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Biomedical subjects

M G Paule

Publications and source records attributed to M G Paule.

At least 19 recordsLinked to original sources
PubMed2006

L-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture.

1-Methyl-4-phenylpyridinium ion (MPP+), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with an elevation of intracellular reactive oxygen species (ROS) and apoptosis. L-carnitine plays an integral role in attenuating the brain injury associated with mitochondrial neurodegenerative disorders. The present study investigates the effects of L-carnitine against the toxicity of MPP+ in rat forebrain primary cultures. Cells in culture were treated for 24 h with 100, 250, 500 and 1000 microM MPP+ alone or co-incubated with L-carnitine. MPP+ produced a dose-related increase in DNA fragmentation as measured by cell death ELISA (enzyme-linked immunosorbent assay), an increase in the number of TUNEL (terminal dUTP nick-end labeling)-positive cells and a reduction in the mitochondrial metabolism of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). No significant effect was observed with the release of lactate dehydrogenase (LDH), indicating that cell death presumably occurred via apoptotic mechanisms. Co-incubation of MPP+ with L-carnitine significantly reduced MPP+-induced apoptosis. Western blot analyses showed that neurotoxic concentrations of MPP+ decreased the ratio of BCL-X(L) to Bax and decreased the protein levels of polysialic acid neural cell adhesion molecules (PSA-NCAM), a neuron specific marker. L-carnitine blocked these effects of MPP+ suggesting its potential therapeutic utility in degenerative disorders such as Parkinson's disease, Alzheimer's disease, ornithine transcarbamylase deficiency and other mitochondrial diseases.

1-Methyl-4-phenylpyridinium↗
PubMed2001

No alterations in the performance of two interval timing operant tasks after alpha-difluoromethylornithine (DFMO)-induced cerebellar stunting.

The cerebellum is critically involved in temporal processes in the millisecond range and may be involved in longer time estimations (i.e. in the seconds range). Estimates in the millisecond range are impaired after developmentally induced cerebellar alterations, however, little is known about the effects of similar alterations on longer timing performance. Appropriately timed DFMO treatment reliably causes cerebellar stunting in rats, however, its effects on temporal estimation performance are unknown. Here, male and female Sprague-Dawley rats were treated with subcutaneous injections of 500 mg/kg DFMO on postnatal days 5-12, causing a 10% cerebellar weight reduction at adulthood. As adults, subjects were tested under one of two paradigms - a differential reinforcement of low response rate (DRL) task requiring that subjects withhold a lever press response for 10-14 s or a temporal response differentiation (TRD) task requiring that subjects maintain a lever press response for 10-14 s. Training and steady-state performance of the DRL and TRD tasks were not significantly altered by DFMO treatment. Performance after acute challenges with two dopaminergic agonists (2.00-7.50 mg/kg methylphenidate and 0.10-1.00 mg/kg d-amphetamine) was measured after which all subjects underwent behavioral extinction. Generally, performance after methylphenidate and d-amphetamine was similar in control and DFMO-treated rats and DFMO treatment had no differential effects on performance during extinction. These results support findings from an earlier study [Ferguson SA, Paule MG, Holson RR. Neonatal dexamethasoneon day 7 in rats causes behavioral alterations reflective of hippocampal, but not cerebellar, deficits. Neurotoxicol Teratol, 2001; 23:57-69] indicating that developmental cerebellar stunting has few effects on time estimation within the range of seconds.

Animals↗
PubMed2000

Analysis of methylphenidate and its metabolite ritalinic acid in monkey plasma by liquid chromatography/electrospray ionization mass spectrometry.

Methylphenidate (MP, Ritalin) is a psychotropic drug widely prescribed to children for treating the symptoms of attention deficit disorder with and without hyperactivity. Because little information exists about the effects of chronic MP administration on cognitive function in children, measures of behavior changes in non-human primates are important surrogates. An essential component of such studies is the determination of MP plasma levels under chronic and acute dosing conditions. An analytical method was developed that provided sufficient sensitivity to measure low levels of the active parent drug (lower limit of quantitation = 0.25 ng/mL) and the inactive metabolite, ritalinic acid (RA), in monkey plasma as well as the ability to conveniently analyze large numbers of samples. The method uses a polymeric reversed-phase sorbent for solid phase extraction, an efficient reverse-phase high performance liquid chromatography (HPLC) separation, deuterated internal standards for isotope dilution quantification of MP and RA, and detection by sensitive electrospray ionization mass spectrometry (ES-MS) with a single quadrupole instrument. The method responses are linear over the range of plasma concentrations of MP and RA observed in monkeys, gives respective analyte recoveries of 75 and 60% with reasonable precision and accuracy, and demonstrates robust MS performance for rapid determination of MP/RA plasma levels. The average peak MP concentration (ca. 16 ng/mL) and half-lives for MP and RA elimination in monkeys (1.79 and 2.31 h, respectively) were not significantly different under acute vs. chronic dosing conditions and were comparable to values previously reported from human studies.

