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C J Schmidt

Publications and source records attributed to C J Schmidt.

At least 91 records · Page 5Linked to original sources
PubMed1987

In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain.

A single high dose of methylenedioxymethamphetamine, a psychedelic agent, produced a rapid and persistent depletion of striatal indoles similar to that observed following administration of the serotonergic neurotoxin p-chloroamphetamine. The drug had little effect on dopaminergic variables. Like p-chloroamphetamine, methylenedioxymethamphetamine was found to be a relatively selective agent for inducing [3H]serotonin release in vitro. The serotonin uptake inhibitor, citalopram, blocked both [3H]serotonin release in vitro and striatal serotonin depletion in vivo, indicating that both processes were carrier dependent. In vivo comparisons of the stereoisomers of methylenedioxymethamphetamine indicated two phases of serotonin depletion similar to those reported for p-chloroamphetamine. Although both the (+)- and (-)-stereoisomers produced an acute (3 hr) decrease in striatal indoles, the long-term effects of the drug showed stereoselectivity in that the (+)-enantiomer produced the most dramatic serotonin depletion. Comparison of the effects of the stereoisomers of methylenedioxymethamphetamine and its n-desmethyl analog, methylenedioxyamphetamine, on [3H]serotonin and [3H]dopamine release in vitro showed the (+)-enantiomer of both drugs to be the more potent releasing agent. In spite of its reported lack of hallucinogenic activity, (+)methylenedioxyamphetamine was found to be of a potency similar to that of (+)methylenedioxymethamphetamine in inducing [3H]serotonin release in vitro. The results are discussed in terms of the neurochemical similarities between methylenedioxymethamphetamine and p-chloroamphetamine as well as the proposed role of serotonin release in the behavioral effects of methylenedioxymethamphetamine.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Ascorbic acid-deficient condition alters central effects of methamphetamine.

Effects of multiple doses of methamphetamine (METH) were examined in normal and ascorbic acid-deficient (scorbutic) guinea pigs. METH-induced decreases of striatal serotonin concentrations were completely antagonized in scorbutic animals. Elevations of nigral substance P-like immunoreactivity also differed significantly in METH-treated scorbutic compared to METH-treated normal animals. Various lines of evidence indicate that dopamine is an essential mediator of METH-induced effects in both serotonergic and substance P systems in the brain areas examined; however, results from the present study indicate that, along with dopamine, ascorbic acid also plays a role in mediating the effects of METH in the central nervous system.

Animals↗
PubMed1987

Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine.

The neurochemical effects of the unique psychedelic agent, methylenedioxymethamphetamine (MDMA), indicate it may be a serotonergic neurotoxin related to agents such as p-chloroamphetamine. MDMA had a biphasic effect on cortical serotonin concentrations beginning with an acute depletion of the transmitter which reached a maximum between 3 and 6 hr after drug administration. This early phase of depletion was reversible because cortical serotonin concentrations had recovered to control levels by 24 hr. However, transmitter concentrations were reduced significantly 1 week later, indicating a second phase of depletion. The latter phase of depletion was associated with a decrease in synaptosomal [3H]serotonin uptake due to a loss in the number of uptake sites with no change in the affinity of the carrier for serotonin. This neurotoxic effect of MDMA was found to be a property of the (+)-stereoisomer of the drug as only this enantiomer produced the depletion of cortical serotonin and the decrease in synaptosomal serotonin uptake at 1 week. In contrast to this, both stereoisomers of the drug could produce the acute depletion of cortical serotonin measured 3 hr after drug administration. Coadministration of the selective serotonin uptake inhibitor, fluoxetine, completely blocked the reduction in cortical serotonin concentrations 1 week after MDMA. Administration of fluoxetine at various times after MDMA revealed that the long-term effects of the drug developed independently of the acute depletion of serotonin and could be partially blocked by the uptake inhibitor as long as 6 hr after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1986

Response of mesolimbic substance P systems to methamphetamine treatment.

Administration of methamphetamine (METH) has been shown to increase substance P (SP) concentrations in striatonigral structures. Data described herein demonstrate that SP pathways associated with the mesolimbic systems also are influenced by METH treatment. Specifically, multiple doses of METH significantly decreased SP concentrations in the ventral tegmental area and the medial habenular nucleus; whereas, a single METH injection increased the levels of this neuropeptide in the ventral tegmental area. The possible significance of these observations is discussed.

Animals↗
PubMed1986

Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue.

