Differences between inbred strains of mice in Morris water maze performance.
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Animals↗
Biomedical subjects
J M Wehner
Publications and source records attributed to J M Wehner.
Nicotine tolerance: an analysis of the time course of its development and loss in the rat.
The time course of the development and loss of tolerance to nicotine was measured in female rats that were injected subcutaneously (SC), twice daily with 1.6 mg/kg nicotine. Tolerance to nicotine-induced decreases in locomotor activity and body temperature were observed. Tolerance to the effects of nicotine on both of these measures developed rapidly, with maximal changes occurring within 2-4 days after initiation of treatment. The binding of L-[3H]-nicotine was measured in six brain regions. Chronic nicotine treatment resulted in increases in binding in most brain regions. The increase in binding correlated significantly with the development of tolerance. Rats that had been injected chronically with nicotine did not lose their tolerance throughout a 7-day post-treatment test period. Control levels of binding were regained in all of the brain regions except cortex by 7 days after nicotine treatment was stopped. These findings indicate that changes in receptor binding may relate to the development of tolerance but the retention of tolerance is clearly not related to the number of brain nicotinic receptors, unless nicotine-induced decreases in body temperature and locomotor activity are controlled by cortical [3H]-nicotine binding sites.
Animals↗
Further characterization of benzodiazepine receptor differences in long-sleep and short-sleep mice.
Molecular and conformational characteristics of benzodiazepine (BZ) receptors in cortex and cerebellum from long-sleep and short-sleep mice were investigated using heat inactivation and beta-carboline competition techniques. To investigate differences in the allosteric coupling between GABA and BZ receptors, the protection of BZ receptors from heat inactivation, by GABA, was also evaluated. The two genotypes do not differ in the affinity or number of BZ receptors in the cortex or cerebellum. They do, however, appear to differ in the molecular structure and/or regulation of the conformational state of the receptor in the cortex, as indicated by a greater sensitivity of LS mice to both heat inactivation and beta-carboline competition of 3H-flunitrazepam (FNZ) binding in this region. Evidence for differences in the nature of coupling between GABA and BZ receptors is provided by the finding that in both regions, GABA protected BZ receptors from inactivation to a greater degree in LS mice. The relationship between these differences and the multiplicity of expression of BZ receptors is discussed.
Animals↗
Classical genetic analysis of GABA-related seizures.
Differences in resistance to 3-mercaptopropionic acid (MP)-induced seizures exist between DBA/2Ibg and C57BL/6Ibg inbred strains of mice; C57BL/6Ibg mice are more resistant to MP-induced seizures. To determine the mode of inheritance for seizure resistance, a classical genetic analysis was conducted using these two parental strains, their F1, F2, and backcross generations. Latencies to seizure onset and tonus after intraperitoneal (IP) injections of MP (25-40 mg/kg) were quantified. For all populations mean latencies to onset and tonus decreased in a dose dependent manner with the hybrid generations exhibiting a seizure resistant phenotype resembling the C57BL/6Ibg strain. In general, female mice were less resistant to MP-induced seizures than males; however, a significant degree of resistance was retained by the C57BL/6Ibg females and their female progeny. A quantitative assessment of the pattern of inheritance for seizure resistance using a weighted least-squares regression approach indicated that an additive-dominance model explained latency to seizure onset data at 25, 35 and 40 mg/kg. However, at 30 mg/kg, the model required the addition of an epistatic parameter to best describe mean scores at this dose. The results of these analyses suggest that resistance to MP-induced seizures is transmitted in a dominant manner.
3-Mercaptopropionic Acid↗
Influence of genotype on nicotine-induced increases of plasma corticosterone in mice as a result of acute nicotine pretreatment.
Acute exposure to nicotine produces an elevation of plasma corticosterone levels in rodents. The consequences of repeated exposure to nicotine administered intraperitoneally (IP) were examined in three inbred strains of mice, DBA/2Ibg, C3H/2Ibg and A/J. These strains of mice have been shown previously to differ in a variety of behavioral and physiological responses to acute nicotine exposure. Mice were administered saline or 1.00 mg/kg nicotine IP, followed 30 min later by a range of nicotine doses (0.25-1.00 mg/kg). Strain differences were observed for the dose-response to the second injection; however, no effect of acute nicotine pretreatment was demonstrated. The observed lack of desensitization was consistent across genotype. An intragastric administration of a pretreatment dose of nicotine (4.00 mg/kg) also failed to produce desensitization to a subsequent IP nicotine injection in any strain. Increasing the time interval between injections to 45 min did not alter the CCS response. However, at 90 min between injections, a supersensitive CCS response was measured in all strains.