Animals↗
PubMed2000

Ethanol enhances Nicotine's effects on DRL performance in rats.

The present experiment examined effects of nicotine (0.0, 0.3, 0.56, and 1.0 mg/kg; IP) and ethanol (0.0, 0.5, 1.5, and 3.0 g/kg; IG) on operant behavior using a differential reinforcement of low response rate (DRL) schedule in rats. DRL schedules are sensitive to effects of nicotine and provide an assessment of the subject's ability to accurately estimate time and to inhibit schedule-controlled responding. When administered alone, nicotine shifted the mode of the interresponse time distribution to the left and reduced the percentage of reinforced responses. Nicotine also had an inverted U-shaped dose effect on the number of "bursting" responses. When administered after pretreatment with ethanol, nicotine's effects on the distribution of interresponse times and bursting were potentiated. These effects are consistent with previous reports and with the suggestion that ethanol pretreatment can potentiate effects of subsequently administered nicotine. Published by Elsevier Science Inc.

Animals↗
PubMed2000

Comparison of drug effects on the performance of two timing tasks in rats.

Previous evidence suggests that different timing tasks are differentially sensitive to pharmacological manipulation, especially when different values for the temporal parameters are used. The present series of experiments compared the effects of physostigmine, caffeine, pentobarbital, morphine, and naloxone on the performance of a differential reinforcement of low rates with limited hold (DRL-LH) and a temporal response differentiation (TRD) task. In the DRL-LH task, rats were reinforced for responses that occurred 10-14 s from the end of the previous response. In the TRD task, rats were reinforced for responses with a duration of 10-14 s. The peak response time and peak spread of the initiation time distribution (for DRL-LH) or the response duration distribution (for TRD) were used as indices of temporal discrimination. Physostigmine, caffeine, and pentobarbital produced very similar effects on peak response time for both tasks, but the effects of morphine and naloxone were different for the two tasks. Effects on peak spread for the two tasks did not always correspond to changes in peak response time, suggesting that different processes may be measured by these two endpoints. Further, these effects were independent of changes in response rate suggesting that the effects were not due to gross disruptions in motivation or motor control. These results suggest that the effects of drugs on DRL-LH and TRD performance may differ, even when temporal parameters are identical.

Analysis of Variance↗
PubMed2000

Effects of acute nicotine on several operant behaviors in rats.

The present experiment assessed nicotine's effects on complex cognitive processes using a variety of operant tasks in rats, including incremental repeated acquisition (IRA) to assess learning; conditioned position responding (CPR) to assess auditory, visual, and position discrimination; progressive ratio (PR) to assess motivation; temporal response differentiation (TRD) to assess timing; and differential reinforcement of low response rates (DRL) to assess timing and response inhibition. Acute nicotine administration (0.0, 0.3, 0.42, 0.56, 0.75, and 1.0 mg/kg, IP) increased IRA and CPR response rate without significantly altering accuracy. Nicotine had similar effects on response rate for PR. For TRD, nicotine had a U-shaped dose effect on accuracy, but failed to shift the mode of the TRD response distribution. For DRL, nicotine reduced accuracy and also shifted the mode of the DRL response initiation time distribution to the left. Nicotine produced an inverted U-shaped dose-effect curve for the overall number of "bursting" responses under both of these schedules. The results of this experiment suggest that nicotine can impair performance on some aspects of cognitive-behavioral performance, while simultaneously improving performance on others.

Animals↗
PubMed2000

Similar effects of amphetamine and methylphenidate on the performance of complex operant tasks in rats.

Methylphenidate and D-amphetamine are central nervous system stimulants that have been suggested to share certain behavioral and neurochemical effects. The current study was undertaken to determine whether methylphenidate and D-amphetamine have similar effects on the performance of a battery of complex operant tasks in rats. Thus, the effects of amphetamine (0.1-6.0 mg/kg, i.p.) and methylphenidate (1.12-18.0 mg/kg, i.p) on the performance of rats in three complex food-reinforced operant tasks were examined. The tasks (and the brain functions they are intended to model) included: (1) conditioned position responding (auditory/visual/position discrimination); (2) incremental repeated acquisition (learning); and (3) temporal response differentiation (time estimation). In addition, each of these tasks was paired with a progressive ratio task to assess drug effects on the rats' motivation to lever press for the food reinforcers used. Consistent with their effects in other behavioral paradigms, methylphenidate and D-amphetamine produced very similar patterns of disruption of the four tasks. Drug-induced changes in the endpoints of the progressive ratio task generally paralleled changes in the other three tasks, suggesting a major role for appetitive motivation in the effects of these agents. Several effects of these agents seen in the current study are consistent with their effects in children with attention-deficit-hyperactivity disorder. These data further validate the use of this battery of operant tasks for the characterization of pharmacological agents, and suggest that findings using these tasks may be predictive of what is seen in humans.

