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Biomedical subjects

D J Feller

Publications and source records attributed to D J Feller.

15 recordsLinked to original sources
PubMed1991

Hippocampal mossy fiber zinc deficit in mice genetically selected for ethanol withdrawal seizure susceptibility.

Hippocampal mossy fiber zinc was examined in mice selectively bred for differences in susceptibility to handling-induced convulsions during ethanol withdrawal. The density of mossy fiber zinc in the CA3 stratum lucidum was significantly decreased in the duplicate lines of untreated withdrawal seizure prone (WSP) mice compared to untreated withdrawal seizure resistant (WSR) mice. Mossy fiber zinc densities in randomly bred control lines of mice (WSC) were intermediate to WSP and WSR mice. Serum, whole brain and whole hippocampal zinc were not significantly different between WSP and WSR mice, indicating that the reduction in the chelatable pool of hippocampal mossy fiber zinc was not a consequence of deficits in brain or whole body zinc nutrition. A highly significant correlation between hippocampal mossy fiber zinc density and handling-induced convulsion indices suggests that a reduction in mossy fiber zinc may be one contributing factor in the expression of seizure susceptibility in WSP mice.

Animals↗
PubMed1991

Behavioral and neurochemical studies in diazepam-sensitive and -resistant mice.

Benzodiazepine (BZ) effects include anxiolyis, sedation, seizure protection, and muscle relaxation; the mechanisms underlying these various effects are not understood. We have recently used the rotarod test in conjunction with selective breeding techniques to develop lines of mice which are diazepam-sensitive (DS) and diazepam-resistant (DR). We review the general methods of selective breeding, along with a description of the DS/DR selection study, and then describe a variety of behavioral and neurochemical studies which have been conducted in an attempt to characterize these mice. We have investigated the effects of other sedative drugs believed to interact with the BZ receptor, including ethanol, pentobarbital, and phenobarbital. We have also tested these mice for seizure threshold and open-field activity. DS and DR mice do not differ in diazepam-induced seizure protection, suggesting that different mechanisms underlie rotarod performance and the anti-convulsant effect. These results provide evidence to support the search for nonsedating anti-convulsants. To determine the neurochemical basis for observed differences, BZ receptor density and chloride flux have been measured. We discuss the interaction between behavioral and neurochemical approaches, and describe a conceptual framework to guide future studies with these unique new animals.

Animals↗
PubMed1991

Effect of neurotransmitter-selective drugs in mice selected for differential sensitivity to the hypothermic actions of ethanol.

Mice selectively bred for resistance (HOT) and sensitivity (COLD) to the hypothermic effect of EtOH were tested for their hypothermic response to neurotransmitter-specific drugs and for the effect of such drugs on EtOH induced hypothermia (HT). The drugs administered were the opiate drugs morphine, levorphanol and U50488H, the dopamine agonists apomorphine, LY171535 and SKF38393, the dopamine antagonist chlorpromazine, the alpha adrenergic agonist St587, the cholinergic agonist nicotine and amphetamine, which increases the release of catecholamines. All of the drugs tested, with the exception of SKF38393 and amphetamine, induced a hypothermic response in HOT and COLD mice. SKF38393 had no effect on body temperature or HT produced by EtOH. Amphetamine caused HT at low doses and hyperthermia at high doses. COLD mice were more sensitive than HOT mice to the hypothermic effect of morphine and levorphanol, mu-opiate agonists, and U50488H, a relatively specific kappa agonist. All of the other drugs tested were approximately equally potent in HOT and COLD mice. These results suggest that the differential sensitivity of HOT and COLD mice to EtOH-induced HT may be partially mediated through genetic changes in opiate mechanisms.

Animals↗
PubMed1991

Effect of alcohols and other hypnotics in mice selected for differential sensitivity to hypothermic actions of ethanol.

Mice selectively bred for resistance (HOT) and sensitivity (COLD) to the hypothermic effect of an acute dose of ethanol were tested twice during the course of genetic selection for their hypothermic response to other alcohols and sedative hypnotics. The drugs administered were ethanol, propanol, n-butanol, t-butanol, pentanol, diazepam, phenobarbital, pentobarbital, methyprylon and ethchlorvynol, all of which have sedative effects on the central nervous system, and hydralazine, a peripheral vasodilator. All drugs decreased body temperature of both HOT and COLD mice. In mice selected for seven to nine generations, COLD mice were more sensitive than HOT mice to all sedative drugs. The longer-chain alcohols were more potent than ethanol in inducing hypothermia, but the magnitude of the response difference between HOT and COLD mice appeared to be smaller. The difference between HOT and COLD mice in hypothermic sensitivity to an acute dose of ethanol was greater after 11-15 generations of selection than after seven generations. Similarly, the differential effect of the other alcohols, phenobarbital, pentobarbital, and methyprylon, on HOT and COLD mice increased with more generations of selection but to a lesser extent than ethanol. These data demonstrate that selecting for sensitivity to acute ethanol hypothermia has produced mice that are also differentially sensitive to other sedative hypnotic agents. They also support the hypothesis that the drugs used in the present study share a common mechanism of action for inducing hypothermia, which may be regulated by a common set of genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗
PubMed1990

Effect of chronic ivermectin treatment on GABA receptor function in ethanol withdrawal-seizure prone and resistant mice.