The amphetamine analogue, methylenedioxymethamphetamine (MDMA) has received considerable attention recently as a novel and increasingly popular psychoactive agent. When administered acutely to rats in high doses, MDMA caused a selective and dramatic decrease in brain concentrations of serotonin and its metabolite, 5-hydroxyindoleacetic acid. The depletion of serotonin and its metabolite persisted for up to at least one week after a single injection of MDMA at approximately four to five times the acute dose reported for humans. These results are discussed in terms of the possible neurotoxic effects of MDMA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Inhibition of K+-stimulated [3H]dopamine and [14C]acetylcholine release by the putative dopamine autoreceptor agonist, B-HT 920.

The inhibition of K+-stimulated [3H]dopamine and [14C]acetylcholine release from preloaded rat striatal slices was used to examine the presynaptic selectivity of the putative dopamine autoreceptor agonist, B-HT 920. In the micromolar range, B-HT 920 caused a concentration-dependent inhibition of the release of both labeled neurotransmitters as evoked by 20 mM K+. The effect of B-HT 920 on both [3H]dopamine and [14C]acetylcholine release was completely blocked by (+) butaclamol but not by (-) butaclamol. Sulpiride, a selective D2 antagonist, similarly blocked the inhibitory effect of B-HT 920 on the release of both labeled neurotransmitters indicating both responses were mediated by D2 receptors. (+) Butaclamol alone elevated stimulated [3H]dopamine release suggesting a significant amount of autoreceptor occupancy by endogenously released dopamine. Experiments with tolazoline and the alpha 2 agonist, B-HT 933, did not suggest any involvement of alpha-adrenoceptor activity in the inhibitory effects of B-HT 920 on the release of either transmitter. Inhibition of release was a selective effect of B-HT 920 as the drug was without effect on the K+-stimulated release of [3H]serotonin. The results indicate that in vitro B-HT 920 is active of both pre- and postsynaptic dopamine receptors in contrast to the pattern of effects observed after its in vivo administration.

Acetylcholine↗
PubMed1986

Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal tyrosine hydroxylase and tryptophan hydroxylase in rat.

The results reported here indicate that treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused significant changes in the dopamine-synthesizing enzyme, tyrosine hydroxylase. The authors examined the effects of two doses of MPTP on the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) in the striatum, and also the time-course of these effects. Rats received an intraperitoneal loading dose, followed by a 24-hr infusion of MPTP (total doses of 21 or 42 mg) from subcutaneously-implanted osmotic pumps. Seven days after treatment, the activity of tyrosine hydroxylase was decreased by MPTP (42 mg); however, the activity of tryptophan hydroxylase was not affected. In time-course experiments, the activity of tyrosine hydroxylase was maximally reduced at 3 and 7 days after treatment with MPTP (42 mg). The activity of tryptophan hydroxylase did not significantly change at any time-point. Concurrent administration of haloperidol (HALO; 2 mg/kg, 4 doses) with MPTP significantly enhanced the depression of the activity of tyrosine hydroxylase in the striatum caused by MPTP, while treatment with haloperidol alone had no such effect. Concentrations of dopamine in the striatum were maximally decreased to approx. 50% of control in animals treated with haloperidol and MPTP (42 mg), whereas treatment with MPTP alone decreased concentrations of dopamine to approx. 70% of control.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Cell specificity and an effect of ras on human metallothionein gene expression.

The expression of three human metallothionein (hMT) genes has been compared in various established cell lines and primary liver. The single gene for hMT isoform II is ubiquitously expressed in all cell types in response to cadmium. In contrast, two genes encoding hMT-I isoforms are expressed in a highly specific, reciprocal fashion that correlates with the embryonic germ layer origin of the cells. In one cell line that failed to express detectable amounts of hMT-IE, treatment with the demethylating agent 5-azacytidine led to cadmium-inducible expression of this subtype. The genes for both MT-I isoforms are coordinately inducible by heavy metals but differ in their response to glucocorticoids. Surprisingly, cells transformed with the Ha-ras oncogene contain elevated basal levels of both MT-I and MT-II RNA. The implications of these results for growth-related and developmental functions of MT are discussed.

Cell Differentiation↗
PubMed1985

Studies on the mechanism of tolerance to methamphetamine.

