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J M Wehner

Publications and source records attributed to J M Wehner.

At least 73 records · Page 4Linked to original sources
PubMed1992

Adrenalectomy and stress modulate GABAA receptor function in LS and SS mice.

The effects of manipulation of adrenal steroids by adrenalectomy (ADX) or stress on GABAA receptor function were characterized in long-sleep (LS) and short-sleep (SS) mice. 36Chloride flux was not altered in either line of mouse after ADX; however, exposure to a behavioral stressor resulted in a highly significant inhibition of ion channel activity measured in cortical membranes from both LS and SS mice. Adrenalectomy also had no effect on [3H]FNZ binding; whereas exposure to stress differentially altered benzodiazepine binding in LS and SS mice. In LS cortex both Bmax and Kd values increased, whereas in SS cerebellum, Bmax and Kd values were decreased after stress. In SS mice ADX did not affect GABA-enhancement of [3H]FNZ binding. In LS mice, however, ADX resulted in a potentiation of GABA-enhanced [3H]FNZ binding in cortex and an inhibition of enhancement in cerebellum. Corticosterone (CCS) replacement in ADX-LS mice returned enhancement values to those of sham-operated mice, indicating a role for basal levels of CCS in maintaining normal receptor coupling function in this line of mouse. These results suggest that GABAA receptor sensitivity is more labile under stressful conditions. Differential receptor responses to adrenal manipulation between LS and SS mice may be due to genetic variation in GABAA receptor subunit combinations in these lines of mice.

Adrenalectomy↗
PubMed1992

Biochemical and behavioral effects of steroids on GABAA receptor function in long- and short-sleep mice.

The in vitro and in vivo effects of alphaxalone, a steroid anesthetic, and two physiological steroids, tetrahydrodeoxycorticosterone (THDOC) and pregnenolone sulfate (PS), on GABAA receptor function were evaluated in long-sleep (LS) and short-sleep (SS) mice. In vitro, both alphaxalone and THDOC enhanced GABAergic inhibition as measured by [3H]FNZ binding and GABA-stimulated 36Cl- flux. However, with the exception of alphaxalone potentiation of [3H]FNZ binding, which was greater in SS brain regions, LS and SS mice did not differ in their degree of enhancement. Pregnenolone sulfate produced mixed agonistic and antagonistic effects on GABAergic function, dependent upon brain region, with few differences between the lines of mice. In vivo effects of these steroids on sleep time indicated that, like other anesthetic agents, THDOC and alphaxalone induced longer sleep times in LS mice. Antagonism by PS of ethanol-induced sleep time was observed in LS mice only; however, this effect was dependent upon the dose of ethanol used and on the vehicle used to prepare the steroid. Pentobarbital-induced sleep time was not reduced by PS treatment in either line of mouse. These results demonstrate that few differences in sensitivity of the GABAergic receptor to these steroids exist between LS and SS mice. Thus, unlike the differences between LS and SS mice in GABAergic mediation of responses to ethanol and benzodiazepines, there is little genetic variability in subtypes of GABAA receptors capable of modulation by steroids in these lines of mice.

Anesthetics↗
PubMed1992

The rate of ethanol absorption is influenced by corticosterone in long-sleep and short-sleep mice.

Ethanol was administered by intragastric (IG) injection and absorption was measured in long-sleep (LS) and short-sleep (SS) mice under various conditions that alter levels of adrenal steroids. In naive mice, LS mice absorbed ethanol more quickly than SS mice. Ethanol absorption was slower in both lines of mice after adrenalectomy (ADX). Short-term inhibition of corticosterone synthesis had no effect on ethanol absorption in either line of mice. The effect of ADX was most pronounced in SS mice at 24 hr after surgery and at 168 hr after surgery in LS mice. Therefore, the effects of various steroid replacements were examined at these times. At 24 hr after ADX, ethanol absorption was replaced to SHAM-operated values in SS mice receiving corticosterone treatments. Likewise, in LS mice at 168 hr after ADX, corticosterone implants reversed the effects of ADX while dexamethasome was ineffective. These results support a role for corticosterone in regulation of gastric ethanol absorption and suggest that the lack of repeatability for pharmacokinetic measures of ethanol absorption and metabolism in previous human and animal studies may relate to environmental impact on stress responses.

Adrenal Glands↗
PubMed1992

Classical genetic analyses of responses to sedative-hypnotic drugs in crosses derived from long-sleep and short-sleep mice.