Amphetamine↗
PubMed2000

Effects of acute ethanol on indices of cognitive-behavioral performance in rats.

The present experiment examined the effects of ethanol on several complex operant behaviors in rats. Tasks included: temporal response differentiation (TRD) to assess timing behavior; differential reinforcement of low response rates (DRL) to assess timing and response inhibition; incremental repeated acquisition (IRA) to assess learning; conditioned position responding (CPR) to assess auditory, visual, and position discrimination; and progressive ratio (PR) to assess motivation. Ethanol (0.0, 0.5, 1.0, 1.5, 2.0, and 3.0 g/kg via orogastric gavage) reduced accuracy and/or percent task completed for the TRD, DRL, and CPR tasks. For CPR, this reduction was accompanied by a reduction in response rates. Ethanol also reduced response rates on the PR task. There were no effects of ethanol on IRA performance. These data suggest that ethanol can selectively impair performance on cognitive-behavioral tasks and that these effects can occur at doses that do not affect the subjects' ability to respond.

Alcohol Drinking↗
PubMed2000

Cognitive tests: interpretation for neurotoxicity? (Workshop summary).

The appropriate use and interpretation of cognitive tests presents important challenges to the toxicologist and to the risk assessor. For example, intelligence cannot be measured directly; rather intelligence is quantified indirectly by scoring responses (i.e., behaviors) to specific situations (problems). This workshop, "Cognitive Tests: Interpretation for Neurotoxicity?" provided an overview on the types of cognitive tests available and described approaches by which the validity of such tests can be assessed. Unlike many tools available to the toxicologist, cognitive tests have a particular advantage. Being noninvasive and species-neutral, the same test can be performed in different mammalian species. This enhances one's ability to assess the validity of test results. Criteria for test validity include comparable responses across species as well as similar disruption by the same neurotoxicant across species. Test batteries, such as the Operant Test Battery, have indicated remarkable similarity between monkeys and children with respect to performance of certain tasks involving, for example, short-term memory. Still, there is a need for caution in interpretation of such tests. In particular, cognitive tests, especially when performed in humans, are subject to confounding by a range of factors, including age, gender, and, in particular, education. Moreover, the ability of such tests to reflect intelligence must be considered. Certain aspects of intelligence, such as the ability to plan or carry out specific tasks, are not well reflected by many of the standard tests of cognition. Nonetheless, although still under development, cognitive tests do hold promise for reliably predicting neurotoxicity in humans.

Animals↗
PubMed1998

The effects of cocaine on nonhuman primate brain function are age dependent.

The effects of acute intravenous (i.v.) cocaine (COC) on several complex brain functions were studied in rhesus monkeys at 1.5, 3 and 10-11 years of age. Subjects performed several operant tasks (for food) that were used to model learning, short-term memory, color and position discrimination, and motivation, and disruption of performance of these tasks was used to quantitate drug effect. Drug effects were age dependent: The youngest subjects were 3 to 10 times less sensitive than the oldest. Presuming the observed behavioral effects of cocaine were caused primarily via its interaction with dopamine (DA) systems, changes in sensitivity to its effects with age are likely a reflection of the functional status of the DA system. These data, along with preliminary data on levels of DA transporters, suggest that the age-related differences in sensitivity to cocaine lie in, 'downstream' from, the dopamine receptor.

Aging↗
PubMed1998

Acute effects of dexfenfluramine (d-FEN) and methylenedioxymethamphetamine (MDMA) before and after short-course, high-dose treatment.

The acute behavioral effects of methylenedioxymethamphetamine (MDMA) and dexfenfluramine (d-FEN) were assessed in six rhesus monkeys using performance in the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB); three additional animals served as controls for neurochemical endpoints. The OTB consists of five food-reinforced tasks designed to model aspects of learning, short-term memory and attention, time estimation, motivation, and color and position discrimination. Shortly after the acute effects of each drug were determined, three of the monkeys received a short-course, high-dose exposure (2x /day x 4 days, intramuscular (i.m.) injections) of MDMA (10 mg/kg), while three monkeys were exposed to an identical regimen of d-FEN (5 mg/kg). Approximately one month later, the acute effects of each drug were again determined. In monkeys exposed to high-dose d-FEN, the sensitivities of the OTB tasks to acute disruption by either MDMA or d-FEN were essentially unchanged. Conversely, monkeys treated with high-dose MDMA were less sensitive to the acute behavioral effects of both drugs, although such an effect was seen more frequently for d-FEN and was OTB task specific. Thus a residual behavioral tolerance to the acute behavioral effects of MDMA and d-FEN was noted after high-dose MDMA exposure, but not after high-dose d-FEN exposure. These findings are surprising, as similar neurochemical effects (i.e., significant decreases of ca. 50% in serotonin in frontal cortex and hippocampus) were observed in all monkeys approximately six months after short-course, high-dose MDMA or d-FEN treatment.

