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C L Mitchell

Publications and source records attributed to C L Mitchell.

At least 19 recordsLinked to original sources
PubMed1991

A glutamate antagonist blocks perforant path stimulation-induced reduction of dynorphin peptide and prodynorphin mRNA levels in rat hippocampus.

Stimulation of the perforant path elicits a behavioral response, wet dog shakes (WDS), and reduction in hippocampal dynorphin A(1-8) immunoreactivity (DYN-IR) and prodynorphin mRNA (DYN mRNA) in rats. This study examined whether glutamate, the proposed endogenous transmitter released by perforant fibers, mediated the above responses. A glutamate antagonist, gamma-D-glutamylglycine (DGG, 25 micrograms/0.5 microliters), or artificial cerebrospinal fluid (ACSF, 0.5 microliters) was injected into the ventral hippocampus 10-20 min prior to acute or daily stimulation of the left perforant path in rats. In acute stimulation experiments, 4 consecutive stimulation trials elicited a total of 73 +/- 4 WDS at an average threshold intensity of 0.46 +/- 0.03 mA in ACSF-treated rats. The hippocampal DYN-IR in these animals decreased by more than 40% in both dorsal and ventral hippocampus relative to sham-stimulated rats. DGG injections significantly elevated the threshold for WDS (0.78 +/- 0.05 mA, P less than 0.01), reduced the number of WDS (45 +/- 6, P less than 0.01), and partially antagonized stimulation-induced reduction of DYN-IR in the ventral, but not dorsal, hippocampus. In daily stimulation experiments, rats received a single trial of stimulation once per day for 6 days. Daily DGG pretreatment almost completely abolished WDS at control threshold intensities, and significantly inhibited stimulation-induced decrease of DYN-IR in both dorsal and ventral hippocampus. In situ hybridization using a 35S-labeled oligodeoxyribonucleotide probe demonstrated a clear depletion of DYN mRNA signal in the dentate granule cell layer of ACSF-treated animals. This depletion was completely prevented in DGG-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1991

Opioid mu and delta receptor antagonists reduce wet dog shaking elicited by perforant path stimulation.

Stimulation of the perforant path, a major input to the hippocampal formation, produced significant decreases in the hippocampal levels of methionine enkephalin, dynorphin A(1-8) and an increase in the hippocampal level of gamma-aminobutyric acid. In addition, it was also observed that both mu and delta opioid receptor antagonists reduce wet dog shakes elicited by perforant path stimulation. The antagonists did not affect the changes in hippocampal levels of methionine enkephalin, dynorphin A(1-8) or gamma-aminobutyric acid. The results demonstrate that endogenous opioids are involved in the wet dog shakes elicited by perforant path stimulation. Since electrographic seizure activity occurs in the hippocampus in conjunction with perforant path stimulation-induced wet dog shakes, these data provide further evidence that endogenous opioid peptides play an important role in regulation of limbic system epileptogenic phenomena.

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PubMed1990

Granule cells in the ventral, but not dorsal, dentate gyrus are essential for kainic acid-induced wet dog shakes.

Intrahippocampal injections of colchicine selectively destroy dentate granule cells. Wet dog shaking elicited by systemic administration of kainic acid is eliminated by bilateral destruction of ventral dentate granule cells but unaffected by bilateral destruction of dorsal dentate granule cells. This implies that ventral dentate granule cells are essential for the generation of kainic acid-induced wet dog shakes.

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PubMed1990

Colchicine lesions of ventral, but not dorsal, dentate granule cells attenuate wet dog shakes elicited by perforant path stimulation.

Intrahippocampal injections of colchicine selectively destroy dentate granule cells. Wet dog shaking elicited by perforant path stimulation is unaffected by bilateral destruction of dorsal dentate granule cells but virtually eliminated by bilateral destruction of ventral dentate granule cells. This implies that ventral dentate granule cells are essential for the generation of perforant path stimulation-induced wet dog shakes.

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PubMed1990

Granule cells in the ventral dentate gyrus are essential for kainic acid-induced wet dog shakes but not those induced by precipitated abstinence in morphine-dependent rats.

Wet dog shaking elicited by systemic administration of kainic acid is eliminated by bilateral destruction of ventral dentate granule cells. In contrast, wet dog shaking induced by naltrexone precipitated abstinence in morphine-dependent rats is unaffected by destruction of ventral dentate granule cells. It is concluded that at least two anatomically distinct brain regions modulate wet dog shaking behavior.

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PubMed1990

Diethyldithiocarbamate and dithizone augment the toxicity of kainic acid.