A classical (Mendelian) genetic analysis of responses to eight sedative-hypnotic compounds (ethanol, urethane, trifluoroethanol, chloral hydrate, barbital, paraldehyde, methyprylon, pentobarbital) was conducted in crosses derived from mouse lines that were selectively bred for differential duration of anesthesia following ethanol. The sleep-time responses of these mice, the long-sleep (LS) and short-sleep (SS) mouse lines, as well as the F1, F2 and backcross (F1 x LS, F1 x SS) generations were measured. Generally, differences in responses among the generations were greater for water soluble compounds than were differences for more lipid soluble compounds. Also, the inheritance of responses to water soluble compounds could be explained primarily by additive effects of alleles while the inheritance patterns for more lipid soluble compounds were more complex. Genetic correlation with ethanol response decreased with increasing lipophilicity. These results suggest that the selection of the LS-SS mouse lines was specific for water soluble anesthetic agents. Because several of these agents are known to act at GABA receptors, examination of the interactions of compounds which differ in lipid solubility at GABA receptors from LS and SS mice may prove useful in elucidating the mechanism of the anesthetic actions of ethanol and other drugs.

Alcohol Drinking↗
PubMed1992

A recombinant inbred strain analysis of sleep-time responses to several sedative-hypnotics.

The results of previous studies suggested that the sleep-time differential between long-sleep (LS) and short-sleep (SS) mice decreases for a series of sedative-hypnotic drugs as lipid solubility increases. Using the LS x SS recombinant inbred (RI) strains, we have tested whether this relationship arises because of common genetic influences on the sleep-time responses or was simply a fortuitous difference between LS and SS mice. Mice were sleep-time tested after intraperitoneal injections of a variety of sedative-hypnotic drugs that vary in lipid solubility including alcohols, barbiturates, chloral hydrate, and urethane. Sleep-time values from each of these drugs were compared with ethanol-induced sleep times in the LS x SS RI strains. Significant genetic correlations were observed between ethanol-induced sleep time and those responses elicited by butanol, propanol, and chloral hydrate, but not by pentobarbital or secobarbital. When the partition coefficient (log P) values were compared with the genetic correlations, a significant relationship (r = -0.85) was observed. These data suggest that common genes mediate sedative-hypnotic reactions to ethanol and some drugs resembling it in log P value, and that anesthetic agents with low lipid solubility may be working through different mechanisms than drugs with greater lipid solubilities.

1-Butanol↗
PubMed1992

Lipid solubility of sedative-hypnotic drugs influences hypothermic and hypnotic responses of long-sleep and short-sleep mice.

The anesthetic potency of many agents, including alcohols, barbiturates and other sedative-hypnotic drugs, is influenced by lipid solubility. Previous studies from our laboratory, however, have demonstrated that genetic factors influence this relationship. We have reported that mouse lines selectively bred for differences in duration of ethanol-induced anesthesia, the long-sleep (LS) and short-sleep (SS) mice, differ in sleep-time response to water-soluble, but not lipid-soluble, sedative-hypnotic drugs. The studies described here sought to determine whether this same relationship exists for the hypothermic response produced by 17 sedative-hypnotic drugs in the LS and SS mice. Dose-response and time course relationships for hypothermic actions were determined and were compared with the dose-related anesthetic effects of the drugs. Hypothermic potencies increased along with lipid solubility for both the LS and SS mouse lines, but the rate of change differed for the two mouse lines. LS mice were more responsive to ethanol and other water-soluble drugs whereas the SS were more responsive to lipid-soluble drugs; significant correlations were obtained between lipid solubility (log P-octanol-water partition coefficient) and relative LS-SS responsiveness to both the hypothermic and hypnotic actions of the 17 test drugs. Thus, both hypnotic and hypothermic actions of sedative-hypnotic drugs are correlated with lipid solubility. Possible explanation for these correlations include greater LS central nervous system sensitivity to water-soluble drugs and LS-SS differences in distribution of lipid-soluble drugs.

Animals↗
PubMed1991

Acute phorbol ester treatment improves spatial learning performance in rats.

Recent findings have lead researchers to speculate that hippocampal protein kinase C (PKC) in rodents is involved in spatial learning and memory. The purpose of this study was to determine if treating rats with a compound known to increase PKC activity would improve performance in a task that requires spatial learning processes. Rats were treated with a single intracerebroventricular injection of a phorbol ester, phorbol 12,13-dibutyrate (PDBu) that is known to increase PKC activity and then tested on the hidden-platform version of the Morris water taks. Results showed that PDBu-treated subjects' ability to learn to locate the escape platform was better than controls. In addition, PDBu-treated subjects showed signs of having remembered the location of the platform better than controls when tested 24 h later. These results support a role of brain PKC in processes required to learn the Morris water task.

