responding in a task is thought to depend upon relatively specific brain functions including short-term memory and attention, learning, time perception, motivation, and color and position discrimination. Eight 4-year-old rhesus monkeys served as subjects, and groups (n = 10 to 20) of 4- to 8-year-old children were recruited if they were not known to have any neurological, academic or behavioral problems. In performance of only the learning task was there any significant difference between monkeys and children. This difference was in response rate (not accuracy), with the monkeys responding faster than children. This lone difference in operant responding between monkeys and children was likely due to the fact that monkeys generally use all four appendages to respond whereas children generally do not.
Animals↗
Behavioral and neurochemical effects of chronic methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys.
Effects of chronic treatment with the putative serotonergic neurotoxicant MDMA were assessed in rhesus macaques using behavior in an operant test battery (OTB) designed to model aspects of time estimation, short-term memory, motivation, learning, and color and position discrimination. After an initial acute dose-response assessment, escalating doses of MDMA (0.10-20.0 mg/kg, im, twice daily, for 14 consecutive days at each dose) were administered, followed by three additional acute dose-response assessments. In general, tolerance to MDMA's acute effects was evident in all OTB tasks by the second week of repeated exposure to each individual MDMA dose and as doses escalated. Baseline OTB performance after chronic treatment was not significantly altered. Residual behavioral tolerance to MDMA's acute effects, however, was evident in all OTB tasks but was least pronounced in the motivation task. Monkeys were sacrificed (21 months after chronic treatment) and brains were dissected into several regions for neurochemical analyses. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were analyzed via HPLC. Although MDMA-treated monkeys tended to have lower 5-HT concentrations in the frontal cortex, chronic MDMA treatment had no significant effects on 5-HT concentrations in any brain area sampled. Hippocampal 5-HIAA concentration, 5-HT uptake sites, and turnover of 5-HT of MDMA-treated monkeys were significantly lower than control values. DA concentrations in the CN of MDMA-treated monkeys were significantly greater than control values. No significant effects on DA concentrations were noted in any other brain area sampled. The absence of significant decreases in 5-HT and the general increase in DA concentrations are dissimilar to neurochemical effects reported after a short course of MDMA treatment at relatively high doses. These data suggest that chronic administration of gradually increasing doses of MDMA results in long-lasting tolerance to the drugs acute effects on the complex brain functions modeled in the OTB. It is uncertain, however, if such tolerance is related to the observed decreases in uptake sites and turnover of 5-HT in the hippocampus of these monkeys.
3,4-Dihydroxyphenylacetic Acid↗
Prenatal ethanol exposure in rats: long-lasting effects on learning.
Pregnant Sprague-Dawley rats were fed a liquid diet containing either 0% (group C), 18% (group L), or 36% (group H) ethanol-derived calories (EDC) from gestational day 1 to 20. Male offspring were assessed under a conditioned taste aversion paradigm (PND 35-45), in a complex maze (PND 68-80), and for operant behavior (temporal response differentiation and motivation to work for food, PND 140-198). Although conditioned taste aversion was fully acquired by all groups, retention of the conditioned taste aversion response was impaired in group H animals. Importantly, deficits in the acquisition of timing behavior were found in group H (group L not tested), confirming that this operant task is quite sensitive in detecting prenatal drug effects and demonstrating that neurological effects of prenatal ethanol exposure persist into late adulthood.
Animals↗
The effect of chronic cocaine exposure during pregnancy on the acquisition of operant behaviors by rhesus monkey offspring.
To explore possible long-term effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were treated from about 1 month of gestation until term with either 0 (N = 3), 0.3 (N = 3), 1.0 (N = 3), or escalating doses up to 8.5 (N = 3) mg/kg (IM), three times per day, 5 consecutive days per week. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to the postnatal growth of offspring over an 18-month period following birth. Beginning at 6 months of age, the behavior of offspring was monitored using an operant test battery that included five food-reinforced tasks designed to model aspects of learning, color and position discrimination, time estimation, short-term memory and attention, and motivation. Although the acquisition of each operant behavior by offspring progressed significantly during training between 6 and 18 months of age, this acquisition was not differentially affected by gestational cocaine exposure. It was concluded that, in a rhesus monkey model, chronic cocaine exposure during pregnancy had no significant effect on the offsprings' acquisition of operant behaviors.
