Biomedical subjects

D Overstreet

Publications and source records attributed to D Overstreet.

12 recordsLinked to original sources

PubMed2001

Correlation of intact sensibility and neuropathic pain-related behaviors in eight inbred and outbred rat strains and selection lines.

In some rat strains, total hindpaw denervation triggers autotomy, a behavior of self mutilation presumably related to neuropathic pain. Partial sciatic ligation (PSL) in rats produces tactile allodynia and heat hyperalgesia but not autotomy. Our aims in this study were to examine: (1) whether sensibility of intact rats to noxious and non-noxious stimuli is strain-dependent; (2) whether sensibility of intact rats could predict levels of autotomy, or of allodynia and hyperalgesia in the PSL model; and (3) whether autotomy levels are correlated with levels of allodynia or hyperalgesia. Here we report that in two inbred rat strains (Lewis and Fisher 344), two outbred rat strains (Sabra and Sprague-Dawley) and four selection lines of rats (Genetically Epilepsy-Prone Rats, High Autotomy, Low Autotomy and Flinders Sensitive Line), tactile sensitivity and response duration to noxious heat of intact animals were strain-dependent. Levels of autotomy following hindpaw denervation and of allodynia and hyperalgesia in the PSL model were also strain-dependent. Thus, these traits are determined in part by genetic factors. Sensory sensibility of intact rats was not correlated with levels of autotomy following total denervation, or allodynia and hyperalgesia following partial denervation. We suggest that preoperative sensibility of intact rats is not a predictor of levels of neuropathic disorders following nerve injury. Likewise, no correlation was found between autotomy, allodynia and hyperalgesia, suggesting that neuropathic pain behaviors triggered by nerve injury of different etiologies are mediated by differing mechanisms.

Animals↗

PubMed2001

The effects of perinatal/juvenile heptachlor exposure on adult immune and reproductive system function in rats.

This study was performed to determine if developmental exposure of rats to heptachlor (H) during the last half of gestation through puberty adversely affects adult functioning of the immune and reproductive systems. Time-bred pregnant female Sprague-Dawley rats were dosed by gavage with H (0, 30, 300, or 3000 microg/kg/day) from gestation day (GD) 12 to postnatal day (PND) 7, followed by direct dosing of the pups with H through PND 42. Separate groups of rats were evaluated with a battery of immune function tests, while other groups of rats were evaluated for reproductive development and function. Additional groups of rats were euthanized at the end of the dosing period for histological analyses of major organ systems. Some dams and PND 7 pups were euthanized; milk, plasma, fat and/or tissues were assayed for H and heptachlor epoxide B (HEB), a major metabolite of H. The amount of H and HEB found in milk, blood, fat, and tissues was proportional to the dose of H administered. There were no effects on the number or survival of pups born to H-exposed dams nor to pups exposed postnatally. There were no effects on the number of treated dams delivering litters or on litter size, nor were there any effects on any of the reproductive end points examined in the F(0) or F(1) rats. There were no effects of H exposure on lymphoid organ weights, splenic natural killer (NK) cell activity, and splenic lymphoproliferative (LP) responses to mitogens and allogeneic cells in a mixed lymphocyte response (MLR) assay at 8 weeks of age. H exposure did not alter delayed or contact hypersensitivity at 10 or 17 weeks of age, respectively. However, the primary IgM antibody response to sheep red blood cells (SRBCs) was suppressed in a dose-dependent manner in males, but not females, at 8 weeks of age. The percentage of B lymphocytes (OX12(+)OX19(-)) in spleen was also reduced in the high-dose males. The anti-SRBC IgM response was reduced only in males exposed to 30 microg H/kg/day in a separate group of rats 21 weeks of age. In these same rats, at 26 weeks of age, the secondary IgG antibody response to SRBCs was suppressed in all of the H-exposed males, but not females. These data indicate that perinatal exposure of male rats to H results in suppression of the primary IgM and secondary IgG anti-SRBC responses. Suppression of these antibody responses persisted for up to 20 weeks after the last exposure to H, at a total exposure of approximately 1500 microg H/kg/rat.

Animals↗

PubMed2001

The effects of perinatal tebuconazole exposure on adult neurological, immunological, and reproductive function in rats.