Animals↗
PubMed1991

Comparative bladder tumor promoting activity of sodium saccharin, sodium ascorbate, related acids, and calcium salts in rats.

Sodium saccharin and sodium ascorbate are known to promote urinary bladder carcinogenesis in rats following initiation with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-butyl-N-(4-hydroxybutyl) nitrosamine. Sodium salts of other organic acids have also been shown to be bladder tumor promoters. In addition, these substances increase urothelial proliferation in short term assays in rats when fed at high doses. When they have been tested, the acid forms of these salts are without either promoting or cell proliferative inducing activity. The following experiment was designed to compare the tumor promoting activity of various forms of saccharin and to evaluate the role in promotion of urinary sodium, calcium, and pH as well as other factors. Twenty groups of 40 male F344 rats, 5 weeks of age, were fed either FANFT or control diet during a 6-week initiation phase followed by feeding of a test compound for 72 weeks in the second phase. The chemicals were administered to the first 18 groups in Agway Prolab 3200 diet and the last 2 groups were fed NIH-07 diet. The treatments were as follows: (a) FANFT----5% sodium saccharin (NaS); (b) FANFT----3% NaS; (c) FANFT----5.2% calcium saccharin (CaS); (d) FANFT----3.12% CaS; (e) FANFT----4.21% acid saccharin (S); (f) FANFT----2.53% S; (g) FANFT----5% sodium ascorbate; (h) FANFT----4.44% ascorbic acid; (i) FANFT----5% NaS plus 1.15% CaCO3; (j) FANFT----5.2% CaS plus 1.34% NaCl; (k) FANFT----5% NaS plus 1.23% NH4Cl; (l) FANFT----1.15% CaCO3; (m) FANFT----1.34% NaCl; (n) FANFT----control; (o) control----5% NaS; (p) control----5.2% CaS; (q) control----4.21% S; (r) Control----control; (s) FANFT----5% NaS (NIH-07 diet); (t) FANFT----control (NIH-07 diet). NaS, CaS and S without prior FANFT administration were without tumorigenic activity. NaS was found to have tumor promoting activity, showing a positive response at the 5 and 3% dose levels, with significantly greater activity at the higher dose. CaS had slight tumor promoting activity but without a dose response, and S showed no tumor promoting activity. In addition, NaCl showed weak tumor promoting activity, but CaCO3 was without activity. NH4Cl completely inhibited the tumor promoting activity of NaS when concurrently administered with it. NaCl administered with CaS or CaCO3 administered with NaS showed activity similar to that of NaS. Sodium ascorbate was also shown to have tumor promoting activity, with slightly less activity than NaS. Ascorbic acid showed no tumor promoting activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Adrenalectomy increases bicuculline-induced seizure sensitivity in long-sleep and short-sleep mice.

Susceptibility to bicuculline-induced seizure onset and tonus was increased in LS and SS mice after adrenalectomy (ADX). Replacement with 10% corticosterone (CCS) in ADX animals resulted in a return to seizure latencies equal to those of sham-operated (SHAM) mice. In SS mice, dexamethasone (DEX) and cholesterol-control replacement was as effective as 10% CCS in returning seizure thresholds to SHAM values. In LS mice, DEX was only effective at a low bicuculline dose. Within the sham-operated group SS mice were more susceptible to bicuculline-induced seizure onset than LS mice; however, after ADX latencies did not differ between the two lines. These results suggest that seizure thresholds are regulated to some extent by the hypothalamic-pituitary-adrenal (HPA) axis. The effects of ADX on GABA-related seizure activity may also be influenced by genotype, such that genetic differences in GABAA receptor function and adrenocortical responses in LS and SS mice may be responsible for the differential seizure latencies observed in sham-operated mice.

Adrenal Glands↗
PubMed1991

The use of recombinant inbred strains to study mechanisms of drug action.

