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Biomedical subjects

M G Paule

Publications and source records attributed to M G Paule.

At least 73 records · Page 4Linked to original sources
PubMed1988

Quantitation of complex brain function in children: preliminary evaluation using a nonhuman primate behavioral test battery.

The performance of twenty children (3-11 years of age) in a complex operant test battery (OTB) was evaluated. The operant schedules, or tasks, used in the OTB were identical to those originally designed and currently used to assess complex brain function in nonhuman primate laboratory animals (monkeys). The OTB consisted of five operant tasks: 1) Progressive-Ratio [PR]; 2) Conditioned-Position Responding [CPR]; 3) Temporal Response Differentiation [TRD]; 4) Delayed Matching-to-Sample [DMTS] and 5) Incremental Repeated Acquisition [IRA]. These operant tasks are thought to engender responding indicative of processes associated with: 1) motivation; 2) color and position discrimination; 3) time-perception; 4) short-term memory and attention; and 5) learning, respectively. The parameters for each of the tasks in the OTB were optimized for use in the clinical setting to assess cognitive function in children. In the small population studied, performance in the IRA, DMB and TRD tasks was age related. Of the four 6-yr-olds studied, only those categorized as having either learning disabilities (LD, n = 1) or attention deficit disorders (ADD, n = 2) did not complete the "learning" task. By comparison of human and monkey performance in the OTB, we also hope to validate the use of laboratory animal models in research efforts designed to yield insight into complex human brain function. It is also hoped that assessment of children's performance in the tasks in the OTB will assist in the diagnosis and treatment of certain childhood disorders such as learning disabilities and/or attention deficit disorders.

Animals↗
PubMed1988

Complex brain function in monkeys as a baseline for studying the effects of exogenous compounds.

We have examined the population characteristics of a group of 69 monkey subjects performing in a complex operant test battery designed to generate behaviors indicative of specific brain functions. These functions include learning, short-term memory and attention, time perception, position and color discrimination and motivation. Performance by a subject in one of these operant tasks is not necessarily correlated with or predictive of performance in the other tasks, indicating that the tests in the battery are monitoring the functions of different brain systems. Additionally, as demonstrated by challenging a few of the animals with intravenous delta-9-tetrahydrocannabinol, we have shown that the performances in the various components of the test battery are differentially sensitive to disruption by exogenous compounds.

Animals↗
PubMed1987

Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC).

Persistent behavioral effects resembling those of hippocampal brain lesions have been reported following chronic administration of marijuana or its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) to rats. We used morphometric techniques to investigate the effects of chronic THC on the anatomical integrity of the hippocampus. Rats dosed orally for 90 days with 10 to 60 mg/kg THC or vehicle were evaluated by light and electron microscopy up to 7 months after their last dose of drug. Electron micrographs revealed a striking ultrastructural appearance and statistically significant decreases in mean volume of neurons and their nuclei sampled from the hippocampal CA3 region of rats treated with the highest doses of THC. A 44% reduction in the number of synapses per unit volume was demonstrated in these same rats. Golgi impregnation studies of additional groups of rats treated with 10 or 20 mg/kg/day THC and sacrificed 2 months after their last treatment with THC revealed a reduction in the dendritic length of CA3 pyramidal neurons, despite normal appearing ultrastructure and no changes in synaptic density. The hippocampal changes reported here may constitute a morphological basis for behavioral effects after chronic exposure to marijuana.

Administration, Oral↗
PubMed1987

Fetal disposition of delta 9-tetrahydrocannabinol (THC) during late pregnancy in the rhesus monkey.

