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C L Mitchell

Publications and source records attributed to C L Mitchell.

At least 37 records · Page 2Linked to original sources
PubMed1988

Seizure-induced alterations in the metabolism of hippocampal opioid peptides suggest opioid modulation of seizure-related behaviors.

The evidence accumulated so far indicates that seizure activity exerts profound changes on the metabolism of opioid peptides in the hippocampus. Our data consistently show a large transient decrease in dynorphin and a modest decrease in enkephalin in the hippocampus following either a single ECS or KA injection. These initial reductions, which are indicative of increased release, may trigger the biosynthetic process of hippocampal opioids and result in an overproduction of the peptides seen in the rebound phase. However, the amount and timing of the rebound in enkephalin and dynorphin levels in response to repeated ECS, amygdaloid kindling, or KA differ drastically: a rapid and sustained increase in ME-LI follows all three treatments, in contrast to a slow recovery after a large and sustained decrease in DN-LI induced by repeated ECS and amygdaloid kindling. These results, which are unique to the hippocampus, suggest that differential mechanisms are operative in regulating the metabolism of these two opioid peptides in the hippocampus. It is likely that a well-coordinated regulation of hippocampal function can be achieved through the differential release of enkephalin and dynorphin and their subsequent interactions at different subtypes of opioid receptors following seizure activities. From a functional point of view, our data provide a neurochemical correlate of previous reports that brain opioid peptides may mediate ECS-induced behavioral alterations, such as changes in seizure threshold, postictal depression, and retrograde amnesia. The robust changes in the levels of opioid peptides in kindled rats, plus shortening of the kindling process by pretreatment with mu opioid antagonists, strongly suggest the involvement of brain opioid peptides in the development of kindling. Finally, these studies show clear evidence that enkephalin in the hippocampus is important in KA-induced WDS, a component of the opiate withdrawal syndrome in rodents (Isaacson and Lanthorn 1981). Further studies should help distinguish the regulatory mechanisms responsible for changes in opioid peptide metabolism during states of hyperexcitability in the hippocampal formation.

Amygdala↗
PubMed1987

Effects of corticosterone on shaking and seizure behavior induced by deep prepyriform cortex kindling.

The influence of adrenocorticosteroids on seizures and wet dog shakes (WDS) induced by deep prepyriform cortex kindling was studied by bilateral adrenalectomy and corticosterone replacement. The rate of kindling, latency to the onset and duration of motor seizures were not significantly affected by adrenalectomy or corticosterone treatment. However, the number of WDS observed after stage 5 seizures was reduced in adrenalectomized animals and it was not restored until 3 h following corticosterone replacement. This delay in onset of action suggests that the effects of adrenocorticosteroids and/or ACTH on WDS may be mediated by an indirect mechanism.

Adrenalectomy↗
PubMed1987

Stimulation of the perforant path alters hippocampal levels of opioid peptides, glutamine and GABA.

This investigation demonstrates that stimulation of the perforant path under conditions which elicit wet dog shakes in rats produces a significant decrease in hippocampal levels of methionine-enkephalin, dynorphin A(1-8) and glutamine, and an increase in gamma-aminobutyric acid (GABA). Levels of these substances are not altered by stimulus parameters insufficient to elicit wet dog shakes. These results lend support to the notion that endogenous opioid peptides play a role in regulation of hippocampal excitability but may only be released under relatively intense stimulus conditions. The increase in GABA levels could be due to an increase in synthesis, an increase in reuptake or a reduction in release. The latter possibility is consistent with reports that iontophoretically applied enkephalin exerts its apparent excitatory effects via an inhibitory action on inhibitory neurons in the hippocampus.

Amino Acids↗
PubMed1987

Regional variation in the response of cerebral ornithine decarboxylase to electroconvulsive shock.

Levels of ornithine decarboxylase activity were measured in brain regions and in adrenal glands of adult male rats exposed to electroshock. Five hours after shock at levels causing transient loss of consciousness and fore and hindlimb tonic extensor seizures, major increases in ornithine decarboxylase activity were found in adrenals, hippocampus, brain stem, frontal cortex, and cerebellum, but striatal levels were unchanged. These increases were reversed by 24 h after electroshock. When lower levels of shock, which caused no loss of consciousness, were also used, a clear dose-response relationship of shock intensity and ornithine decarboxylase activity was found for hippocampus and brain stem. The ornithine decarboxylase response in brain increased with higher shock levels. However, the changes of ornithine decarboxylase in adrenal glands were maximal at intermediate, and diminished at maximal shock values, as were levels of circulating testosterone. These data suggest a differing role for cerebral and adrenal ornithine decarboxylase in the mature rat. The brain enzyme may be primarily related to metabolic repair processes, whereas adrenal ornithine decarboxylase may function in the activation of secretion.

Adrenal Glands↗
PubMed1986

Amygdaloid kindling increases enkephalin-like immunoreactivity but decreases dynorphin-A-like immunoreactivity in rat hippocampus.