Ivermectin, a potent, effective anthelmintic, is easy to administer, has a broad spectrum of action and a wide safety margin. However, no testing has been done in hosts genetically selected for seizure susceptibility which may be more sensitive to the effects of ivermectin than other animals. This was done in the present experiments with seizure prone and seizure resistant mice infested with Syphacia obvelata (pinworm). These subjects were treated daily with oral ivermectin in their drinking water every other week for six weeks, for a total of 21 days. The treatment cleared the mice of the pinworm infestation, but did not alter the seizure susceptibility or binding parameters of [3H]flunitrazepam in either of the selected lines.

Animals↗
PubMed1989

Selected mouse lines, alcohol and behavior.

The technique of selective breeding has been employed to develop a number of mouse lines differing in genetic sensitivity to specific effects of ethanol. Genetic animal models for sensitivity to the hypnotic, thermoregulatory, excitatory, and dependence-producing effects of alcohol have been developed. These genetic animal models have been utilized in numerous studies to assess the bases for those genetic differences, and to determine the specific neurochemical and neurophysiological bases for ethanol's actions. Work with these lines has challenged some long-held beliefs about ethanol's mechanisms of action. For example, lines genetically sensitive to one effect of ethanol are not necessarily sensitive to others, which demonstrates that no single set of genes modulates all ethanol effects. LS mice, selected for sensitivity to ethanol anesthesia, are not similarly sensitive to all anesthetic drugs, which demonstrates that all such drugs cannot have a common mechanism of action. On the other hand, WSP mice, genetically susceptible to the development of severe ethanol withdrawal, show a similar predisposition to diazepam and phenobarbital withdrawal, which suggests that there may be a common set of genes underlying drug dependencies. Studies with these models have also revealed important new directions for future mechanism-oriented research. Several studies implicate brain gamma-aminobutyric acid and dopamine systems as potentially important mediators of susceptibility to alcohol intoxication. The stability of the genetic animal models across laboratories and generations will continue to increase their power as analytic tools.

Animals↗
PubMed1989

Sensitivity and tolerance to ethanol-induced hypothermia in genetically selected mice.

COLD mice have been genetically selected for pronounced hypothermia (HT) after acute EtOH administration, whereas HOT mice have been selected for attenuated HT. In the current experiments, HOT and COLD mice were found to differ significantly in sensitivity to EtOH-induced HT across a range of doses: the difference was greater at higher doses. After 3 g/kg of EtOH, HOT mice displayed a 1.8 degrees C HT, whereas COLD mice had a 3.6 degrees C HT. Male mice had greater HT responses than female mice regardless of genotype. Nonselected control mice were intermediate to the HOT and COLD mice in responsiveness to EtOH. After an acute EtOH dose, HOT mice were found to have slightly lower brain EtOH concentrations than COLD mice 3 and 4 (but not 1 and 2) hr after administration of EtOH, and may have eliminated EtOH slightly more rapidly than COLD mice. When tested repeatedly in a cool ambient environment (18 degrees C), COLD mice developed tolerance to EtOH hypothermia, whereas HOT mice did not. These results confirm that sensitivity to the hypothermic effects of EtOH is influenced markedly by genotype. Furthermore, selection for neurosensitivity to EtOH has produced a correlated difference in rate or magnitude of tolerance development, which is consistent with an hypothesis of the influence of common genes determining these responses to EtOH. The difference in tolerance could not be accounted for by initial HT sensitivity differences between the lines. The HOT and COLD lines should be useful for studies of the neurobiological mechanisms of EtOH-induced HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1988

Differences in GABA activity between ethanol withdrawal seizure prone and resistant mice.

