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At least 19 recordsLinked to original sources
PubMed1977

Analysis of drugs by pyrolysis. I. Selected ion monitoring combined with a pyrolysis method for the determination of carpronium chloride in biological samples.

In order to establish an analytical method for carpronium chloride, a parasympathomimetic agent, the pyrolysis reaction of carpronium chloride was examined in a g.c.m.s. system, which revealed that gamma-butyrolactone was produced directly from the drug as the main pyrolysis product. In the case of conversion of [2,2,3,3-2H4]carpronium chloride into the deuterated gamma-butyrolactone, 2H/1H scrambling was observed and confirmed to occur during the pyrolysis process of the deuterated compound. The proportion of gamma-[2H4]butyrolactone among the pyrolysis products was almost independent of the operating conditions, so [2,2,3,3-2H4]carpronium chloride was of practical use as an internal standard for selected ion monitoring. By incorporation of the pyrolysis reaction of carpronium chloride with selected ion monitoring and the use of [2,2,3,3-2H4]carpronium chloride as an internal standard, a rapid, sensitive and selective method was devised for the determination of the drug in biological samples. The method was utilized successfully for the biopharmaceutical studies of carpronium chloride in ma.

4-Butyrolactone↗
PubMed1978

Structure-activity relationships among in vivo active germacranolides.

Nine structurally related germacranolides from Eupatorium semiserratum and Eriophyllum confertiflorum were assayed in two standard tumor systems (PS and KB) to determine the structural features required for in vivo antileukemic activity. The moieties necessary for in vivo activity were found to be an alpha,beta-unsaturated ester side chain adjacent to the gamma-lactone and either a primary or secondary allylic alcohol or both.

4-Butyrolactone↗
PubMed1976

Differential actions of dopamine agonists and antagonists on the gamma-butyrolactone-induced in mouse brain dopamine.

gamma-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apomorphine dose-dependently antagonized the GBL effect, while piribedil was less effective. Haloperidol prevented the antagonism of GBL by apomorphine but pimozide was ineffective in blocking apomorphine. After chronic treatment with haloperidol or pimozide, there was no alteration of the maximum GBL-induced increase in dopamine nor was there any significant change in the antagonism by apomorphine, although a trend toward increased sensitivity to apomorphine was noted in the group withdrawn from haloperidol. These results suggest that in the mouse, haloperidol is a more effective antagonist of presynaptic dopamine autoreceptors than pimozide, while apomorphine is a better presynaptic agonist than piribedil.

4-Butyrolactone↗
PubMed1978

The effect of gamma-butyrolactone on locomotor activity in the rat.

The effect of gamma-butyrolactone (GBL) on locomotor activity in the rat was studied. Low doses of GBL (100 and 200 mg/kg) had a biphasic effect on activity. Initially, the activity of the rats was reduced, and this reduction was then followed by a period of hyperactivity. The effect of alpha-flupenthixol (50 microgram/kg alpha-FPT), atropine (10 mg/kg), benztroine (25 mg/kg), protriptyline (15 mg/kg), and clomipramine (25 mg/kg) was investigated on this biphasic effect. alpha-FPT reduced the hyperactivity while benztropine potentiated it; atropine, clomipramine, and protriptyline had little effect. It is concluded that the increase in activity could be due to a release of dopamine.

4-Butyrolactone↗
PubMed1978

On the mode of action of diazepam on brain catecholamine metabolism.

Intraperitoneal injection of diazepam in moderate dosage (1--10mg/kg) to rats caused a decrease in dopa and 5-hydroxytryptophan (5-HTP) formation, measured as the accumulation of these intermediates induced by inhibition of the aromatic L-aminoacid decarboxylase by means of NSD 1015 (3-hydroxybenzylhydrazine (HCl), in limbic forebrain, striatum and the remaining hemisphere portion. These effects are opposite to those induced by gamma-aminobutyric acid (gaba) and gamma-butyrolactone (100 and 750 mg/kg i.p. respectively), and the effects of the latter agents were significantly counteracted by diazepam. The effect of diazepam on dopa formation persisted after the acute transection of dopaminergic axons (transverse cerebral hemisection at the level of the caudal hypothalamus). The elevation of dopamine following hemisection was also significantly counteracted on the hemisected side of the brain, the intact side remaining unchanged. The data do not support the hypothesis that benzodiazepines act by enhancing gabaergic transmission. They rather suggest that these agents exert an inhibitory action on transmitter synthesis and utilization at the synaptic level, i.e. an action not necessarily bearing any direct relationship to gaba.