Male Fischer-344 rats were injected i.p. with diethyldithiocarbamate or dithizone 15 min after kainic acid (KA), s.c. Diethyldithiocarbamate and dithizone reduced both the number of wet dog shakes and the latency to onset of seizures induced by KA. Moreover, they increased the severity of seizures. These compounds may be useful tools for investigating the role of zinc in central nervous system excitatory transmission and/or convulsive phenomena.

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PubMed1990

Differential effects of colchicine lesions of dentate granule cells on wet dog shakes and seizures elicited by direct hippocampal stimulation.

Direct electrical stimulation of either the dorsal or ventral hippocampal formation elicits wet dog shakes and overt seizures. Destruction of dentate granule cells in the dorsal hippocampal formation does not significantly reduce the number of wet dog shakes elicited by ventral hippocampal stimulation. However, destruction of dentate granule cells in the ventral hippocampus virtually eliminates wet dog shaking elicited by dorsal hippocampal stimulation. Destruction of either dorsal or ventral dentate granule cells lowers the threshold for eliciting forelimb clonus with rearing. These results suggest that dentate granule cells in the ventral hippocampus are essential for wet dog shakes elicited by intrahippocampal stimulation. However, dentate granule cells throughout the hippocampal formation appear to play an important inhibitory role in the spread of seizure activity within the hippocampus.

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PubMed1990

Perforant path stimulation differentially alters prodynorphin mRNA and proenkephalin mRNA levels in the entorhinal cortex-hippocampal region.

The regulatory effect of the perforant path on opioid gene expression in the entorhinal cortex-hippocampal region was investigated. The left perforant path was electrically stimulated at the angular bundle under conditions which elicit wet dog shakes but no motor seizures in rats. Animals were given either an acute stimulation composed of several consecutive stimulation trials, or daily stimulations with a single trial every day for 6 days. Rats were then sacrificed at 24 h or 6 days after the last trial. The amounts of prodynorphin mRNA (DYN mRNA) and proenkephalin A mRNA (EK mRNA) in the hippocampus and entorhinal cortex were measured by RNA blot analysis. Dynorphin A(1-8) and [Met5]enkephalin immunoreactivities were determined by radioimmunoassay. A decrease in DYN mRNA level of approximately 50-80% was found on both sides of the hippocampus 24 h after both acute and daily stimulation. Hippocampal dynorphin A(1-8) immunoreactivity was also reduced at 24 h, and persisted for at least 6 days. In contrast, bilateral increases in EK mRNA level were observed in the hippocampus (54-101%) and entorhinal cortex (97-165%) 24 h after the acute stimulation. Also, [Met5]enkephalin immunoreactivity in the hippocampus tended to be increased at this time. These results indicate that activation of the perforant path inhibits the gene expression of prodynorphin, but enhances that of proenkephalin in the entorhinal cortex-hippocampal region.

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PubMed1990

Opioid-induced epileptiform bursting in hippocampal slices: higher susceptibility in ventral than dorsal hippocampus.

The disparity between the seizure sensitivity of the dorsal and ventral hippocampus to opioid peptides was studied by an in vitro electrophysiological method. Slices taken from the ventral (temporal) and dorsal (septal) regions of rat hippocampi were perfused in artificial cerebrospinal fluid bubbled continuously with 95% O2-5% CO2 at 34 degrees C. A stimulating electrode was placed in the stratum radiatum of CA3 region and electrical activity was recorded from the pyramidal cell body layer of the CA3b region. Paired dorsal and ventral hippocampal slices were perfused with [N-Me-Phe3-D-Pro4]morphiceptin (PL017), a specific mu opioid receptor agonist. Application of 0.05 microM PL017 produced triggered and spontaneous bursting in 20% of ventral hippocampal slices, but no such effect was observed in dorsal hippocampal slices. At 0.5 microM PL017, 80% of ventral hippocampal slices developed spontaneous bursting, whereas only 10% of dorsal hippocampal slices had spontaneous bursting. Slices from the ventral hippocampus consistently produced greater degrees of bursting at lower doses relative to the dorsal hippocampus. The addition of 0.1 microM naloxone before or after PL017 inhibited the triggered response but could not block the spontaneous bursting. Perfusion of ACSF for 1 hr also eliminated the triggered response but could only reduce the frequency of the spontaneous bursting. These results suggest that the ventral hippocampus has a higher susceptibility to PL017-induced epileptiform bursting, and this effect is mediated, at least in part, through mu opioid receptors.

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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.

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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.

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PubMed1978

The reinforcing properties of procaine and d-amphetamine compared in rhesus monkeys.

