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Biomedical subjects

D J Feller

Publications and source records attributed to D J Feller.

24 records · Page 2Linked to original sources

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↗

Drug-induced surface membrane phospholipid composition in murine fibroblasts.

The effects of drug on phospholipid composition of cell surface membranes are not well understood at this time. The effects of membrane-active drugs and membrane depolarization on the phospholipid composition were determined in murine LM fibroblasts. Receptor-aggregating drugs such as concanavalin A and cytoskeleton-disrupting agents such as colchicine, vinblastine, and cytochalasin B decreased phosphatidylserine content of the plasma membrane from 5.4 +/- 1.5% to as low as 1.4 +/- 0.2%. In addition, concanavalin A and colchicine increased the phosphatidylglycerol content from 6.9 +/- 1.6% to 13.1 +/- 0.7% and 10.6 +/-1.7%, respectively, while vinblastine and cytochalasin B had no effect. Pentobarbital decreased the content of phosphatidylinositol+ phosphatidylserine and of phosphatidylglycerol almost 2-fold. Propranolol, ethanol, and depolarization with 120 mM KCl had small or ne effects on plasma membrane phospholipid composition. None of the above drugs or treatments significantly altered the asymmetric distribution of phosphatidylethanolamine across the LM cell plasma membrane under the conditions tested. In addition, energy inhibitors that deplete the proton-motive force of the cell (NaN3 and KCN) and inhibitors of ATP synthesis such as NaAsO4 did not affect the asymmetric distribution of phosphatidylethanolamine. It is concluded that the mechanism of action of membrane-active drugs such as concanavalin A, vinblastine, colchicine and pentobarbital may involve alterations in plasma membrane composition. It also appears that microfilaments, microtubules, beta-adrenergic receptors, membrane fluidity, and membrane potential are not critical for the regulation of the asymmetric distribution of membrane phosphatidylethanolamine.

Animals↗

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↗

Olfactory bulb kindling in mice susceptible and resistant to ethanol withdrawal.

The relation between kindling and susceptibility to ethanol withdrawal seizures was investigated using withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice. These lines were developed by selective breeding to be prone and resistant, respectively, to handling-induced convulsions after chronic exposure to ethanol. Development of kindled seizures in response to electrical stimulation of the olfactory bulb was investigated in mice aged 2 and 8 months with no exposure to ethanol. Older WSP mice kindled more slowly than older WSR mice, requiring significantly more stimulations to reach the first stage 3 and the first stage 5 seizures. In younger mice, there was no significant difference between the two lines in the rate of kindling. The lower kindling rate in mature WSP mice is in contrast to their higher sensitivity to handling-induced convulsions on withdrawal from ethanol and other agents. This finding suggests that separate genetic factors underlie these two models of mouse seizures.

Age Factors↗

Audiogenic seizure susceptibility in WSP and WSR mice.

Mice selectively bred for susceptibility (WSP, withdrawal seizure prone) and resistance (WSR, withdrawal seizure resistant) to ethanol (EtOH) withdrawal seizures were tested for susceptibility to audiogenic seizures (AGS). The seizure response of mice was studied at four ages: 17, 22, 28, and 71-78 days. WSR mice exhibited no response at any age, whereas WSP mice were sensitive on days 17, 22, and 28. The maximum number of WSP mice responding to audiogenic stimulation was observed on day 22. However, the frequency and severity of responses by WSP mice was less than that of DBA/2J mice tested under identical conditions (60 vs. 100% showing at least some response). Overall, these data suggest that susceptibility to AGS and handling-induced convulsions (HIC) during EtOH withdrawal may share some common genetic determinants and presumably some common neurochemical systems. Various treatments have been shown to enhance HIC more in WSP as compared with WSR mice. Acoustic stimulation did not induce AGS in adult mice, but the treatment significantly enhanced HIC in WSP but not WSR mice. These data strongly imply that some common neurochemical pathway may regulate susceptibility to HIC elicited by diverse treatments.

Acoustic Stimulation↗