Withdrawal seizure prone (WSP) and withdrawal seizure resistant (WSR) lines of mice have been genetically selected based on the severity of handling-induced convulsions after identical chronic ethanol exposure. The present experiments showed that naive WSP mice were more sensitive than WSR mice to a subconvulsant dose of picrotoxin, bicuculline or pentylenetetrazole as measured by the ability of these drugs to exacerbate handling-induced convulsions. This may reflect a difference between lines in the GABA-chloride channel. The density and affinity of [35S]t-butylbicyclophosphorothionate (TBPS) binding sites, a cage convulsant which binds to the picrotoxin site on the GABA-chloride channel, was measured in the frontal cortex, remainder of the cortex, cerebellum and hippocampus. The binding properties of [3H]flunitrazepam and the potency of gamma-aminobutyric acid (GABA) to enhance flunitrazepam binding was characterized in whole brain samples. There were no differences between lines. The behavioral results suggest a role for the GABA-chloride channel in the differential ethanol withdrawal seizure behavior of WSR and WSP mice, but this is not due to changes in receptor densities or affinities.

Animals↗
PubMed1986

Functional properties of rat brain sodium channels lacking the beta 1 or beta 2 subunit.

The sodium channel purified from rat brain is a heterotrimeric complex of alpha (Mr 260,000), beta 1 (Mr 36,000), and beta 2 (Mr 33,000) subunits. alpha and beta 2 are attached by disulfide bonds. Removal of beta 1 subunits by incubation in 1.0 M MgCl2 followed by reconstitution into phospholipid vesicles yielded a preparation of alpha beta 2 which did not bind [3H]saxitoxin, mediate veratridine-activated 22Na+ influx, or bind the 125I-labeled alpha-scorpion toxin from Leiurus quinquestriatus (LqTx). In contrast, removal of beta 2 subunits by reduction of disulfide bonds with 1.5 mM dithiothreitol followed by reconstitution into phospholipid vesicles yielded a preparation of alpha beta 1 that retained full sodium channel function. Alpha beta 1 bound [3H]saxitoxin with a KD of 4.1 nM at 36 degrees C. It mediated veratridine-activated 22Na+ influx at a comparable initial rate as intact sodium channels with a K0.5 for veratridine of 46 microM. Tetracaine and tetrodotoxin blocked 22Na+ influx. Like intact sodium channels, alpha beta 1 bound 125I-LqTx in a voltage-dependent manner with a KD of approximately 6 nM at a membrane potential of -60 mV and was specifically covalently labeled by azidonitrobenzoyl 125I-LqTx. When incorporated into planar phospholipid bilayers, alpha beta 1 formed batrachotoxin-activated sodium channels of 24 pS whose voltage-dependent activation was characterized by V50 = -110 mV and an apparent gating charge of 3.3 +/- 0.3. These results indicate that beta 2 subunits are not required for the function of purified and reconstituted sodium channels while a complex of alpha and beta 1 subunits is both necessary and sufficient for channel function in the purified state.

Amphibian Proteins↗
PubMed1985

The sodium channel from rat brain. Reconstitution of voltage-dependent scorpion toxin binding in vesicles of defined lipid composition.

Purified sodium channels incorporated into phosphatidylcholine (PC) vesicles mediate neurotoxin-activated 22Na+ influx but do not bind the alpha-scorpion toxin from Leiurus quinquestriatus (LqTx) with high affinity. Addition of phosphatidylethanolamine (PE) or phosphatidylserine to the reconstitution mixture restores high affinity LqTx binding with KD = 1.9 nM for PC/PE vesicles at -90 mV and 36 degrees C in sucrose-substituted medium. Other lipids tested were markedly less effective. The binding of LqTx in vesicles of PC/PE (65:35) is sensitive to both the membrane potential formed by sodium gradients across the reconstituted vesicle membrane and the cation concentration in the extravesicular medium. Binding of LqTx is reduced 3- to 4-fold upon depolarization to 0 mV from -50 to -60 mV in experiments in which [Na+]out/[Na+]in is varied by changing [Na+]in or [Na+]out at constant extravesicular ionic strength. It is concluded that the purified sodium channel contains the receptor site for LqTx in functional form and that restoration of high affinity, voltage-dependent binding of LqTx by the purified sodium channel requires an appropriate ratio of PC to PE and/or phosphatidylserine in the vesicle membrane.

Animals↗
PubMed1984

Comparison of alpha-2 adrenergic receptors and their regulation in rodent and porcine species.

The alpha-2 adrenergic antagonist [3H]yohimbine (YOH) and the alpha-2 agonist [3H]p-aminoclonidine (PAC) saturably label high-affinity binding sites in the submandibular gland from 3-week-old rats and 5-week-old pigs and in the lung from neonatal rats and 5-week-old pigs. [3H]YOH had KD values of 5.5, 1.8, 0.45 and 0.22 nM in the rat gland and lung and porcine gland and lung, respectively. KD values of 2.4, 5.3 and 1.3 nM were found for [3H]PAC in rodent and pig submandibular gland and pig lung, respectively. Both 3H-ligands labeled approximately the same density of sites within each tissue except in the rat lung in which [3H]PAC binding was too low to reliably estimate. In all cases the pharmacologic profile was indicative of an alpha-2 adrenergic receptor site. However, the Ki of yohimbine vs. [3H]PAC was 30- to 140-fold higher for the rodent relative to the porcine species. GTP decreased the affinity of (-)-epinephrine and PAC at [3H]YOH-labeled sites in the pig gland and lung, but did not shift the affinity of epinephrine in the rat gland. These results suggest the possibility of subtype or species differences for the alpha-2 receptor. The Ki values of the antagonists YOH and phentolamine were different at [3H]PAC and [3H]YOH sites. GTP caused a dose-dependent reduction in [3H]PAC binding in the porcine submandibular gland and lung. At 10 microM GTP, this loss was due to a decrease in 3H-agonist affinity, but not density.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1983