Studies are under way to address concerns of potential persistent immunotoxic, reproductive, and neurotoxic effects of perinatal exposure to several pesticides. Tebuconazole, a triazole fungicide, was evaluated as part of this project. Sprague-Dawley dams were administered tebuconazole (0, 6, 20, or 60 mg/kg) by oral gavage daily from gestational day 14 to postnatal day (PND)7; the pups were then dosed daily at the same levels from PND7-42. Separate groups of rats were used for testing of immunological parameters, neurobehavioral testing using a screening battery of functional tests, and cognitive evaluations. Other groups of rats were evaluated for reproductive development and function, while yet others were sacrificed at the end of the dosing period for histological analyses of major organs systems, including neuropathological assessments. Pup viability and body weight were decreased in the highest dose group. There were no differences in the fertility indices in the exposed rats mated as adults. In the sheep RBC-immunized high-dose rats, spleen weights and cellularity were increased, and the ratio of cell types was altered compared to controls. There were, however, no biologically significant changes in the immune function of these rats. At necropsy on PND46 or 152, kidney, liver, and spleen weights were altered by tebuconazole treatment, but a dose-response relationship was not clear for most organs; only decreased kidney and increased liver weights were consistent in both sexes. Histological analyses were generally unremarkable outside of the brain. One month after the end of dosing, acquisition of learning the platform location in a water tank (i.e., Morris water maze) was impaired in the high-dose group; there were no differences in neuromuscular ability, motor activity, or swim speed to account for this finding. Furthermore, there was no effect on recall of the position during a free-swim trial. Neuropathological evaluations revealed pyknotic cells across hippocampal cell fields in animals of all tebuconazole treatment groups, with the highest incidence in the 20 and 60 mg/kg/day dose groups, coincident with cell loss within pyramidal cell layer of CA3-4 cell fields of the hippocampus and layer V of the neocortex. Thus, perinatal exposure to tebuconazole produced neurobehavioral deficits and neuropathology in rats, but did not alter immunological or reproductive function.

Animals↗

PubMed1998

Expression of cholinergic markers in the pons of Flinders rats.

The Flinders sensitive line of rats (FSL rats) have an altered REM sleep pattern which includes a shorter REM sleep latency and an increased percentage of REM sleep [R.M. Benca, D.H. Overstreet, M.A. Gilliland, D. Russell, B.M. Bergmann, W.H. Obermeyer, Increased basal REM sleep but no difference in dark induction or light suppression of REM sleep in Flinders rats with cholinergic supersensitivity, Neuropsychopharmacology 15 (1996) 45-51; P.J. Shiromani, D.H. Overstreet, D. Levy, C.A. Goodrich, S.A. Campbell, J. C. Gillin, Increased REM sleep in rats selectively bred for cholinergic hyperactivity, Neuropsychopharmacology 1 (1988) 127-133]. Cholinergic mechanisms have been implicated in REM sleep generation [reviewed in P.J. Shiromani, J.C. Gillin, S.J. Henriksen, Acetylcholine and the regulation of REM sleep: basic mechanisms and clinical implication for affective illness and narcolepsy, Annu. Rev. Pharmacol. Toxicol. 27 (1987) 137-156]. In the present study, specific aspects of the cholinergic system were examined in the pontine region of the FSL rats. The number of cholinergic neurons in the LDT and PPT were not different in FSL and control rats. Analysis of steady state levels of mRNAs encoding the acetylcholine synthesizing protein, choline acetyltransferase (ChAT) or the m2, m3 and m5 muscarinic receptor subtypes were also comparable in FSL and control rats. These data raise the possibility that the cellular events underlying the altered REM sleep pattern in FSL rats may include mechanisms that effect the muscarinic or nicotinic receptor in the pons.

Acetylcholine↗

PubMed1994

Free-running period of circadian rhythms is shorter in rats with a genetically upregulated central cholinergic system.