Twelve rhesus monkeys were studied under a fixed-ratio (FR) schedule of intravenous procaine or d-amphetamine injection from 8 A.M. to 4 P.M. daily. Under the FR schedule, every nth lever press produced an injection. The FR value (n) and the dose per injection of procaine and d-amphetamine were varied systematically. At a FR value of 10, responding was maintained by doses of procaine ranging from 0.125 to 12 mg/kg/injection and by doses of d-amphetamine ranging from 0.01 to 0.1 mg/kg/injection. At doses of 1 mg/kg/injection of procaine and 0.1 mg/kg/injection of d-amphetamine, responding was maintained at FR values up to 100 by procaine and d-amphetamine but not by saline. Responding and drug intake were relatively constant throughout each 8-hour session with procaine, but responding tended to decrease and was more variable over the session with d-amphetamine. No toxic effects were observed in doses up to 6 mg/kg/injection with procaine. At this dose, eating and drinking ceased during the period of access to the drug. One of the four monkeys died at 8 mg/kg/injection of procaine. At 12 mg/kg/injection all three monkeys tested showed signs of toxicity.

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PubMed1977

The surgical technique for hindquarter amputation. A report of 19 cases.

The surgical technique for hindquarter amputation is described in a step-by-step manner. Since 1955 we have performed 19 such operations for eradication of malignant bone and soft tissue tumors in the pelvic, hip and upper thigh regions. Three hindquarter amputations were performed for local recurrence following initial wide excision. The overall 5-year survival rate for our 19 patients was 42.1 per cent. Malignant soft tissue tumors appear to have a much better 5-year survival rate than malignant bone tumors (60 per cent vs. 22.2 percent). We feel that surgery is still the treatment of choice. However, in the presence of proper indications, chemotherapy and radiotherapy should be added to surgery in order to prolong survival time and save lives.

Adolescent↗
PubMed1977

Analgesic studies with nefopam hydrochloride.

Nefopam hydrochloride[3] is a novel analgesic agent possessing an activity profile distinct from that of narcotic, narcotic agonist-antagonist and analgesic antiinflammatory agents. Analgesic activity is demonstrated in a variety of laboratory procedures with rodents, cats and monkeys. The analgesic potency of nefopam hydrochloride is generally similar to that of codeine phosphate. The compound lacks potential for tolerance development and does not exhibit cross-tolerance with morphine sulfate.

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PubMed1976

The design and analysis of experiments for the assessment of drug interactions.

It was pointed out that all fields of biological research have one feature common: inherent variability. Since this is the case and since it is not feasible to examine the entire population one is interested in, the experimenter is forced to give probability statements concerning any treatment differences observed. In order to do this, it is necessary for the experiment to be designed in such a way that a statistical analysis of the data will yield a valid answer to the question, "What is the probability that the differences observed could have occurred by chance?" The importance of randomization in the selection of the samples was emphasized. The problem of determining the sample size was discussed in relation to Type I (rejecting the null hypothesis when it is true) and Type II (accepting the null hypothesis when it is false) errors. It was suggested that too little attention is given to the possibility of Type II errors in biological research. It was emphasized that the specific question, or questions, one is asking should be precisely formulated prior to the design of the experiment, since hazily formulated ideas are difficult to discuss and virtually impossible to test for correctness. Once the experiment has been designed, both the questions and the design should be critically and logically evaluated for any fallacies. If the investigator has any doubts about the design or the manner in which the data will be analyzed, a statistician should be consulted before the experiment is conducted. A statistician cannot extract meaningful results from data collected with a faulty design. It was emphasized that it is important to know both the dose effect and time effect of each substance on the responses to be measured, in order to provide a rationale for the doses used in the interaction studies and the time after dosing at which the effect is to be measured. The design of drug interaction experiments is based, in part, on whether or not both substances when given alone affect the response. If both substances are active, one determines the potency of one substance relative to the other in affecting the response. This can be done for either quantitative or quantal data. Once the relative potency has been determined, subsequent studies involve combining fractional doses of the substances and comparing the results against those obtained using standard doses of the substances individually. Doses of the combination and the single substances are picked such that equivalent responses should be obtained if the effect of the two together is additive. The null hypothesis is that the two compounds behave as though they were different forms of the same substance, one of which is possibly (depending on the potency ratio) diluted with an inert substance. Equivalence of response can be tested using such parametric tests as Student's t or analysis of variance (or their nonparametric equivalents) for quantitative data. Additivity is inferred if the null hypothesis is accepted...

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