Three late-term (Gestational Days 146-151) rhesus monkeys were given 0.3 mg/kg delta 9-tetrahydrocannabinol (THC) intravenously via the maternal radial vein to quantify the placental transfer and fetal disposition of THC, the major psychoactive component of marijuana. Simultaneous blood samples were obtained from a maternal uterine vein and an intraplacental artery at 0, 3, 15, 30, 45, 60, 90, 120, and 180 min after dosing using an intraplacental cannulation technique. Samples of fetal plasma, spleen, testis, lung, brain, liver, bile, kidney, adrenals, thymus, and placenta were obtained at 180 min postdose. Samples were analyzed for THC and a major metabolite, 11-nor-9-carboxy-THC (11-nor), by radioimmunoassay (RIA). Peak plasma THC values were obtained 3 and 15 min after dosing in the mother (1419 ng/ml) and fetus (83 ng/ml), respectively. By 3 hr, maternal and fetal plasma THC levels were equal (37 ng/ml). Maternal plasma was sampled beyond 180 min at 24, 48, 72, and 96 hr postdose, times at which THC and 11-nor concentrations were either near or at the lower limit of sensitivity for the RIA (2 ng/ml). While maternal plasma 11-nor levels peaked at 1 hr (44 ng/ml), almost no 11-nor was detected in fetal plasma (less than 5 ng/ml). Fetal tissue concentrations of THC were 53 +/- 6 ng/g (SE) for brain and 114 +/- 10 ng/g for liver, while 11-nor was undetectable in placenta, fetal liver, and fetal brain. These data demonstrate that THC rapidly crosses the placenta and enters the fetus. The lack of 11-nor in fetal plasma and tissues suggests that this metabolite does not readily cross the placenta and that the fetus does not readily metabolize THC to 11-nor at this stage of development. A portion of this data was presented at the 1985 meeting of The American Society of Primatologists and at the 1986 meeting of The Teratology Society.

Animals↗
PubMed1987

Effects of chronic delta-9-THC treatment on cardiac beta-adrenoceptors in rats.

This study was designed to determine if chronic treatment with delta-9-tetrahydrocannabinol (THC) alters cardiac beta-adrenoceptors in the rat. Following daily oral administration of 10 or 20 mg/kg THC or an equivalent volume of control solvent for 90 days, rats were sacrificed, and sarcolemmal membranes were prepared from ventricular myocardium. Beta-adrenoceptor density and binding affinity estimated with (-)[3H]dihydroalprenolol; a beta-adrenergic antagonist, were not significantly affected by treatment with THC when compared to vehicle controls. These results suggest that the tolerance to cardiovascular effects of THC which develops during chronic exposure in the rat is not associated with alterations in cardiac beta-adrenoceptors as monitored by radiolabeled antagonist binding.

Animals↗
PubMed1986

Developmental toxicology of trimethyltin in the rat.

Pregnant rats were treated on either gestational day (GD) 7, 12, or 17 with single doses of trimethyltin chloride (TMT) ip at either 0, 5, 7, or 9 mg/kg. A significant effect of dose was manifest as decreased maternal weight at term, which persisted during lactation until postnatal day (PND) 15 in some groups. For all treatments combined, term weights of dams exposed on GDs 7 and 12 were greater than those treated on GD 17. Litter sizes were decreased for groups treated on GD 17 with 9 mg/kg TMT. Pups treated in utero and exhibiting treatment-induced decreases in weight at or near birth remained smaller than untreated animals into adulthood (PND 280). By PND 20, weights of pups treated on GD 7 greater than GD 12 greater than GD 17. Neuropathology of pups sacrificed on PND 1 was minimal in all animals with lesions only identified in animals treated on GDs 12 or 17 which consisted of subtle degenerative changes in the CA3 and CA4 regions of Ammon's horn of the hippocampus. Muscarinic cholinergic receptor binding in whole brains from pups on PND 1 did not show any significant changes compared to controls for any dose or day of exposure. These data indicate that prenatal TMT exposure results in postnatal toxicity in treated pups but only in the presence of maternal toxicity.

Animals↗
PubMed1986

Bias of morphine generalization to cyclazocine by drug history.

Pigeons trained to discriminate morphine from saline under a color tracking procedure received cumulative doses of cyclazocine after various regimens of daily morphine or saline administration. Cyclazocine generalization curves were obtained after zero, one, two, or six completely drug-free days. In four or five animals, cyclazocine produced more response generalization to morphine after six drug free days than after no drug free days. In two animals the cyclazocine dose-effect generalization curves were generally shifted to the left with increased time from last drug exposure. Morphine response generalization to cyclazocine was also related to the degree of stimulus control evident in the non-drug (saline) condition during early portions of the subjects' experimental histories. The less stimulus control evident in the non-drug (saline) condition (i.e., the more morphine-appropriate responses made after saline injections and the greater variability of such responding), the more likely it was to obtain morphine-appropriate responding after cyclazocine administration.