The free-running circadian rhythm of drinking activity was monitored in constant darkness in a genetic line of rats, the Flinders Sensitive Line (FSL), which show increased muscarinic receptors in several brain regions. Compared to control rats, the Flinders Resistant Line (FRL), that do not show increased muscarinic receptors, the free-running period of drinking activity was shorter in the FSL rats (FSL period = 24.02 +/- 0.01 vs FRL period = 24.12 +/- 0.02; p < .001). In an attempt to determine whether other rhythms were similarly affected, we simultaneously monitored drinking activity, gross motor activity, and core temperature in free-running constant darkness conditions. The results from three FSL and FRL rats showed that the circadian periods of all three rhythms were shorter in FSL rats. These findings indicate that an animal model with an upregulated central cholinergic system demonstrates an accelerated circadian pacemaker.

Animals↗

PubMed1991

Effects of sleep deprivation on sleepiness and increased REM sleep in rats selectively bred for cholinergic hyperactivity.

In this study we employed a modification of the multiple sleep latency test (MSLT) to determine whether rats of a strain with increased cholinergic activity were sleepier compared to randomly bred control rats. Seven rats each from the Flinders sensitive line (FSL, hypercholinergic) and Flinders resistant line (FRL, age-matched controls) were kept awake for 20 min and then allowed to sleep ad libitum for 20 min. The regimen of 20 min of wakefulness followed by 20 min of sleep was repeated 12 times during the day. There were no differences in latency to sleep or to rapid eye movement (REM) sleep or in percent total sleep time, drowsy, or slow-wave sleep between FSL rats and FRL rats. However, FSL rats showed a significant increase in REM sleep compared to FRL rats. This selective increase in REM sleep may be coupled to an increase in brain muscarinic receptors in the FSL rats.

Animals↗

PubMed1990

MK-801 potently inhibits alcohol withdrawal seizures in rats.

The ability of MK-801, an N-methyl-D-aspartate (NMDA)-channel antagonist, to suppress alcohol withdrawal seizures generated audio-genically was studied in adult male rats using a cross-over experimental design. MK-801 treatment reduced overall seizure score and proportion of rats seizing. In comparison to other seizure models, alcohol withdrawal seizures seem to be particularly sensitive to MK-801, suggesting that mechanisms which result in seizure susceptibility after withdrawal of chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes.

Acoustic Stimulation↗

PubMed1988

Increased REM sleep in rats selectively bred for cholinergic hyperactivity.

We have examined the sleep profile of the Flinders Sensitive Line (FSL) of rats, which were selectively bred for supersensitive responsivity to an acetylcholinesterase inhibitor (DFP). These animals have an increased density of muscarinic receptors in striatum and hippocampus and display a number of behavioral and neuroendocrine characteristics that may represent a rodent analogue of clinical depression. A continuous 48-hour sleep EEG recording was obtained. Compared to control rats (the Flinders Resistant Line), the FSL rats had selectively more rapid-eye-movement (REM) sleep as a percentage of total sleep time. In addition, the REM sleep latency was significantly shorter and the REM-REM cycle length was significantly faster in the FSL than in the FRL strain. The two strains did not differ in total sleep time, drowsy sleep, or slow-wave sleep. The increased REM sleep in the FSL rats is consistent with the amassed evidence that cholinergic mechanisms selectively promote REM sleep, and suggests that the FSL rats may be useful in understanding the mechanism responsible for short REM latency in depression and narcolepsy.

Animals↗

PubMed1984

Self-injection of diazepam in naive rats: effects of dose, schedule and blockade of different receptors.

The present series of experiments had two main objectives: The first was to determine the conditions under which self-injection of the benzodiazepine diazepam would be optimal; the second was to identify neurochemical substrates which underlie the maintenance of diazepam self-administration. Data from the first experiment indicated that rats maintained on an FI-1 (Fixed Interval of 1 min) schedule of food delivery self-injected significantly more diazepam than rats not maintained on this schedule. Results from the second experiment demonstrated that the benzodiazepine antagonist Ro 15-1788, and the GABA antagonist bicuculline, significantly reduced diazepam self-administration, but the opiate antagonist naloxone was without effect. Data from the third experiment showed that the dopamine antagonist haloperidol also significantly reduced the rate of diazepam self-injection. Thus, these findings indicate that the acquisition of diazepam self-injection occurs under an FI-1 schedule of food delivery, which has been shown to be middly stressful, while its maintenance depends upon the functional integrity of benzodiazepine and GABA receptors and upon the activity of dopaminergic pathways.

Animals↗

PubMed1980

Benzodiazepine receptors: the effect of GABA on their characteristics in human brain and their alteration in Huntington's disease.