The effects of amygdaloid kindling on the regional levels and distribution of enkephalin-like and dynorphin-A (DN)-like immunoreactivity (LI) were examined. One day after completion of kindling, radioimmunoassay revealed a 71% decrease in DN1-8-LI and a 43% increase in [Met5]-enkephalin-LI in the hippocampus. Immunostaining revealed a depletion of DN1-17-LI in the hippocampal mossy fiber pathway and an increase in [Leu5]-enkephalin-LI in the temporoammonic pathway. Four weeks after completion of kindling, the levels and immunostaining intensity of dynorphin and enkephalin in the hippocampus had returned to control values.

Amygdala↗
PubMed1986

Influence of pre- and postnatal exposure of rats to 2.45-GHz microwave radiation on neurobehavioral function.

Rats exposed to microwaves prenatally (2,450 MHz, 10 mW/cm2, 3 h/day, days 5-20 of gestation) or perinatally (same as above plus days 2-20 postnatally) were examined by a neurobehavioral test battery on postnatal days 30 and 100. Body mass, locomotor activity, startle to acoustic and air-puff stimuli, fore- and hindlimb grip strength, negative geotaxis, reaction to thermal stimulation, and swimming endurance were assessed. The prenatally and the perinatally exposed rats (male and female) weighted more than sham-exposed rats at 30, but not at 100, days of age. In addition, the perinatally exposed animals had less swimming endurance at 30, but not at 100, days of age relative to sham-exposed rats. For the other measures, only the air-puff startle response was altered and was limited to the prenatally exposed female pups; ie, at postnatal day 30, the startle response was increased in magnitude, and at postnatal day 100, the response was decreased. No other reliable effects were observed. In a second experiment, rats treated as described above were examined for alterations in body mass, locomotor activity, reaction to air-puff stimuli, reaction to thermal stimulation, and swimming endurance at postnatal days 30-36. Again, perinatally exposed rats were larger in body mass and had less swimming endurance compared with sham-exposed rats. The latency to the air-puff startle response was longer in female pups exposed prenatally. These data indicate that altered endurance and gross motor activity result from perinatal exposure to microwave irradiation.

Animals↗
PubMed1986

Dynorphin- and enkephalin-like immunoreactivity is altered in limbic-basal ganglia regions of rat brain after repeated electroconvulsive shock.

In an attempt to determine whether the opioid peptides derived from prodynorphin participate in the effects of electroconvulsive shock (ECS), we used radioimmunoassay and immunocytochemistry to measure dynorphin-like immunoreactivity (DN-LI) in various rat brain regions after repeated ECS treatments. Ten daily ECSs caused a significant increase in dynorphin A (1-8)-LI in most limbic-basal ganglia structures, including hypothalamus (50%), striatum (30%), and septum (30%). No significant change was found in the frontal cortex or the neurointermediate lobe of the pituitary. In contrast, 10 ECS treatments depleted DN-LI in hippocampal mossy fibers by 64%. A detailed time-course study revealed that a single shock caused a small but significant increase in hippocampal DN-LI, whereas three consecutive shocks depleted DN-LI by 30%. The maximal decrease in DN-LI was reached after six daily ECSs. The level of DN-LI in the hippocampus partly recovered, but remained lower than the control value 4, 7, and 14 d after the cessation of six daily ECSs (50, 77, and 83% of control value, respectively). In contrast with the ECS-induced depletion of hippocampal dynorphin, 10 daily ECSs caused a significant increase (40%) in (Met5)-enkephalin-LI in the hippocampus, as well as in other limbic-basal ganglia structures. Immunocytochemistry revealed that enkephalin-LI was increased in the perforant pathway, which is presynaptic to the dynorphin-containing mossy fiber pathway in the hippocampus. These observations suggest that different mechanisms may regulate these two opioid peptide systems in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Statistical analysis of drug interactions.

The design of drug interaction experiments focusing on whether to characterize the interaction as addition, antagonism, synergism or potentiation 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. The chi-square or Fisher's exact probability test may be used for quantal data. Additivity is inferred if the null hypothesis is accepted. One infers either antagonism or synergism (depending upon the direction of the deviation from additivity) if the null hypothesis is rejected. If one substance is inactive when given alone the null hypothesis is that it has no effect when given with the other. This is tested using the same techniques as mentioned above, except that there is no need, obviously, to determine relative potency. The isobolographic method for studying drug interactions was compared with those mentioned above. Both approaches have the same conceptual basis. The isobolographic method is more tedious, however, since it entails determination of doses required to cause a specific response, whereas the other methods focus on the responses caused by specific doses. It was cautioned that, whatever the approach, it is the investigator's responsibility to know what assumptions are being made and to take all possible precautions before, during, and after the experiment to ensure that the reported results are meaningful.

Animals↗
PubMed1985

Repeated electroconvulsive shock downregulates the opioid receptors in rat brain.