Animals↗
PubMed1986

Morphine discrimination in the pigeon using a color tracking procedure.

Pigeons were trained to discriminate 5.0 mg/kg morphine from saline. After morphine, subjects tracked the location of red response keys and after saline, the location of green keys. When stimulus generalization to other drugs was investigated dl-methadone produced morphine-like responding and this response generalization was primarily due to the l-isomer. Pretreatment with 1.0 mg/kg naloxone shifted the morphine generalization curve 10-fold to the right but only shifted the rate suppression curve 3-fold to the right. dl-Cyclazocine generated dose-related increases in responding on the red key location and in 3 of 5 birds, responses after 1.0 mg/kg were indistinguishable from those after morphine training doses. Meperidine did not produce responding on the red keys, nor did diazepam, cocaine, d-amphetamine, phencyclidine or pentobarbital. The discriminative stimulus effects of morphine are thus stereo-selective and pharmacologically specific. Generalization of responding to dl-cyclazocine but not to phencyclidine suggests that the morphine-like discriminative dl-cyclazocine cue was not due to interaction at sigma opiate receptors.

Animals↗
PubMed1986

Behavioral toxicity of chronic ethosuximide and sodium valproate treatment in the epileptic baboon, Papio papio.

The purpose of this study was to assess the effects of chronic administration of gradually increasing doses of the anti-petit mal agents, ethosuximide (15-60 mg/kg/day) and valproic acid (7.5-240 mg/kg/day) on the performance of incremental repeated acquisition and incremental fixed-ratio tasks in the epileptic baboon, Papio papio. At approximately equipotent anticonvulsant doses, ethosuximide (45-60 mg/kg/day) was more behaviorally toxic than valproic acid (7.5-60 mg/kg/day), as determined by the ability of each drug to suppress the incremental repeated acquisition of behavioral chains. The behavioral deficits induced by ethosuximide (60 mg/kg/day) were still present 8 weeks after cessation of drug treatment in two of four animals. Evidence of enhanced acquisition of behavioral chains (decreases in errors) was noted in two of six animals during chronic treatment with valproic acid at a dose of 60 mg/kg/day but was never seen during chronic treatment with ethosuximide. Responding under an incremental fixed-ratio schedule of reinforcement was only affected minimally by either drug. These data suggest that 1) cognitive processes are more vulnerable to disruption by chronic ethosuximide administration than they are to chronic valproic acid administration, 2) performance under the more complex incremental repeated acquisition schedule is more sensitive to disruption than that under an incremental fixed-ratio schedule and 3) the effects of ethosuximide and valproic acid on performance under the incremental repeated acquisition schedule are not due to decreases in motivation or ability to manipulate the response levers.

Animals↗
PubMed1986

Fetomaternal kinetics of 14C-trimethyltin.

The mechanism of trimethyltin (TMT)-induced neuropathology remains unknown but likely relates to its time-course in the nervous system. To determine the pharmacokinetic profile of TMT in the fetomaternal unit, pregnant rats were injected on gestational day (GD) 17 with 7.0 mg/kg TMT plus 10 uCi 14C-TMT ip. Whole blood and plasma, cerebrum (CBR), cerebellum (CBE), and brainstem (BS) were sampled from mother and fetus/pup (f/p). Whole body saline perfusions of mother and f/p were performed independently to remove 14C contaminated blood. Whole blood total radioactivity showed f/p levels to be below maternal levels: at 4 hr, 42.6%, 24 hr, 54.2%, 96 hr, 64.8%. Litters were cross-fostered (CF) at birth with those from untreated mothers. Two weeks after treatment (postnatal day 10), pups exposed in utero (n=13, 2 litters) had whole blood 14C levels 13.9% that of their mothers. Untreated pups CF to treated mothers showed a blood concentration 1.8% of the dosed mother, indicating that TMT is transferred in milk. Radioactivity in maternal whole blood at 2 weeks was 49 +/- 11% (SEM) of peak (1 hr) levels. Only 2.5 +/- 0.2% of maternal whole blood radioactivity was present in plasma. 14C in urine accounted for 17.5 +/- 1.5% of the dose at 2 weeks (n=4). Both maternal and fetal brains contained about 2-4% as much radioactivity as found in maternal and fetal whole blood, respectively. TMT crosses the placenta, enters fetal blood and attains fetal brain levels that are equal to those found in maternal brain.

