Biomedical subjects

G Gianutsos

Publications and source records attributed to G Gianutsos.

At least 37 records · Page 2Linked to original sources

PubMed1987

Differential effects of gamma-hexachlorocyclohexane (lindane) on pharmacologically-induced seizures.

Gamma-hexachlorocyclohexane (gamma-HCH), the active ingredient of the insecticide lindane, has been shown to decrease seizure threshold to pentylenetrazol (PTZ) 3 h after exposure to gamma-HCH and conversely increase threshold to PTZ-induced seizures 24 h after exposure to gamma-HCH (Vohland et al. 1981). In this study, the severity of response to other seizure-inducing agents was tested in mice 1 and 24 h after intraperitoneal administration of 80 mg/kg gamma-HCH. One hour after the administration of gamma-HCH, the activity of seizure-inducing agents was increased, regardless of their mechanism, while 24 h after gamma-HCH a differential response was observed. Seizure activity due to PTZ and picrotoxin (PTX) was significantly decreased; however, seizure activity due to 3-mercaptopropionic acid (MPA), bicuculline (BCC), methyl 6,7-dimethoxy-4-ethyl-B-carboline-3-carboxylate (DMCM), or strychnine (STR) was not different from control. In vitro, gamma-HCH, pentylenetetrazol and picrotoxin were shown to inhibit 3H-TBOB binding in mouse whole brain, with IC50 values of 4.6, 404 and 9.4 microM, respectively. MPA, BCC, DMCM, and STR showed no inhibition of 3H-TBOB (t-butyl bicyclo-orthobenzoate) binding at concentrations of 100 micron. The pharmacological challenge data suggest that tolerance may occur to seizure activity induced by PTZ and PTX 24 h after gamma-HCH, since the response to only these two seizure-inducing agents is decreased. The in vitro data suggest that the site responsible for the decrease in seizure activity 24 h after gamma-HCH may be the GABA-A receptor-linked chloride channel.

Animals↗

PubMed1987

Prevention of fluphenazine-induced changes in dopaminergic and muscarinic receptors by lithium.

Co-administration of lithium carbonate to mice through their diet prevented the increase in dopamine receptor binding and the decrease in muscarinic receptor binding normally produced in striatum by chronic (12 week) administration of the neuroleptic, fluphenazine. The lithium treatment failed to prevent the muscarinic down-regulation induced by the muscarinic agonist pilocarpine in the hippocampus. These results (along with previous data) suggest that fluphenazine-induced striatal muscarinic receptor down-regulation and its reversal by lithium may be the consequence of changes in dopamine receptors in this brain region.

Animals↗

PubMed1987

Neurotoxic effects of methylcyclopentadienyl manganese tricarbonyl (MMT) in the mouse: basis of MMT-induced seizure activity.

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese-containing compound which is used as an additive in unleaded gasoline. One neurotoxic effect of MMT in mice is seizure activity. In this study, seizures were observed in mice treated with MMT in propylene glycol or corn oil. The LD50 associated with seizure activity was lower in mice receiving MMT in propylene glycol (152 mg/kg) than in those receiving MMT in corn oil (999 mg/kg). Manganese concentrations in the brains of mice which showed seizure activity due to MMT were higher than in those that did not (2.45 micrograms/g vs. 1.14 micrograms/g for MMT treated in propylene glycol and 3.25 micrograms/g vs. 1.63 micrograms/g for MMT in corn oil). Mice treated with manganese chloride (MnCl2) showed increases in brain manganese comparable to those of the mice showing seizure activity due to MMT, but exhibited no sign of seizure activity. MMT in non-lethal seizure-inducing doses had no effect on the accumulation of 4-aminobutyric acid (GABA) in mouse brain. However, MMT inhibited the binding of t-[3H]t-butylbicycloorthobenzoate [3H]-TBOB (a ligand for the GABA-A-receptor linked chloride channel) in mouse brain membranes with an IC50 value of 22.8 microM. The data suggest that MMT (organic manganese) or a closely related metabolite and not elemental manganese itself is responsible for the seizure activity observed. The seizure activity may be the result of an inhibitory effect of MMT at the GABA-A receptor linked chloride channel.