Animals↗
Differential effects of two NMDA receptor antagonists on cognitive--behavioral performance in young nonhuman primates II.
The present experiment examined the effects of chronic exposure to remacemide (an NMDA antagonist that also blocks fast sodium channels) or MK-801 (which blocks NMDA receptors more selectively) on the acquisition of color and position discrimination and short-term memory behavior in juvenile rhesus monkeys. Throughout the 2-year dosing period, a conditioned position responding (CPR) task was used to assess color and position discrimination and a delayed matching-to-sample (DMTS) task was used to assess memory. Chronic exposure to high doses of either drug delayed the acquisition of accurate color and position discrimination without altering response rates. In the case of MK-801, these effects abated within 6 months of the start of treatment. In the case of remacemide, the effects persisted for 17 months of dosing. Neither compound significantly altered performance of the short-term memory task at any time point or at any dose tested. The fact that the effects of remacemide on behavioral performance were more persistent than those seen for MK-801 suggests that tolerance may develop to the behavioral effects of MK-801, which does not develop to the effects of remacemide. Alternatively, these results may suggest that the concurrent antagonism of NMDA receptors and fast sodium channels may have more profound consequences for behavior than does the antagonism of NMDA receptors alone.
Acetamides↗
Differential effects of two NMDA receptor antagonists on cognitive-behavioral development in nonhuman primates I.
The present experiment examined effects of chronic exposure to remacemide (an N-methyl-D-aspartate [NMDA] antagonist which also blocks fast sodium channels) or MK-801 (which blocks NMDA receptors, exclusively) on learning and motivation in young rhesus monkeys. Remacemide (20 or 50 mg/kg/day) or MK-801 (0.1 or 1.0 mg/kg/day) was administered every day to separate groups of animals via orogastric gavage for up to 2 years. Immediately prior to dosing, 5 days per week (M--F), throughout the 2-year dosing period, an incremental repeated acquisition (IRA) task was used to assess learning and a progressive ratio (PR) task was used to assess motivation. The results indicate an effect of 50 mg/kg/day remacemide to impair learning (IRA) which persisted even after drug treatment was discontinued. MK-801 had no effect on learning but transiently increased motivation. Because the effects of remacemide occurred independently of changes in motivation or response rates, they are likely due to specific cognitive impairments and are not due to an inability of subjects to fulfill the motoric requirements of the task. The fact that MK-801 did not alter learning suggests that NMDA antagonism alone may be insufficient to produce learning deficits in young monkeys and that such deficits may rely on the ancillary blockade of fast sodium channels.
Acetamides↗
Assessing the potential toxicity of MK-801 and remacemide: chronic exposure in juvenile rhesus monkeys.
The present experiment examined the effects of chronic exposure to either 0.1 or 1.0 mg/kg MK-801 [a selective N-methyl-D-aspartate (NMDA) receptor antagonist] or 20.0 or 50.0 mg/kg remacemide (an NMDA receptor antagonist which also blocks fast sodium channels) in juvenile rhesus monkeys. Endpoints were monitored to provide a general index of subjects' health and included measures of clinical chemistry, hematology, ophthalmology, spontaneous home-cage behavior, and peak drug plasma levels. In general, both drugs were well tolerated and produced no treatment-related effects during 2 years of dosing and assessment. Periodic plasma drug level determinations provided limited evidence that both compounds may induce their own metabolism. The present results contrast sharply with previously reported effects of long-lasting impairments in the acquisition of incremental learning and in the development of color and position discrimination in these same subjects. These observations highlight the importance of collecting a broad range of toxicology data, including tests of cognitive function, to make comprehensive assessments of new drug safety. In the present case, the less obvious effects of these drugs on cognition defined the toxicologic response.
Acetamides↗