The characteristics of bezodiazepine (BDZ) receptors were studied in the putamen and substantia nigra (SN) of control and Huntington's disease (HD) human brains. In the putamen, there was a significant decrease in density BDZ receptors in the HD tissue. In addition the application of GABA significantly potentiated DBZ receptor binding in both the HD and control putamen. In the SN, an increase in BDZ receptor density was detected in the HD tissue. GABA enhanced [3H]flunitrazepam binding in both the HD and control SN by increasing the affinity of BDZ receptors for [3H]flunitrazepam. The results suggest that there are alterations in BDZ receptors in HD human brain and that these alterations may be related to the neuronal pathology of this disease. This study also provides evidence for a coupling of GABA receptors to BDZ receptors in human brain.

Aged↗

PubMedDate not supplied

Comparative disposition and metabolism of 1,2,3-trichloropropane in rats and mice.

1,2,3-Trichloropropane (TCP) has been used as a solvent and degreasing agent and as an intermediate in pesticide manufacture. TCP is currently the subject of a National Toxicology Program chronic toxicity study. The present study is part of a larger effort to characterize the toxicity of TCP. Following acute oral exposure of male and female F344 rats (30 mg/kg) and male B6C3F1 mice (30 and 60 mg/kg), TCP was rapidly absorbed, metabolized, and excreted. The major route of excretion of TCP was in the urine. By 60 hr postdosing, rats had excreted 50% and mice 65% of the administered dose by this route. Exhalation as 14CO2 and excretion in the feces each accounted for 20% of the total dose in 60 hr rats and 20 and 15%, respectively, in mice. No apparent sex-related differences were observed in the ability of the rats to excrete TCP-derived radioactivity. At 60 hr, TCP-derived radioactivity was most concentrated in the liver, kidney, and forestomach in both rats and male mice. Male mice eliminated TCP-derived radioactivity more rapidly than rats and lower concentrations of radioactivity were found in tissues 60 hr after dosing in mice. Two urinary metabolites were isolated and identified by NMR, mass spectroscopy, and comparison with synthetic standards, as N-acetyl- and S-(3-chloro-2-hydroxypropyl)cysteine. Analyses of the early urine (0-6 hr) showed this mercapturic acid to be the major metabolite in rat urine and was only a minor component in mouse urine. 2-(S-Glutathionyl)malonic acid was identified by NMR and mass spectrometry and by chemical synthesis as the major biliary metabolite in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Metabolism of citral, an alpha,beta-unsaturated aldehyde, in male F344 rats.

Citral is a naturally occurring aliphatic aldehyde of the terpene series and is an isomeric mixture of geranial and neral. It is the main component (approximately 80%) of lemongrass oil, which is found in all citrus fruits and used extensively in the food, cosmetic, and detergent industries. In this study, urinary metabolites of citral in male F344 rats were characterized and identified by comparison with synthetic standards of known stereochemistry. Stereospecific oxidation of citral at the C-8 methyl was investigated, as was the hydrolytic sensitivity of biliary and urinary metabolites. For metabolite identification, urine was collected over dry ice for 24 hr after a single po 500 mg/kg dose of [14C]citral. Elimination in urine was rapid, with approximately 50% of the dose excreted within 24 hr. The urine was fractionated by reverse-phase HPLC, monitoring both radioactivity and UV. Synthetic standards were prepared; a comparison of their spectra with the isolated metabolites was used for identification. Citral was rapidly metabolized and excreted as metabolites, including several acids and a biliary glucuronide. Seven urinary metabolites were isolated and identified: 3-hydroxy-3,7-dimethyl-6-octenedioic acid; 3,8-dihydroxy-3,7-dimethyl-6-octenoic acid; 3,9-dihydroxy-3,7-dimethyl-6-octenoic acid; E- and Z-3,7-dimethyl-2,6-octadienedioic acid; 3,7-dimethyl-6-octenedioic acid; and E-3,7-dimethyl-2,6-octadienoic acid. Although citral is an alpha,beta-unsaturated aldehyde and has the potential of being reactive, the urinary metabolites of citral appear to arise from metabolic pathways other than nucleophilic addition to the double bond.

Acyclic Monoterpenes↗