Animals↗

PubMed1987

Disposition and toxicity of methylcyclopentadienyl manganese tricarbonyl in the rat.

The disposition and toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT) was studied in Sprague-Dawley rats after subcutaneous administration at a dose of 4 mg/kg. Blood, lung, liver and kidney Mn levels were increased between 1.5 and 96 h after MMT injection, with peak organ levels occurring at 3-6 h. At this time the MMT-derived Mn concentration in lung, liver and kidney averaged 13-, 4- and 4-fold higher, respectively, than in the blood, indicating the accumulation and retention of MMT (or metabolite) in these tissues. Maximal pulmonary toxicity, as assessed by pulmonary lavage protein levels, occurred 24-48 h after injection. Plasma urea and sorbitol dehydrogenase levels were not increased at any time after MMT, suggesting minimal or no hepatic or renal injury. That maximal pulmonary toxicity occurred after peak Mn accumulation, and that the organ-specific toxicity of MMT correlated with its accumulation and retention, suggests a causal relationship between tissue Mn accumulation and MMT-induced toxicity.

Animals↗

PubMed1986

Effect of chronic imipramine or baclofen on GABA-B binding and cyclic AMP production in cerebral cortex.

Long-term (14 days) treatment of mice with the antidepressant drug imipramine increased the number of GABA-B receptors in the cerebral cortex and also led to an increase in the potentiation of norepinephrine-induced cAMP accumulation by baclofen (a GABA-B agonist) in cortical slices. Chronic baclofen treatment decreased both of these measures. These results suggest that previous evidence of increased GABA-B binding by antidepressants is coupled to a functional increase in adenylate cyclase activity, but that the mechanism responsible for this effect is not due simply to direct GABA-B receptor stimulation.

Animals↗

PubMed1986

Alteration of in vivo and in vitro effects of heroin by esterase inhibition.

Selective inhibition of peripheral esterases by tri-ortho-tolyl phosphate in the mouse resulted in an increase in the analgetic activity of heroin, without affecting the activity of morphine. In vitro inhibition of esterases by paraoxon reduced the affinity of heroin for the opiate receptor, while that of morphine was unaffected. These results suggest that both central and peripheral esterases are involved in the metabolism of heroin and that interference with critical esterases can alter its pharmacologic and toxicologic effects.

Acetates↗

PubMed1986

Pharmacological changes induced by repeated exposure to phenylethylamine.

Mice receiving daily injections of phenylethylamine (PEA) exhibited an enhanced PEA-induced motor stimulation, beginning on day 21 of administration. The mice receiving PEA were also more sensitive to the stimulatory effect of amphetamine and PCP. There was no change in brain or hepatic monoamine oxidase activity nor in hepatic mixed function oxidase after this treatment, indicating that altered metabolism was not a factor in the sensitization. Striatal dopamine receptors, labelled by spiroperidol, were increased after the long-term PEA, suggesting that the sensitization may be due to increased dopaminergic receptor activity.

Animals↗

PubMed1986

3,7-Diazabicyclane: a new narcotic analgesic.

The synthesis of a series of 9-phenyl-3,7-diazabicyclanes and 9-(m-hydroxyphenyl)-3,7-diazabicyclanes is described. Members of both series were tested for antinociception in rat tail withdrawal and mouse acetic acid writhing assays. Their affinities for opiate receptors in rat brain homogenate were also determined. The 9-phenyl compounds, 1a-c, were inactive. However, the 9-(m-hydroxyphenyl) analogues, 2a-c, were found to possess significant activity in the writhing assay, comparable to that of morphine. All activity was reversed by naloxone.

Analgesics, Opioid↗

PubMed1986

Pharmacological activity of amantadine: effect of N-alkyl substitution.

Alkyl substitution on the nitrogen atom of the anti-parkinsonian drug amantadine resulted in changes in its pharmacological potency. Greater behavioural stimulation (i.e. increased motor activity) was observed following s.c. injection of several of the analogues, with optimal activity produced by N-n-propyl substitution. These molecular changes did not alter the activity of amantadine on inhibition of dopamine uptake or its weak affinity for dopamine receptors in-vitro. Several of the analogues were more effective than the parent compound in increasing the concentration of dopamine metabolites (suggesting an increase in dopamine utilization) following systemic injection, and these effects generally followed the same pattern as observed in the test of behavioural activity. These results provide further support for the concept that the activity of amantadine may be improved by molecular alterations, although the pharmacological basis for this activity remains obscure.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

Pharmacological changes in dopaminergic systems induced by long-term administration of amantadine.