Animals↗
DBA/2Ibg mice are incapable of cholinergically-based learning in the Morris water task.
In comparison to C57BL/6Ibg mice, DBA/2Ibg mice are slow to find a submerged platform in the Morris water task. Spatial learning in this task is known to be severely disrupted by treatments that reduce muscarinic cholinergic function. DBA mice were chronically treated with diisopropylfluorophosphate (DFP) in order to decrease muscarinic binding in the brain. Despite significant losses of binding sites in cortex, midbrain, hindbrain, hippocampus, and striatum, the mice failed to show an effect of DFP treatment on latency to reach the platform. Saline-treated DBA mice showed only marginal preference for searching the appropriate region of the pool during a probe trial in which the platform was absent from the pool. The pattern of search behavior was not altered by DFP treatment. These data are in strong contrast to data obtained previously with C57BL/6Ibg mice, which show accurate search behavior that is completely disrupted by DFP treatment. DBA mice thus appear incapable of true, cholinergically-mediated spatial learning. It is hypothesized that these mice lack normal function of the septo-hippocampal system.
Animals↗
Differential response to flurazepam in long-sleep and short-sleep mice.
In addition to differing in ethanol sensitivity, long-sleep (LS) and short-sleep (SS) mice also differ in response to GABAergic agents. In the present study the sensitivity of LS and SS mice to the anesthetic, hypothermic and anticonvulsant effects of benzodiazepine, flurazepam, was determined. Flurazepam (75-300 mg/kg) induced a dose-dependent loss of righting response in both lines. The LS line displayed a two-fold greater sensitivity to the anesthetic effects of flurazepam. A dose-dependent decrease in body temperature was also observed following administration of flurazepam (25-150 mg/kg), but the two lines did not differ on this measure. Determination of the anticonvulsant effects of flurazepam (1-6 mg/kg) against seizures induced by 3-mercaptopropionic acid revealed that the SS line was more sensitive to the anticonvulsant effects of this benzodiazepine. These studies demonstrate that LS and SS mice differ in response to flurazepam, but the nature of the difference depends on the type of response measured and the dose of flurazepam employed.
3-Mercaptopropionic Acid↗
Heterosis and resistance to DFP effects on spatial learning in C57BL X DBA hybrids.
The inbred mouse strains C57BL/6Ibg and DBA/2Ibg differ in their ability to exhibit spatial learning in the Morris water task. C57BL mice learn the task well and show impairment of spatial learning following disruption of cholinergic function. DBA mice show rudimentary spatial learning ability, and are not further impaired when cholinergic function is decreased. These mice may carry genes regulating a noncholinergic spatial learning system. To test this hypothesis, first generation (F1) hybrids between DBA and C57BL mice were tested for spatial learning in the Morris water task. The hybrids performed better than either parental strain, suggesting that both parents contributed genes for spatial learning ability. Chronic treatment with diisopropylfluorophosphate (DFP), which abolished spatial learning ability in C57BL mice, produced only minor impairments in the hybrids. The behavioral resistance to DFP occurred despite significant reductions in hippocampal and cortical muscarinic binding. The results suggest either that the hybrids inherited a noncholinergic neurochemical system influencing spatial learning from their DBA parents or that the DFP treatment did not disrupt cholinergic function to a sufficient degree to impair the superior learning abilities of the F1 hybrids.
Acetylcholinesterase↗
Correlation between the enhancement of flunitrazepam binding by GABA and seizure susceptibility in mice.
Various populations of mice exhibit differential sensitivity to seizure-inducing agents. The relationship of seizure susceptibility to alterations in the GABA receptor complex was investigated in six different populations of mice consisting of four inbred strains (C57BL, DBA, C3H, and BALB) and two selected lines (long sleep and short sleep). Seizure activity was induced by intraperitoneal administration of the GAD inhibitor, 3-mercaptopropionic acid, and latencies to seizure onset and tonus were measured. In naive mice of the same populations, GABA enhancement of 3H-flunitrazepam binding was measured in extensively washed whole brain membranes at several GABA concentrations. Both differential seizure sensitivity to 3-mercaptopropionic acid and differential enhancement of 3H-flunitrazepam binding by GABA were observed in these six populations of mice. Correlational analyses indicated a positive correlation between the degree of GABA enhancement of 3H-flunitrazepam binding and resistance to the seizure-inducing properties of 3-mercaptopropionic acid. These data suggest that genetic differences in sensitivity to seizure-inducing agents that disrupt the GABAergic system may be related to differences in coupling between the various receptors associated with the GABA receptor complex.