Animals↗
PubMed1984

Incremental repeated acquisition in the rat: acute effects of drugs.

Rats lever pressed for food and learned new response sequences on three levers. At the beginning of each daily session, responses on only one of the levers produced food. After meeting criterion on one lever, the task was "incremented" so that sequential responses on two levers were required and so on up to five sequential responses. Each new required response was added in front of the previously performed sequence. Sequences of lever presses required to produce food changed each session. Following establishment of stable acquisition behavior, the acute effects of d-amphetamine (0.30-3.0 mg/kg), diazepam (0.125-4.0 mg/kg), morphine (0.30-10.0 mg/kg), pentobarbital (1.0-17.5 mg/kg), and chlorpromazine (0.10-3.0 mg/kg) were examined. All drugs decreased the number of response sequences completed in a dose-dependent fashion. Response rates generally decreased at or below those doses that caused an increase in errors. For d-amphetamine, the profound disruption of incremental repeated acquisition behavior was primarily due to drug-induced perserverative responding. Pentobarbital and chlorpromazine increased errors both when the sequence was incremented and within the sequence whereas diazepam only increased errors when the sequence was incremented. Morphine generally increased within sequence errors without affecting errors when the sequence was incremented.

Animals↗
PubMed1982

Modification of the anticonvulsant efficacy of diazepam by Ro-15-1788 in the kindled amygdaloid seizure model.

The effects of various doses of diazepam and the new central benzodiazepine antagonist Ro-15-1788 were investigated in fully amygdaloid kindled rats. Diazepam had a pronounced dose-dependent anticonvulsant effect in this model. Ro-15-1788 dose-dependently reduced the behavioral ranks of the elicited kindled seizures to a maximum of 60% of control without consistently modifying the afterdischarge duration. No prestimulation convulsant effects were seen with Ro-15-1788. When 2 mg/kg i.p. of Ro-15-1788 was given after various doses of diazepam, the prestimulation sedation and ataxia anticonvulsant effects of diazepam (0.5-2.0 mg/kg) were attenuated by treatment with 2 mg/kg dose of Ro-15-1788. At the low dose of diazepam (0.25 mg/kg), increased reduction of behavioral rank and after discharge duration was seen after the 2 mg/kg dose of Ro-15-1788. Thus, Ro-15-1788 appears not to have proconvulsant properties in the kindled amygdaloid seizure model. Further, Ro-15-1788 appears to have some anticonvulsant properties of its own. Mixed agonist and antagonist effects were seen with Ro-15-1788 when given after various doses of diazepam in this model.

Amygdala↗
PubMedDate not supplied

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↗
PubMedDate not supplied

Pharmacokinetics of cocaine in pregnant and nonpregnant rhesus monkeys.

To determine pharmacokinetic parameters for cocaine in rhesus monkey plasma, samples were taken over several hours after i.m. administration of cocaine plus a tritiated cocaine tracer. Cocaine and its metabolites, benzoylecgonine and norcocaine, were isolated via HPLC and quantitated using liquid scintillation spectrometry. Pregnant subjects were dosed with cocaine at 0.3 (n = 3) or 1.0 (n = 3) mg/kg, whereas nonpregnant female subjects were dosed with 1.0 mg/kg (n = 3). For the pregnant subjects, pharmacokinetic studies were conducted on about gestational day 125 and areas under the concentration versus time curve (AUCs, ng/mL x h) were 64 +/- 26 (+/- SEM) and 143 +/- 12; half-lives (t1/2s, h) were 1.9 +/- 0.6 and 1.1 +/- 0.1 after 0.3 and 1.0 mg/kg i.m., respectively. For nonpregnant subjects dosed acutely with 1.0 mg/kg, the AUC was 262 +/- 63 and the t1/2 was 1.4 +/- 0.3. There appear to be few differences in the pharmacokinetic parameters of cocaine and benzoylecgonine between pregnant and nonpregnant monkeys in this study.

Animals↗