The pharmacological effects of 6 weeks administration of amantadine was evaluated in the mouse. Motor stimulation induced by amphetamine or the amantadine analog memantine was reduced while that of apomorphine was enhanced by the long-term amantadine treatment. This was accompanied by an increase in the binding of spiroperidol to putative striatal dopamine receptors, without a change in amantadine-induced inhibition of dopamine uptake in the striatum. The possible significance of changes in pre- and postsynaptic dopamine mechanisms is discussed in relation to the anti-parkinson activity of the drug.

Amantadine↗

PubMed1985

Brain manganese accumulation following systemic administration of different forms.

The content and retention of manganese in the blood and brain of mice exposed to different forms of the metal was compared. Mice received an acute sc injection of manganese as the chloride or oxide (Mn3O4) or as the organic MMT. A single injection markedly elevated brain manganese concentrations within 1 day and elevated levels were maintained for at least 21 days. Repeated injections led to further increases in both brain and blood, although the levels in the brain appeared to persist at consistently high levels for longer periods. The chloride form produced higher brain levels than either of the other two forms. These results appear to suggest that the slowly developing neurotoxicity in response to manganese exposure may be due to a persistent retention of manganese by the brain.

Animals↗

PubMed1985

GABAergic effects of reserpine following chronic treatment.

Reserpine-induced depression has been used as an animal model to screen for antidepressant agents. Chronic (14-day) treatment with reserpine resulted in a significant increase in beta-adrenergic receptor binding in the cerebral cortex and the hippocampus, which was partially prevented by chronic treatment with either the antidepressant imipramine, the GABA-A agonist THIP or, the GABA-B agonist baclofen. Chronic treatment with reserpine also significantly increased 3H-GABA receptor binding, which was partially prevented by chronic treatment with either imipramine or THIP. Both subchronic and chronic administration of reserpine resulted in a decrease in GABA concentrations in the cerebral cortex and hippocampus. These data demonstrate the effect of reserpine treatment on the GABA-ergic system, and add further support for a functional coupling between the noradrenergic and GABA-ergic systems, which may be important for the mechanism of action of antidepressant agents.

Animals↗

PubMed1985

GABA-noradrenergic interaction: evidence for differential sites of action for GABA-A and GABA-B receptors.

Treatment of mice with DSP4 (a neurotoxin that abolishes the presynaptic noradrenergic neuron; Dooley et al., 1983) resulted in: (A) a decrease in the Bmax for the low affinity GABA-B receptor site in the cerebral cortex and hippocampus, whereas the Bmax for the high affinity GABA-B receptor site was unaffected; (B) a greater potentiation of norepinephrine stimulated adenylate cyclase by baclofen in cerebral cortex slices; and (C) a decrease in the Bmax for both the high and low affinity GABA-A receptor sites in the cerebral cortex and hippocampus. These data, coupled with previous work from our laboratory, suggest that the GABA-B receptor may be associated with both the noradrenergic nerve terminal and the post-synaptic neuron receiving noradrenergic input, whereas the GABA-A receptor may be associated with the noradrenergic nerve terminal. These data further suggest a functional coupling between the noradrenergic and GABA-ergic systems.

Adrenergic Fibers↗

PubMed1985

Differential coupling of GABA-A and GABA-B receptors to the noradrenergic system.