4-Butyrolactone↗
PubMed1976

Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors.

An in vivo system has been used to investigate the ability of dopamine agonists and antagonists to alter dopamine synthesis by acting at what appear to be presynaptic dopamine receptors. In order to eliminate postsynaptically induced changes in dopamine synthesis caused by the effects of these drugs on the firing rate of dopamine neurons, gammabutyrolactone was administered to block impulse flow in the nigro-neostriatal pathway. The accumulation of Dopa in the rat striatum after administration of Dopa decarboxylase inhibitor was used as an index of striatal tyrosine hydroxylase activity. It was found that administration of the dopamine agonists, apomorphine or ET-495 [1-(2-pyrimidyl)-piperonyl-piperazine], modified the apparent activity of striatal tyrosine hydroxylase when impulse flow was blocked in dopamine neurons. This presynaptic effect of apomorphine could be prevented by low doses of loxapine haloperidol and spiroperidol. Chlorpromazine, fluphenazine, and thioridizine were much less effective than the butyrophenones in blocking the effects of apomorphine. Molindone and (+) butaclamol, but not (-) butaclamol, reversed the presynaptic agonist effects, pimozide was a weak blocker and clozapine had no effect at all. All these neuroleptics except (-) butaclamol caused a significant increase in Dopa accumulation when impulse flow was intact. Compared with haloperidol the phenothiazines and pimozide appeared less potent in reversing the presynaptic effects of apomorphine than in blocking the behavioral effects of this agonist. Possible functional significance of the presynaptic dopamine receptors are considered.

4-Butyrolactone↗
PubMed1976

3-Methoxytyramine as an indicator of impulse-induced dopamine release in rat brain in vivo.

3-Methoxtyramine and dopamine accumulated in vivo in rat brain after monoamine oxidase inhibition with pargyline HCl. A dose of 100 mg/kg i.p. appeared to inhibit monoamine oxidase completely and led to a linear accumulation of 3-methoxytyramine for the first 90 min. Axotomy of the ascending dopaminergic fiber tract by means of a complete transverse cerebral hemisection almost completely blocked 3-methoxytyramine formation provided that catecholamine synthesis was inhibited with H 44/68 (Methylester of alpha-methyl-p-tyrosine). The dopamine receptor agonist apomorphine, 0.5 mg/kg i.p., decreased, while the dopamine receptor antagonist haloperidol, 2 mg/kg i.p., accelerated 3-methoxytyramine formation. gamma-Butyrolactone, 750 mg/kg i.p., not only decreased 3-methoxytyramine formation per se but also effectively antagonized the haloperidol-induced increase in 3-methoxytyramine accumulation. 3-Methoxytyramine formation after inhibition of monoamine oxidase appears to be a reliable indicator of impulse-induced dopamine release and metabolism.

4-Butyrolactone↗
PubMed1976

Effect of anesthetic doses of gamma-hydroxybutyrate on the acetylcholine content of rat brain.

Gamma-hydroxybutyrate administered in anesthetic doses produces a time dependent increase in the levels of rat barin acetylcholine. A maximal increase in whole brain and subcortical levels of acetylcholine is observed about 15 min after administration of the lactone form of the drug. A similar GHB-induced increase in acetylcholine is observed in the striatum and a 75% increase in the hippocampus 15 min after administration of the drug. A good temporal correlation was not obtained between the increase in acetylcholine and the depth of anesthesia produced by the drug. Gamma-hydroxybutyrate did not cause a significant change in the striatal or hippocampal levels of choline. Possible mechanisms involved in the production of this increase in acetylcholine are discussed.

4-Butyrolactone↗
PubMed1976

Dopaminergic neurons: reversal of effects elicited by gamma-butyrolactone by stimulation of the nigro-neostriatal pathway.