Long-sleep (LS) and short-sleep (SS) mice which were selectively bred for sensitivity to the sedative-hypnotic effects of ethanol have been used extensively in the examination of sensitivity to ethanol as well as to other CNS depressants. Understanding the relationship between sensitivity to ethanol and other depressants using LS and SS mice has been limited to a two mouse line comparison because these mice do not exist as replicate lines. To circumvent this problem, DeFries et al. have bred LSXSS recombinant inbred strains (LSXSS RIs) from a cross of LS and SS mice. These mice are being characterized on their responses to a variety of CNS depressants and agents that interact with the GABAergic system. Preliminary results are presented here on the sensitivity of these LSXSS RIs to pentobarbital, phenobarbital, and flurazepam as measured by sleep times. Additionally, analyses of seizure susceptibility to the GABAergic antagonist, bicuculline, in 24 LSXSS RIs indicate that there is no significant relationship between this measure of GABAergic function and sensitivity to ethanol as measured by the sleep-time response. These results are presented in the context of questions that can be resolved using RIs in drug-abuse research.

Animals↗
PubMed1990

Hippocampal protein kinase C activity is reduced in poor spatial learners.

Activation of protein kinase C (PKC) via neurotransmitter coupling processes has been associated with long-term potentiation (LTP) or classical conditioning, but whether natural variation in PKC activity affects learning performance remains to be determined. Inbred strains of mice differ in their ability to exhibit spatial reference memory as measured by the Morris water task. C57BL/6Ibg (C57) mice perform the task better than DBA/2Ibg (DBA) mice, which show relatively little spatial preference. Hippocampal PKC activity extracted from the particulate fraction was lower in DBA mice than in C57 mice. To examine the potential relationship of PKC activity with spatial learning performance, 11 C57BL/6J x DBA/2J recombinant inbred strains (BXD RIs) were trained in the place learning version of the Morris water task. Cortical and hippocampal PKC activities were measured. Variation in spatial learning performance and PKC activity from cortex and hippocampus was observed. A positive significant correlation was observed between measures of spatial learning accuracy and hippocampal PKC in these strains. No correlation was observed between spatial learning accuracy and cortical PKC activity. These data suggest that animals with lower hippocampal PKC activity may have problems performing spatial reference memory tasks with the same degree of accuracy as those with higher hippocampal PKC activity.

Animals↗
PubMed1990

Effects of N-methyl-D-aspartate antagonism on spatial learning in mice.

C57BL/6Ibg mice were treated with the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and tested for selective deficits in spatial learning ability in the Morris water task. Two types of training protocols were used during the initial exposure to the training environment. In protocol 1, animals were given four massed trials before being returned to their home cages. In protocol 2, animals were returned to their home cages after each of the first four trials. Following the initial four trials, both sets of animals were given massed trials in blocks of four. CPP had minor effects on nonspatial learning, with greater impairment seen in animals trained according to protocol 1 than in animals trained according to protocol 2. The drug increased latency to find the platform in the spatial learning form of the task, with no effect of training protocol on latency. When spatial learning ability was measured in terms of the search behavior exhibited by the animals after the platform was removed from the pool, animals trained according to protocol 1 showed a severe CPP-induced impairment in search accuracy. Animals trained according to protocol 2 showed no effect of drug treatment. The results suggest that CPP does not have a reliable effect on place learning and that factors other than the type of learning being tested may contribute to performance deficits following CPP treatment.

Animals↗
PubMed1990

Dissociation of the apparent relationship between nicotine tolerance and up-regulation of nicotinic receptors.

Saline or nicotine (0.8 mg/kg/hr) was administered chronically to rats via subcutaneous infusion for 7 days. After chronic treatment, the effects of a challenge dose of nicotine, injected subcutaneously, on open-field activity and body temperature were measured. Nicotine responses were measured 2 hours after infusion had been stopped (day 0) or 1, 2, 4, 8, or 21 days after cessation of treatment. Brain nicotinic receptors were measured using nicotine binding or bungarotoxin binding in six brain regions. Tolerance to nicotine's effects on open-field activity and body temperature were observed; this tolerance was lost before the fourth day of withdrawal. Both nicotine and BTX binding were increased after chronic nicotine treatment. The return of the receptors to control values was dependent on brain region, but in general receptors were still increased at 4 days after withdrawal. The half-lives for receptors returning to normal were greater for nicotine binding compared to BTX binding. These results suggest that a relatively short-lived tolerance results from chronic nicotine infusion and that alterations in nicotinic receptors can be dissociated from behavioral tolerance.

Animals↗
PubMed1989

[35S]TBPS binding sites are decreased in the colliculi of mice with a genetic predisposition to bicuculline-induced seizures.

