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Biomedical subjects

G Gianutsos

Publications and source records attributed to G Gianutsos.

At least 55 records · Page 3Linked to original sources
PubMed1984

Evidence for down-regulation of GABA receptors following long-term gamma-butyrolactone.

Long-term oral administration (12 weeks) of gamma-butyrolactone (GBL) to mice resulted in pharmacological and neurochemical changes which may be interpreted as a decrease in GABA-mediated synaptic activity. The depression in motor activity produced by the GABA-mimetic muscimol was reduced following long-term GBL. The binding of GABA to its putative receptor was reduced in the GBL group as evidenced by a decrease in the Bmax in the cerebral cortex, cerebellum, and striatum, but not in the hippocampus. No difference in the concentration of GABA was observed between the two groups. However, the reduction in GABA accumulation which normally results after an acute injection of GBL (560 mg/kg) was markedly attenuated in the mice receiving 12 weeks of GBL. Similarly, the muscimol-induced alteration in the concentration of DOPAC, a dopamine metabolite, was also reduced in the GBL group. These results, illustrating tolerance to the pharmacological effects of GBL and muscimol and in vitro evidence of a reduction in GABA binding sites, suggest that long-term exposure to GBL is accompanied by an alteration in GABA receptors and provides a possible mechanism for the tolerance to GBL-induced changes in dopamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Effects of three dopamine agonists on cage climbing behavior.

The effects of three structurally related dopamine (DA) agonists (pergolide, lergotrile, bromocriptine) on motor activity and induction of cage climbing behavior were compared in mice. Pergolide stimulated activity and induced cage climbing that persisted for at least 5 h. Lergotrile depressed activity and failed to induce climbing over a wide range of doses. Bromocriptine produced stimulation and climbing, but only after a 2-3 h delay following injection. The qualitative differences among these drugs may represent an action involving different DA receptor subjects.

Animals↗
PubMed1983

Drug-induced changes in motor activity after selective MAO inhibition.

The increase in motor activity produced in mice by phenylethylamine (PEA), L-DOPA and amphetamine was evaluated after selective inhibition of MAO Type A (by clorgyline) or Type B (by low doses of pargyline). PEA-induced motor stimulation was intensified in the presence of MAO-B inhibition, but not when MAO-A was inhibited. This was paralleled by higher concentrations of brain and plasma PEA (after injection) in mice in which there was inhibition of MAO-B compared with control or MAO-A inhibition. Conversely, L-DOPA produced significant stimulation only when MAO-A was inhibited. The clorgyline pretreatment resulted in larger increases in brain dopamine concentrations (in the striatum, olfactory tubercles and in the area containing the substantia nigra) than did MAO-B inhibition. This effect occurred both in mice receiving L-DOPA + inhibitor and in mice receiving the inhibitor alone. Amphetamine-induced stimulation was increased following the inhibition of either form of MAO, and this was not the result of changes in the distribution or metabolism of amphetamine. These results support the concept that MAO-A and MAO-B deaminate different substrates in the rodent CNS and that amphetamine may utilize either dopamine or PEA in producing its stimulant effects.

Amphetamine↗
PubMed1982

Dopaminergic properties of nomifensine.

Nomifensine and a proposed dihydroxy metabolite produced stimulation of motor behavior in mice with nomifensine being more potent. Weak cage-climbing behavior (stereotypy) was also produced. The stimulatory effects were greater in mice in which dopamine receptor sensitivity was increased by long-term haloperidol. Both of the analogs were potent inhibitors of dopamine and norepinephrine uptake in vitro with nomifensine approximately 3 times more potent than the metabolite. In contrast, the two analogs had weak affinity for the post-synaptic dopamine receptor (as measured by displacement of ligand binding in vitro) with dihydroxynomifensine approximately 6 times more potent than nomifensine. These results suggest that the behavioral effects of nomifensine are largely dependent on presynaptic catecholamine mechanisms but that weak direct dopamine agonist properties do exist, particularly in vivo where the drug may be metabolized to a more active form.

Animals↗
PubMed1982

Structure-anti-Parkinson activity relationships in the aminoadamantanes. Influence of bridgehead substitution.

A limited series of bridgehead alkyl-, dialkyl-, and trialkyl-substituted amantadines was synthesized and tested for potential anti-Parkinson activity as dopamine (DA) agonists. The compounds were evaluated using a battery of three murine bioassays, including stimulation of locomotor activity, induction of circling in animals with unilateral striatal lesions, and reversal of reserpine/alpha-methyltyrosine induced akinesia. Apparent mechanistic differences were seen between the methyl-substituted series and the ethyl-substituted series. While activities in both series increase with increasing liphophilicity, the methyl series (1b--d), as well as amantadine itself (1a), exhibit only indirect DA agonist activity, as evidenced by ipsilateral rotation in the circling model and no significant difference from control in reversal of akinesia. The ethyl series (1e,f) exhibits weak but reproducible direct DA agonist activity, as shown by contralateral rotation in the circling assay for 1e and reversal of akinesia by 1e and 1f. The 3-n-propyl derivative (1g) was devoid of any DA agonist activity.