In vivo studies demonstrate that administration of gamma-butyrolactone, a precursor of gamma-hydroxybutyric acid causes a rapid increase in endogenous levels of striatal dopamine and an increase in tyrosine hydroxylase activity measured by following the short term accumulation of dihydroxyphenylalanine. The increase in dopamine produced by GBL is blocked by stimulation of the nigro-neostriatal pathway. If dopamine is allowed to accumulate for 30 min following administration of GBL this increased dopamine can be released by stimulation of the nigro-neostriatal pathway. Maintenance of neuronal activity in the nigro-neostriatal pathway by continuous stimulation at a physiological frequency of 3/s effectively blocks the ability of GBL to cause an increase in tyrosine hydroxylase activity in the striatum on the stimulated side. Tyrosine hydroxylase activity in the non-stimulated contralateral striatum is increased over 100% by administration of GBL. Stimulation of the nigro-neostriatal pathway 30 min after GBL administration causes about a 500% increase in the accumulation of dihydroxyphenylacetic acid in the striatum on the stimulated side. These results suggest that the increased dopamine is present in a pool which is releasable by neuronal stimulation and is subsequently exposed to MAO. These results are also consistent with the hypothesis that GBL activates tyrosine hydroxylase and increases endogenous dopamine levels primarily by blocking impulse flow in central dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1977

Interaction of haloperidol and gamma-butyrolactone with (+)-amphetamine-induced changes in monoamine synthesis and metabolism in rat brain.

The interaction of (+)-amphetamine with haloperidol and gamma-butyrolactone on synthesis of monoamines in rat brain regions was investigated using an in vivo method, in which the accumulation of dopa and 5-hydroxytryptophan (5-HTP) was measured after inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine. The accumulation of 3-methoxytyramine (3-MT) after inhibition of the monoamine oxidase with pargyline was taken as an indicator of the in vivo release of dopamine (DA) into the extraneuronal space. (+)-Amphetamine at doses of 1--3 mg/kg caused an increase of dopa formation in the DA-rich areas c. striatum and mesolimbic forebrain but had no effect on dopa formation in neocortex and 5-HTP formation in all brain regions investigated. At a dose of 10 mg/kg (+)-amphetamine decreased dopa as well as 5-HTP formation in all brain regions studied. 3-MT accumulation in whole rat brain was stimulated by (+)-amphetamine as well as haloperidol and inhibited by gamma-butyrolactone. Combined treatment with haloperidol and (+)-amphetamine not only potentiated the stimulation of dopa formation but also the increase of 3-MT accumulation. Pretreatment with gamma-butyrolactone antagonized the stimulation of 3-MT formation induced by (+)-amphetamine at a dose of 10 mg/kg. This dose of (+)-amphetamine markedly counteracted the gamma-butyrolactone-induced increase in dopa formation especially in the DA-rich areas. The data support the view that impulse flow in DA neurons facilitates the effect of (+)-amphetamine on DA release and DA synthesis. Inhibition of catecholamine synthesis after high doses of (+)-amphetamine may be due to an increase in cytoplasmatic DA concentration causing end-product inhibition of tyrosine hydroxylase.

4-Butyrolactone↗
PubMed1979

Attenuation of the gamma-butyrolactone-induced increase in DOPA accumulation by chronic ethanol administration.

The effect of gamma-butyrolactone (GBL) on the accumulation of dopa after inhibition of aromatic amino acid decarboxylase was studied in rats following chronic treatment with ethanol. The GBL-induced dopa accumulation was significantly decreased in ethanol-treated rats. With the increased duration of the ethanol treatment this effect appears to be more marked in the limbic forebrain. It is suggested that chronic ethanol treatment may produce a decreased sensitivity of central GABA receptors.

4-Butyrolactone↗
PubMed1977

Suppression by GABAergic drugs of the locomotor stimulation induced by morphine, amphetamine, and apomorphine: evidence for both pre- and post-synaptic inhibition of catecholamine systems.