3-Mercaptopropionic Acid↗
Genetic variation in paraoxonase activity and sensitivity to diisopropylphosphofluoridate in inbred mice.
The mechanism underlying genetic variation in the acute and chronic responses of mice to diisopropylphosphofluoridate (DFP) are unknown. We investigated whether variation in metabolism of organophosphates by A-esterase, as exemplified by the enzyme paraoxonase, was correlated to the degree of sensitivity to DFP in four inbred mouse strains. LD50s and plasma paraoxonase were measured in each strain. We observed genetic variation in both of these measures, but there was no significant correlation between the two measures. We conclude that plasma paraoxonase activity does not underlie genetic variation in sensitivity to the lethal effects of DFP in mice since it does not determine the degree of sensitivity or resistance to DFP.
Animals↗
Effects of chronic diisopropylfluorophosphate treatment on spatial learning in mice.
The Morris water task was used to measure the effects of chronic diisopropylfluorophosphate (DFP) treatment on C57BL/6Ibg mice. Control mice showed good task acquisition and searched accurately for the platform after it was removed from the pool, suggesting that they had formed a spatial map of the platform's location relative to distal cues. In contrast, mice chronically treated with DFP prior to training showed a marked deficit in spatial learning. Chronic DFP treatment did not affect ability to locate a visible platform and did not impair task retention in mice trained to find the hidden platform prior to DFP treatment. The chronic DFP treatment decreased muscarinic binding in cortex, hippocampus, and striatum. These results indicate that C57BL mice are capable of spatial learning in the water task. The ability of chronic DFP treatment to impair place but not cue learning suggests that the cholinergic dysfunction produced by DFP is similar to those produced by lesions of central cholinergic systems and acute treatments with muscarinic antagonists.
Animals↗
Differential sensitivity to bicuculline in three inbred mouse strains.
We examined the inbred mouse strains DBA/2Ibg, C57BL/6Ibg, and C3H/2Ibg for differences in susceptibility to bicuculline-induced seizures, as well as to bicuculline-induced epileptiform activity recorded in the CA1 pyramidal cell layer of hippocampal slices. For susceptibility to seizure onset the strain rank order was (most to least susceptible): C3H = DBA greater than C57. The rank order for sensitivity to effects of bicuculline on tonic seizure latency and on hippocampal epileptiform activity were identical: C3H greater than DBA = C57. It is suggested that mechanisms underlying the development of bicuculline-induced epileptiform events in the hippocampal slice may be similar to those involved in the development of tonic seizures measured in vivo.
Action Potentials↗
GABA enhancement of flunitrazepam binding in mice selectively bred for differential sensitivity to ethanol.
The binding of the benzodiazepine [3H]flunitrazepam (FNZ) and the allosteric enhancement of FNZ binding by gamma-aminobutyric acid (GABA) were investigated in brain tissue from short-sleep (SS) and long-sleep (LS) mice, lines selectively bred for differential sensitivity to ethanol. GABA enhanced FNZ binding in a dose-dependent manner in both lines. This enhancement was greater in SS than in LS cortical and cerebellar regions, but did not differ between lines in midbrain or hindbrain regions. In whole brain, no difference was observed between the two lines in the number or affinity of benzodiazepine receptors, as determined by FNZ binding. These results suggest that the nature of allosteric interactions within the GABA-benzodiazepine receptor complex is different for LS and SS mice.
Animals↗
Strain-selective effects of nicotine on electrophysiological responses evoked in hippocampus from DBA/2Ibg and C3H/2Ibg mice.
We used the hippocampal slice to examine extracellular electrophysiological responses to nicotine and the difference in sensitivity to nicotine-induced electrophysiological effects between the DBA and C3H mouse strains. Nicotine enhanced CA1 population spikes (PS) evoked by Schaffer collateral stimulation in a concentration-dependent manner (100 microM to 3.2 mM). This enhancement was slow to appear, achieving a maximum after 15 min. The enhanced PS was accompanied by the development of epileptiform activity (multiple PS's) at nicotine concentrations greater than or equal to 400 microM. Slices from DBA mice were significantly more sensitive than those from the C3H strain to these electrophysiological effects of nicotine. Mecamylamine (400 microM) blocked both the nicotine-induced PS enhancement and secondary population spikes in both strains, suggesting the involvement of nicotinic cholinergic receptors.