Binding of [3H]flunitrazepam to the LM cell, a transformed murine fibroblast.

LM cells have a saturable, high affinity binding site for [3H]flunitrazepam with a KD of 13 nM and a Bmax of 19 pmoles/mg protein. The IC50 values for Ro 5-4864, flunitrazepam and clonazepam against [3H]flunitrazepam were 6, 23 and 2800 nM, respectively, indicating that this receptor is of the peripheral type. A decrease of 37, 26 and 26% in Bmax was associated with substituting dimethylethanolamine, monomethylethanolamine or ethanolamine, respectively, for choline in the cell culture medium. These treatments did not change either the KD of [3H]flunitrazepam binding or the IC50 values of the different benzodiazepine drugs. Metastatic cell lines of the LM cell obtained from either athymic or C3H/Hef mice exhibited alterations in the binding parameters of [3H]flunitrazepam. There was a reduction in the Bmax values of the athymic (34%) and the C3H/Hef (44%) cell lines compared to the LM cell. In both groups there was a 90% increase in the KD. In the C6 astrocytoma, the peripheral type receptor appears to regulate plasma membrane mediated synthesis of phosphatidylcholine from phosphatidylethanolamine. However, this was not observed in the LM cell. Nor did it modulate cyclic AMP metabolism as assessed by measurement of cyclic AMP levels in whole cells after drug treatment.

Animals↗
PubMed1982

Alterations in neurotransmitter receptor binding in discrete areas of the copper-deficient rat brain.

Neonatal copper deficiency produced alterations in central neurotransmitter receptors that were selective with respect both to brain region and to neurotransmitter receptor type. Both high- and low-affinity dopamine receptor densities in the corpus striatum were significantly lowered, 55% and 29%, respectively, when expressed on a wet weight basis. There was a significant decrease in the level of muscarinic receptors in the striatum whether expressed on the basis of wet weight (50%) or protein (27%). A smaller reduction in muscarinic receptor density was observed in the cortex, whereas there was no effect of copper deficiency in the cerebellum. The treatment did not change beta-adrenergic receptor binding in either the cortex or cerebellum. The affinities of the receptors for the ligands was not affected by the low-copper diet. It was previously reported that copper deficiency produces regionally specific decreases in the concentrations of dopamine and norepinephrine. The greatest reduction occurred in the concentration of dopamine in the corpus striatum. The results from both studies suggest that copper deficiency in post-weanling rats may induce a selective morphological lesion.

Animals↗
PubMedDate not supplied

Genetic components of ethanol responses.

A powerful technique for determining the role of a particular neurotransmitter in mediating a response to ethanol (EtOH) is the analysis of selectively bred lines of animals. Lines selected for sensitivity and resistance to an EtOH effect differ principally in gene frequencies for genes affecting the selected response. Hence, other differences between the lines are likely due to pleiotropic actions of those genes. We discuss behavioral pharmacological experiments in two sets of selected lines. Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mouse lines were selected for severe and minimal handling-induced convulsions (HIC), respectively, after withdrawal from chronic EtOH inhalation. The HIC is also elevated after acute administration of low doses of convulsant drugs. WSP mice were found to be more sensitive than WSR mice to many such drugs. There was no apparent specificity of such effects to any particular neurotransmitter system. Thus, genetic determination of a behavioral response to EtOH in this case cannot be traced to the influence of a single neurotransmitter system. COLD and HOT mice were selectively bred to show severe and mild hypothermia, respectively, after acute EtOH administration. COLD mice are also more sensitive to a number of other alcohols, barbiturates, and other general central nervous system depressants. When tested for sensitivity to a number of drugs with specific effects on neurotransmitter systems, COLD and HOT mice did not differ in sensitivity to drugs affecting dopaminergic, alpha-adrenergic, or nicotinic acetylcholinergic systems. COLD mice were more sensitive, however, to opioid and serotonergic drugs. Thus, analysis of these selected lines was successful in identifying particular neurotransmitters which may be important in EtOH-induced hypothermia.

Animals↗