Locomotor stimulation induced in mice by morphine and amphetamine was antagonized by pretreatment with gamma-butyrolactone (GBL) and amino-oxyacetic acid (AOAA) at doses which had little effect on saline treated animals. The effects of morphine and AOAA on the turnover of brain catecholamines (CA) were determined by measuring both the accumulation of dopa after inhibition of central aromatic L-amino acid decarboxylase and by measuring the depletion of noradrenaline (NA) after inhibition of tyrosine hydroxylase by alpha-methyltyrosine (alpha-MT). Morphine and AOAA were found to have opposite effects on CA turnover, i.e. morphine caused an increase and AOAA, a decrease. AOAA also antagonized the morphine-induced increase in CA turnover. These data might suggest that the well documented ability of GABAergic drugs to inhibit the firing of DA-containing neurons may be of importance in explaining the present findings. However, the locomotor stimulation induced by the directly-acting CA agonists, apomorphine and clonidine after pretreatment with reserpine and alpha-MT was also inhibited by the GABAergic drugs. It is therefore concluded that the suppressant effects of the GABAergic agents on hypermotility and not solely mediated by their effects on presynaptic CA mechanisms, but also by a postsynaptic inhibition at some point beyond the CA neurons.

4-Butyrolactone↗
PubMed1979

Comparison of dopamine synthesis regulation in the terminals of nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons.

The rate of accumulation of DOPA after the administration of decarboxylase inhibitor (NSD 1015) was determined in the striatum, olfactory tubercle, median eminence and posterior pituitary of the rat brain in order to obtain an index of the rate of synthesis of dopamine (DA) in the terminals of nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons, respectively. In all brain regions an increase in the concentration of DA by the administration of a monoamine oxidase inhibitor decreased DOPA accumulation while a decrease in the concnetration of DA by the administration of reserpine increased DOPA accumulation. These results indicate that end product inhibition plays a role in regulating DA synthesis in all four neuronal systems. Injections of DA agonists decreased and DA antagonists increased the accumulation of DOPA instriatum, olfactory tubercle and posterior pituitary, but not in median eminence. The administration of gamma-butyrolactone (GBL) and baclofen increased the concentration of DA and the accumulation of DOPA in the striatum, olfactory tubercle and posterior pituitary, and these effects were reversed by the administration of apomorphine. On the other hand, GBL and baclofen had no effect on the concentration of DA or the accumulation of DOPA in the median eminence. These two drugs did, however, reduce the alpha-methyltyrosine-induced decline of DA in the median eminence suggesting that they inhibit the activity of tuberoinfundibular nerves just as they do DA nerves in other systems. These results suggest that the regulation of DA synthesis in terminals of nigrostriatal, mesolimbic and tuberohypophyseal nerves is different from that in tuberoinfundibular nerves in that the latter nerves appear to lack an autoreceptor regulatory mechanism.

4-Butyrolactone↗
PubMed1978

Effect of lergotrile on 3,4-dihydroxyphenylacetic acid (DOPAC) concentration and dopamine turnover in rat brain.

Lergotrile, a dopamine agonist, lowered whole brain DOPAC (3,4-dihydroxyphenylacetic acid) concentration in rats. At low doses down to 0.5 mg/kg of lergotrile mesylate, this effect occurred within 30 min, whereas at higher doses (20 mg/kg) the decline in DOPAC was delayed. The decrease in DOPAC persisted for several hours and presumably resulted from a compensatory decrease in brain dopamine turnover secondary to receptor stimulation by lergotrile. Other indications of decreased brain dopamine turnover after lergotrile included (a) a slower decline in dopamine concentration after synthesis inhibition by alpha-methyltyrosine, (b) a slower decline in alpha-methyl-m-tyramine, a false transmitter that is stored and released by dopamine neurons, and (c) a decreased accumulation of dopamine in response to gamma-butyrolactone, an agent that blocks firing and dopamine release by dopamine neurons. Lergotrile mesylate (20 mg/kg) also increased brain levels of 5-hydroxyindoleacetic acid and of 3-methoxy-4-hydroxyphenylethylene glycol sulfate, metabolites of serotonin and norepinephrine, respectively, and these increases were not antagonized by spiperone, a dopamine receptor antagonist.

3,4-Dihydroxyphenylacetic Acid↗