Animals↗
Osteomyelitis of the sacrum as the initial manifestation of Crohn's disease.
A 17-year-old boy had low back pain for four months prior to the development of sacral osteomyelitis, which led to the initial diagnosis of Crohn's disease. Musculoskeletal problems occur in about one-third of the patients with Crohn's disease. Only a few patients with osteomyelitis complicating Crohn's disease have been reported. This case is rare because he had had no gastrointestinal symptoms. This patient illustrates the point that musculoskeletal signs and symptoms, including osteomyelitis, may prove to be a manifestation of gastrointestinal tract disease.
Adolescent↗
Genetic differences in the effects of delta-aminolevulinic acid on seizure latency in mice.
delta-Aminolevulinic acid, an intermediate in heme formation, is elevated in certain human disorders including acute intermittent porphyria, tyrosinemia, and lead poisoning. It has been implicated in the central nervous system manifestations of these disorders via interactions with the GABAergic system. This potential interaction was examined by testing whether or not delta-aminolevulinic acid could alter the latency to seizure in mice. Seizures were induced in a variety of inbred strains of mice including C57BL, C3H, DBA mice and in a heterogeneous stock of mice. Flurothyl and 3-mercaptopropionic acid were used to induce seizures in the presence and absence of delta-aminolevulinic acid administered either i.p. (0.5 and 1.5 mmol/kg), or i.c.v. (4.5 and 450 nmol). delta-Aminolevulinic acid increased the latency to myoclonic and clonic seizures induced by flurothyl when administered i.p.; i.c.v. injections also delayed clonic seizures induced by flurothyl, and increased the latency to tonic seizures induced by 3-mercaptopropionic acid. The degree to which delta-aminolevulinic acid altered seizure latency in all tests was dependent on strain of mouse tested. These data support the conclusion that delta-aminolevulinic acid can act as an anticonvulsant agent, and mimic the effects of GABA. Moreover, there is genetic variation in the sensitivity of the various strains of mice to delta-aminolevulinic acid.
Aminolevulinic Acid↗
Genetic influences on GABA-related seizures.
Genetic differences in susceptibility to chemically induced seizures were examined in various populations of mice. Three inbred strains: C57BL, DBA, and C3H and a heterogenous stock (HS) of mice were tested for sensitivity to seizures induced by 3-mercaptopropionic acid (MP) and flurothyl. Dose response curves were constructed for each population of mice with each agent by quantitating latencies to specific stages of seizures. Significant strain and sex differences were observed in sensitivity to MP-induced seizures. Rank order from least sensitive to most sensitive was C57BL, HS, DBA, and C3H. Sensitivity to flurothyl-induced seizures was also strain dependent, but the rank order of sensitivity was different than for MP. The least sensitive strain was C57BL followed by HS, C3H, and DBA. Analysis of GABA receptors in seven brain regions obtained from C57BL and DBA using 3H-muscimol to measure high affinity GABA binding did not reveal significant differences in receptor number between these two strains. It thus appears that different genetic factors influence susceptibility to MP-induced seizures than to flurothyl-induced seizures. Furthermore, there is probably little correlation between the number of high affinity GABA receptors and sensitivity to seizures.
3-Mercaptopropionic Acid↗
Nicotinic binding sites in rat and mouse brain: comparison of acetylcholine, nicotine, and alpha-bungarotoxin.
The properties of the binding sites for radiolabeled acetylcholine (measured in the presence of atropine), nicotine, and alpha-bungarotoxin were compared in brain tissue prepared from both rat and mouse. These three binding sites were tested for the following properties: affinity and density of ligand binding, effects of competitive inhibitors, regional distribution, effects of treatment with dithiothreitol and the reversal of these effects by treatment with 5,5'-dithiobis(2-nitrobenzoic acid), thermal lability, effects of protease treatment, and response to chronic administration of nicotine in vivo. The binding sites for acetylcholine and nicotine were affected identically for all measurements, whereas the binding site for alpha-bungarotoxin was affected in a manner different from that for the other two ligands. Although the regional distribution of nicotine and acetylcholine binding differed between rat and mouse brain, other properties of this binding site were very similar between the two species. The results are consistent with the proposal that acetylcholine and nicotine bind to the same sites in both rat and mouse brain, whereas alpha-bungarotoxin binds to different sites.
Acetylcholine↗