Several differences have been found in GABAergic function between the long sleep (LS) and short sleep (SS) mice which were genetically selected for different ethanol-induced sleeptimes, and it has been suggested that these differences may explain their differential ethanol sensitivity. However, these lines also differ in seizure susceptibility, a behavior which may also be mediated by GABAergic pathways. Thus, it is difficult to associate differences in GABA neurochemistry with either of these behaviors, particularly when only two selected lines are used. We measured differences in the density and affinity of the [35S]TBPS binding site on the GABAA receptor/Cl- ionophore complex in discrete brain areas; and in order to determine the relationship between receptor binding and behavioral differences, we included mice from 5 of the LS and SS recombinant inbred strains (LS x SS RI) in addition to mice from the LS and SS lines. [35S]TBPS binding in sagittal brain sections was analyzed by quantitative autoradiography, and the amount of binding differed depending on whether bicuculline was added to inhibit endogenous GABA binding. In the presence of bicuculline, the number of [35S]TBPS sites in SS mice was highest in the colliculi (4.5 +/- 0.5 pmol/mg protein), cerebellum (4.8 +/- 0.6 pmol/mg), hippocampus (3.2 +/- 0.7 pmol/mg) and cortex (2.9 +/- 0.3 pmol/mg). The Bmax was two-fold lower in both superior and inferior colliculi (IC) of LS mice. There were no differences between lines in Bmax in any other area and in Kd values in any area (58 +/- 4.0 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The effects of chronic oxotremorine treatment on spatial learning and tolerance development in mice.

C57BL mice were treated with 0.5 mg/kg/hr oxotremorine through an implanted subcutaneous cannula for 6 days. Tolerance to oxotremorine was evaluated after treatment by constructing cumulative dose-response curves and measuring body temperature and rotarod performance. At 2 hr after removal, mice exhibited a 15-fold tolerance as measured by body temperature and a 4-fold tolerance as measured by rotarod performance. This tolerance as measured by body temperature was lost by two days after removal from treatment. Immediately after treatment, 3H-QNB binding was reduced in cortex, hippocampus, midbrain, hindbrain, and hypothalamus. Receptors returned to normal within 4 to 8 days after cessation of treatment depending on the brain region. Spatial learning was examined using the Morris water task. Mice that began their training in this task 1 day after they were removed from oxotremorine treatment were impaired in their spatial ability as evidenced by a lack of preference for the trained site during a probe trial. Mice that began their training 2 days after cessation of oxotremorine treatment showed no evidence of impairment in spatial learning. These results suggest that a loss of muscarinic receptors after oxotremorine treatment can be dissociated from tolerance loss and spatial learning deficits.

Animals↗
PubMed1989

Inheritance of spatial learning ability in inbred mice: a classical genetic analysis.

The inheritance of spatial learning ability in inbred mice was examined by performance of a classical genetic cross between the 2 inbred strains C57BL/6Ibg and DBA/2Ibg. The inbreds were crossed to produce the 1st filial generation (F1) hybrids. F1 mice were bred to each other and were backcrossed to the parental strains to produce 3 hybrid generations with recombinant genotypes. The animals were tested for spatial learning ability in the Morris water task. All hybrid generations showed greater spatial learning ability than the inbreds, with F1 hybrids showing the greatest degree of spatial learning. The inheritance pattern for spatial learning differed between male and female mice, with males showing a type of inheritance in which dominant genes made the major contribution to the expression of the behavior. Females showed equal contributions of dominance deviation and additive genetic effects. The results are discussed in terms of fitness value to the animals.

Animals↗
PubMed1988

Evidence for modulation of GABAergic neurotransmission by nicotine.

Bath-application of nicotine (800 microM) to mouse hippocampal slices resulted in an increase in the amplitude of the population spike and the appearance of multiple population spikes in the CA1 pyramidal cell layer. Similar effects were observed after perfusion of the GABAA antagonist bicuculline methiodide (2 microM) and the glutamate decarboxylase inhibitor L-C-allylglycine (4 mM). These apparently excitatory effects of nicotine (800 microM) could be reversed by bath-application of gamma-aminobutyric acid (GABA; 400 microM), as well as by the GABA uptake inhibitor nipecotic acid (5 mM) and the benzodiazepine flurazepam (4 microM). Nicotine did not alter binding of [3H]GABA or [3H]flunitrazepam to whole brain plasma membranes. The results are consistent with the hypothesis that the electrophysiological effects of nicotine on CA1 pyramidal cell excitability is mediated by disruption of GABAergic transmission.

Action Potentials↗