Animals↗
PubMed1997

Effects of MDMA on complex brain function in laboratory animals.

This review surveys experiments that have examined the effects of acute and chronic MDMA exposure on schedule-controlled operant behaviors thought to engender responses that reflect the expression of complex brain functions. Such functions include time estimation, short-term memory, learning, motivation, and color and position discrimination. Recent experiments conducted in the Behavioral Toxicology Laboratory at the National Center for Toxicological Research concerning MDMA's acute and long-term effects on rhesus monkey performance in an operant test battery are compared to previous studies involving the effects of MDMA on operant behaviors. Results of these experiments suggest that when given acutely, MDMA disrupts complex brain functions associated with learning and time estimation more than those associated with short-term memory and visual discrimination, and that behavioral tasks requiring relatively high rates of responding are particularly sensitive to the disruptive effects of MDMA. Repeated exposure to doses of MDMA sufficient to produce long-lasting changes in brain neurotransmitter systems results in residual effects (e.g. tolerance, sensitivity) on behavioral task performance when subjects are subsequently challenged with acute MDMA, whereas baseline (non-challenged) performance of these tasks after such exposure generally remains unchanged. Although the experiments described herein were conducted on a relatively small number of non-human subjects, they raise the possibility that long-term effects on cognitive processes may also occur in humans exposed to repeated or acute high doses of MDMA.

Animals↗
PubMed1997

Acute effects of LSD on rhesus monkey operant test battery performance.

The acute effects of LSD were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation, short-term memory and attention, motivation, learning, and color and position discrimination. The end points monitored included percent task completed, response rate, and accuracy. LSD (0.0003-0.03 mg/kg intravenously) significantly decreased percent task completed and accuracy in the time estimation task at doses < or = 0.003 mg/kg, but did not significantly affect response rate in this task at any dose tested. Accuracy in the short-term memory task was significantly decreased at the highest dose tested (0.03 mg/kg), but no other end points were affected in this task. Response rate was decreased in both the motivation and learning tasks at doses (0.01 and 0.003 mg/kg, respectively) lower than those affecting other end points. In the color and position discrimination task, only response rate was affected (0.01 and 0.03 mg/kg). These data demonstrate that in rhesus monkeys, performance of tasks believed to depend on aspects of time estimation and motivation are more sensitive to the acute disruptive effects of LSD than are tasks thought to model learning, short-term memory, and color and position discrimination.

Animals↗
PubMed1996

Effects of chlorpromazine and diazepam on time estimation behavior and motivation in rats.

The effects of chlorpromazine and diazepam on performance of two operant tasks, one modelling time estimation and the other motivation to work for food reinforcers, were investigated in rats. These same tasks had been used previously in rhesus monkeys to assess the effects of chlorpromazine and diazepam. Rat performance of the time estimation task [temporal response differentiation (TRD)] was nearly identical to that previously described in monkeys. This performance similarity across these two species occurred despite slightly different methodologies. Performance of the motivation task [progressive ratio (PR)] was clearly different between rats and adult monkeys in that rats exhibited lower values on all PR endpoints. Acute administration of chlorpromazine [0.03-5.6 mg/kg, intraperitoneally (IP)] caused decrements in rat TRD and PR performance at doses > or = 1.0 mg/kg. Acute administration of diazepam (0.25-4.0 mg/kg, IP) altered TRD performance only. The effects of chlorpromazine and diazepam in rats were similar to those previously noted in the monkey, indicating the potential utility of rat performance in these operant tasks to predict drug effects in the rhesus monkey.

Animals↗
PubMed1996

Repeated acquisition and the assessment of centrally acting compounds.

Repeated acquisition (RA) procedures are behavioral preparations in which subjects learn new sequences of responses during each experimental session. They have been used with great success to assess the effects of drugs and other compounds on learning processes. As learning can be measured over many sessions in individual subjects, RA procedures can prove invaluable when conducting studies of the effects of chronic drug administration, aging and the long-term effects of exposure to toxic compounds. Analyzing the patterns of responding during acquisition can provide insights into the behavioral mechanisms underlying the effects of drugs and other centrally acting compounds on learning. Systematic comparisons are needed on the influence of many procedural variables on RA and the extent to which they may modulate the effects of chemicals.

Animals↗