Amantadine↗
PubMed1982

Alterations in brain dopamine and GABA following inorganic or organic manganese administration.

Administration of manganese to mice in the form of MnCl2 (4%) in the diet for 6 months or injections of the organic fuel-additive methylcyclopentadienyl manganese tricarbonyl (MMT) for 3 weeks resulted in a decrease in dopamine concentrations in the striatum and olfactory tubercles. The GABA content of the striatum was elevated after either treatment while the cerebellar GABA content did not change; GABA in the substantia nigra of MMT-treated mice was also increased. Choline acetyltransferase activity remained unchanged in response to either manganese treatment. These results are in general agreement with previous studies of inorganic manganese toxicity in other animal species. These changes in neurotransmitter concentrations were observed after longterm manganese administration but were not seen in mice injected acutely with MMT or exposed to MnCl2 for 1-2 months.

Animals↗
PubMed1981

Synthesis and adrenoceptor affinity of some highly polar beta-substituted catecholamines.

In order to assess the potential for sympathomimetic or sympatholytic activity within the series of catecholamine beta-sulfonates 3a-c, alpha- and beta-adrenoceptor binding affinities were determined using rat brain homogenate preparations. Furthermore, their potential for indirect activity was assessed by measurement of blockade of norepinephrine uptake into rat synaptosomal preparations. Activity was uniformly low or nonexistent throughout the series. The possibility of unfavorable solution conformational distribution within the series was investigated by examination of the side chain vicinal 1H NMR coupling constants, but no differences that could account for the lack of affinity were found. The observed behavior may be due to receptor intolerance of the bulky beta-sulfonate substituent or an electronic mismatch in which normal H bonding is significantly altered.

Animals↗
PubMed1980

Differential behavioral and biochemical effects of four dopaminergic agonists.

Some behavioral and biochemical effects of four dopaminergic agonists (apomorphine, piribedil, lergotrile, and bromocriptine) were determined in the mouse. As expected, all four drugs dose-dependently reversed the alpha-methyltyrosine-induced decline of forebrain dopamine. All four compounds reduced locomotor activity at low doses, but only apomorphine and bromocriptine increased motor activity at higher doses. All four drugs caused some reversal of the baclofen-induced elevation in forebrain dopamine concentrations, but only apomorphine and bromocriptine completely reversed the effects of baclofen. After chronic treatment with haloperidol, the behavioral effects of lergotrile and bromocriptine were altered. Doses of those drugs reducing motor activity in normal animals were ineffective after chronic haloperidol. The latent stimulation induced by bromocriptine was enhanced, while a stimulatory effect of lergotrile emerged in these animals. These effects were noted in conjunction with an enhanced sensitivity to the drug-induced decrease in dopamine turnover. These results demonstrate that dopamine agonists may be differentiated on the basis of certain behavioral and biochemical tests and suggest an interaction of these drugs with two different populations of dopamine receptors.

Animals↗
PubMed1979

Altered pilocarpine- or chlorpromazine-induced catalepsy after long-term treatment with cholinergic drugs.

Long-term administration of the cholinergic drug pilocarpine attenuates the catalepsy induced by an acute injection of pilocarpine or the deopamine antagonist chlorpromazine. Similar results (i.e., tolerance to pilocarpine and cross-tolerance to chlorpromazine) were noted in mice chronically treated with the cholinesterase inhibitor physostigmine but not in mice chronically treated with neostigmine, a cholinesterase inhibitor which does not penetrate the central nervous system. Mice maintained on the anticholinergic scopolamine showed the opposite effect; there was an increase in the sensitivity to the catalepsy induced by pilocarpine or chlorpromazine. The results suggest that long-term changes in cholinergic receptors may indirectly alter the behavioral effects of drugs which act via dopamine.

Animals↗
PubMed1978

Tolerance to the effects of baclofen and gamma-butyrolactone on locomotor activity and dopaminergic neurons in the mouse.

Acute injections of baclofen or gamma-butyrolactone (GBL) into mice caused dose-dependent depression of locomotor activity and an elevation of the dopamine content and a reduction of dopamine turnover in the brain. An acute injection of baclofen, but not of GBL, was less effective in producing these effects in mice maintained on a diet containing baclofen for 10 to 12 days. This suggests that baclofen and GBL may influence dopamine neurons by different mechanisms. Acute injections of both baclofen and GBL were less effective in producing behavioral and neurochemical effects in mice pre-treated for 13 days with injections of GBL. Tolerance to the behavioral and neurochemical actions of baclofen and GBL do not appear to be the result of metabolic tolerance but possibly result from changes in the properties of the dopamine neurons.

4-Butyrolactone↗
PubMed1977

Increase in mouse brain dopamine content by baclofen: effects of apomorphine and neuroleptics.

Baclofen, like gamma-butyrolactone, causes a dose-dependent increase in the concentration of dopamine in the mouse brain without affecting the content of norepinephrine. This increase is antagonized by apomorphine. Haloperidol but not pimozide counteracts this effect of apomorphine and dose-dependently enhances the increase in brain dopamine produced by baclofen. The results suggest that baclofen reduces impulse flow in dopaminergic neurons in a manner similar to that produced by gamma-butyrolactone.

Aminobutyrates↗