The GABA-A receptor agonist THIP, or the mixed GABA-A/GABA-B receptor agonist progabide dose dependently increased the release of norepinephrine (as measured by the production of MHPG) in the cerebral cortex and hippocampus. This effect was partially reversed by treatment with the GABA-A receptor antagonist bicuculline. In contrast, the GABA-B receptor agonist baclofen decreased the release of norepinephrine in the cerebral cortex and hippocampus. Pretreatment with the presynaptic noradrenergic neurotoxin DSP4 increased the Bmax for beta-adrenergic receptor binding in the cerebral cortex and hippocampus. This effect was partially prevented by chronic (14 day) treatment with either the beta-adrenergic agonist clenbuterol or the GABA-B receptor agonist baclofen. In contrast, chronic (14 day) administration with either the GABA-A receptor agonist THIP or the antidepressant imipramine failed to alter the increase in beta-adrenergic receptor binding produced by DSP4 pretreatment. These data suggest that the GABA-A receptor may be coupled to the presynaptic noradrenergic neuron and modulate the release of norepinephrine, while the GABA-B receptor is coupled to the postsynaptic noradrenergic neuron and likely functions through the cyclic AMP generating system.

Animals↗

PubMed1985

Parallel changes in the sensitivity of gamma-aminobutyric acid and noradrenergic receptors following chronic administration of antidepressant and GABAergic drugs. A possible role in affective disorders.

Chronic treatment with the antidepressants imipramine or nomifensine, or the gamma-aminobutyric acid (GABAergic) agents, baclofen or THIP, produced a decrease in the Bmax for binding sites of GABAergic and noradrenergic receptors. Chronic treatment with imipramine or nomifensine produced a decrease in the Bmax of both binding of [3H]dihydroalprenolol and [3H]GABA receptors in the cerebral cortex and hippocampus. Chronic treatment with baclofen or THIP also produced a decrease in the Bmax of binding of [3H]dihydroalprenolol receptor in the cerebral cortex and hippocampus. These results suggest a possible link between the GABAergic and noradrenergic systems, which may be important in understanding the mechanism of action of antidepressant drugs, and suggests a possible role for GABA in affective disorders.

Animals↗

PubMed1985

Differential cholinesterase inhibition and muscarinic receptor changes in CD-1 mice made tolerant to malathion.

The lethality of organophosphate (OP) cholinesterase (CHE) inhibitors is thought to result from depression of the respiratory center in the brain stem, constriction of and increased secretion by the airways, and paralysis of the respiratory musculature. While tolerance to the cholinergic toxicity of OPs has been well documented, such studies have not included investigations of the brain stem and extrapulmonary airways. In this report tolerance to the insecticide malathion is demonstrated. At 24 hr after 14 daily doses of malathion (400 mg/kg, ip), CHE activities were 27, 26, and 28% of control in striatum (ST), hippocampus (HI), and cortex (CX), respectively, while brain stem CHE activity was 41% of control. In addition, the numbers of muscarinic receptors (Bmax) decreased 30, 20, and 22% in ST, HI, and CX, respectively. In contrast, there was no change in brain stem Bmax. The lack of parallelism between CHE inhibition and Bmax effects in brain stem as compared to all other tissues tested raises questions as to the mechanism(s) by which the respiratory system adapts during repeated OP exposure.

Animals↗

PubMed1985

Inhibition of 4-aminobutyric acid (GABA) turnover by chlordane.

4-Aminobutyric acid (GABA) turnover was measured in mice 8 h after an acute injection of 1 g/kg of technical grade chlordane in corn oil. Significant decreases in GABA turnover were observed in the cortex, striatum, hippocampus and hypothalamus after chlordane treatment. A smaller, though significant, decrease was also observed in the cerebellum. These results may help to explain the hyperexcitability and convulsions observed after acute high-dose exposure to this compound.

Animals↗

PubMed1985

Neurochemical effects of IDPN on the mouse brain.

Treatment of mice with IDPN (4 injections of 1 gm/kg on alternate days) produced a characteristic syndrome of abnormal movements which was associated with neurotransmitter changes in the extrapyramidal and other regions of the brain. A decrease in the concentration of GABA was observed in the striatum and hippocampus both 1 and 10 days after the last injection, along with a transient decrease in the cerebral cortex. In addition, the specific binding of GABA was increased by this treatment in the striatum and cerebral cortex but reduced in the cerebellum. Other striatal changes included a transient increase in dopamine content and a decrease in choline acetyltransferase activity. No biochemical or behavioral changes were observed after acute injection of IDPN or following 4 injections of the non-neurotoxic analog BAPN. These neurochemical alterations may play a role in the abnormal movements produced by IDPN.

Animals↗