Ten consecutive daily electroconvulsive shocks (ECSs), which produce maximal tonic and clonic convulsions, caused reductions of mu- and delta-opioid receptor binding in the hypothalamus, hippocampus and caudate nucleus, but not in the frontal cortex and brainstem. These changes of opioid receptor binding were not observed in rats receiving a single ECS. Scatchard analysis revealed that ECS-induced reduction of mu- and delta-receptor binding was due to a decrease in the binding sites but not to a change in the binding affinity. Time course studies showed that 7 days after the end of 10 consecutive daily ECSs, both mu- and delta-receptor binding remained lower than those of sham controls. However, the effects of ECS on the opioid receptor binding disappeared in 2-3 weeks. These observations are consistent with the hypothesis that ECS treatments increase the release of opioid peptides in certain brain regions which in turn down-regulate the opioid receptors.

Animals↗
PubMed1985

Injection of diethylstilbestrol on the first day of incubation affects morphology of sex glands and reproductive behavior of Japanese quail.

Japanese quail eggs were injected with DES (0.9-1,000 micrograms) dissolved in 50-microliter of corn oil on day 1 of incubation. Higher doses of DES (250-1,000 micrograms) reduced hatchability to 37-33% compared to 61% for corn oil-injected controls. Lower doses of DES (0.9-125 micrograms) had no effects on hatchability. In a second study, eggs were injected with 0.9 or 1.9 micrograms of DES and the survivors were assessed up to 12 weeks posthatch. DES did not affect hatchability, but did increase mortality during the first 4 weeks posthatch. Females were affected more than males. At 10 days of age, open-field activity of some birds was examined. The acquisition and reversal of a visual discrimination task was studied at 6 weeks of age. DES had no effect on these measurements. Ten females from each group were chosen randomly to determine egg production over a single 28-day period beginning at 6 weeks of age. Exposure to DES blocked egg production in these birds. The oviduct weights of 12-week-old females were decreased by 50%, but ovarian weights were not affected. Testicular weights were not affected. In a third study reproductive behaviors and social-dominance behaviors of males were markedly attenuated in birds exposed to 0.48 or 1.9 micrograms DES in ovo.

Animals↗
PubMed1985

Repeated electroconvulsive shocks alter the biosynthesis of enkephalin and concentration of dynorphin in the rat brain.

Ten daily electroconvulsive shocks (ECSs) caused a two-fold increase in (Met5)-enkephalin-like immunoreactivity (ME-LI) and an 80% increase in the level of mRNA coding for preproenkephalin A in the hypothalamus. These observations suggest that repeated ECSs increase the biosynthesis of hypothalamic ME. Ten daily ECSs also increased dynorphin A (1-8)-like immunoreactivity (DN-LI) in hypothalamus (45%) but not in frontal cortex. Unlike other brain regions, a 64% decrease of DN-LI was found in the hippocampus after 10 daily ECSs whereas a significant increase of ME-LI (40%) was observed. Furthermore, immunocytochemical studies revealed an increase of (Leu5)-enkephalin-like immunoreactivity in the perforant pathway and a decrease of DN-LI in the mossy fiber system of the hippocampus after 10 daily ECSs. These studies suggest that alterations in enkephalin and dynorphin in the limbic system may contribute to the behavioral changes observed after repeated ECSs.

Animals↗
PubMed1983

Long-term effects of behavioral testing on serum hormones and brain weight.

The effects of prior behavioral testing on endocrine function, brain weight, and neurotransmitter receptors were examined. Rats with a history of behavioral testing were significantly different from comparatively naive animals. Prior tested male and females had lower prolactin levels than nontested animals, and serum luteinizing hormone and corticosterone levels were elevated in males. In both sexes, hippocampal brain weight was greater in previously tested animals. However, estimates of brain membrane protein content and neurotransmitter receptors were unaffected by prior testing. These data suggest that prior tested animals respond as if they had experienced a history of chronic stress. Therefore, past history of the organism must be considered in studies designed to evaluate any agent's effect on neuroendocrine or neurochemical parameters.

Aging↗
PubMed1982

Behavioral toxicology in risk assessment: problems and research needs.

Behavioral methods are being used with increasing frequency in toxicology to assess the deleterious effects of chemicals to which we are exposed. The impetus for the use of behavioral techniques in risk assessment resulted from the presumption that they were more sensitive than other tests in detecting toxicity. A more logical reason for the use of behavioral tests is the fact that behavior is the functional indicator of the net sensory, motor, and integrative processes occurring in the central and peripheral nervous system. Thus, the functional capacity of the nervous system cannot be determined independent of behavioral analysis. Some of the problems confronting behavioral toxicology are (1) the translation of human subjective complaints into behavioral tests in animals; (2) determining subtle effects on the nervous system in the face of the well-known functional reserve and adaptability of the system; (3) dealing with the variety of statistical problems resulting from the use of multiple tests, multiple measurements using the same test and the (relatively) large variability inherent in some behavioral phenomena; and (4) selecting the proper tests. Three critical research needs in behavioral toxicology as they relate to risk assessment are (1) development and validation of methods, (2) determining subpopulations at greatest risk, and (3) developing a strategy for determining interactions between two or more agents.

Animals↗
PubMed1982

Bad statistics.

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Research Design↗
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.

Animals↗