We have reported that the ability of high doses of methamphetamine to impair dopamine and serotonin synthesis in the rat brain is attenuated when animals are pretreated with gradually increasing doses of methamphetamine. To examine the mechanism of this tolerance phenomenon, the effect of methamphetamine on several neurochemical parameters was determined in naive and methamphetamine-pretreated rats. The elevation of nigral substance P concentrations by methamphetamine was attenuated in pretreated compared to naive rats. The methamphetamine-induced reduction in [3H]sulpiride binding in the rat neostriatum and nucleus accumbens was similarly attenuated in animals pretreated with methamphetamine. Determination of brain concentrations of methamphetamine and amphetamine revealed significantly lower concentrations of both compounds in the brains of pretreated compared to naive animals. The results indicate a reduction in the ability of methamphetamine to increase dopamine transmission in the brains of methamphetamine-pretreated rats. Furthermore, this effect appears to be due, at least in part, to a change in the disposition of methamphetamine in pretreated animals.

Amphetamine↗
PubMed1985

Dopamine-mediated increases in nigral substance P-like immunoreactivity.

The results reported herein strongly suggest that increased dopaminergic and not increased serotonergic activity is responsible for methamphetamine-induced increases in the nigral concentration of substance P-like immunoreactivity (SPLI). Thus, treatment of rats with the specific dopamine (DA) uptake blockers amfonelic acid (AFA) and nomifensine caused elevations in the SPLI levels within the substantia nigra similar to that of methamphetamine (METH). In contrast, the specific serotonin uptake blockers citalopram and chlorimipramine were without significant effects on this substance P (SP) system. Additional studies revealed that the mechanisms whereby the DA uptake blockers and METH influence the striatonigral SP pathway are likely different. Specifically, AFA, unlike METH, altered the SP system without causing changes in the monoaminergic synthesizing enzymes tyrosine and tryptophan hydroxylase; in addition, pretreatment with reserpine abolished the AFA effect on nigral SPLI but did not interfere with METH-mediated changes in the SP system.

Animals↗
PubMed1985

In vitro demonstration of dopamine uptake by neostriatal serotonergic neurons of the rat.

Dopamine (DA) has been suggested as the penultimate agent in the neurotoxic effects of methamphetamine on serotonergic neurons. DA increases the efflux of tritium from rat neostriatal slices preloaded with [3H]serotonin in a concentration-dependent manner. This serotonin (5-HT) release is inhibited by the same selective uptake blockers previously shown to protect serotonergic neurons from the neurotoxic effects of methamphetamine in vivo. The results indicate that the 5-HT uptake carrier transports DA into the serotonergic neuron by a heteroexchange process with 5-HT. This further suggests that the excessive DA release induced by methamphetamine in vivo could lead to the uptake of DA into serotonergic neurons.

Animals↗
PubMed1985

Structure and expression of two human metallothionein-I isoform genes and a related pseudogene.

Three members of the human metallothionein-I gene family have been cloned and characterized. Two of the genes encode closely related but distinct metallothionein-I subtypes. Both of these genes are functional as shown by their transcription in cultured hepatoblastoma cells and by their ability to render transfected cells resistant to cadmium toxicity. The cotranscription of these nonallelic genes shows that the previously observed microheterogeneity of metallothionein-I protein preparations is due to the expression of distinct gene products. The third clone is incapable of encoding a typical metallothionein due to an early termination codon and two nonconservative amino acid replacements. This nonfunctional pseudogene retains introns. Evolutionary comparisons reveal conserved DNA sequences in both the coding and regulatory regions of these genes.

Amino Acid Sequence↗
PubMed1985

Role of the dopamine uptake carrier in the neurochemical response to methamphetamine: effects of amfonelic acid.

Repeated administration of large doses of methamphetamine depresses both neostriatal tyrosine hydroxylase and tryptophan hydroxylase activity. Neostriatal concentrations of dopamine, serotonin and their acidic metabolites are similarly reduced by methamphetamine. Coadministration of the dopamine uptake inhibitor, amfonelic acid, selectively prevented the methamphetamine-induced decrease in tyrosine hydroxylase activity while not altering the depression of tryptophan hydroxylase activity. In vitro, amfonelic acid blocked methamphetamine-induced [3H]dopamine release from neostriatal slices but had no effect on [3H]serotonin release. In experiments conducted with [3H]amphetamine and amfonelic acid, no evidence was found for carrier-mediated transport of amphetamine. The results demonstrate a role for the dopamine uptake carrier in the neurochemical effects of high doses of methamphetamine. Furthermore, the ability of amfonelic acid to antagonize the neurochemical effects of methamphetamine appears to be due to an inhibition of carrier-mediated dopamine efflux rather than carrier-mediated uptake of methamphetamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Role of the serotonin uptake carrier in the neurochemical response to methamphetamine: effects of citalopram and chlorimipramine.

The role of the serotonin uptake carrier in the methamphetamine-induced depression of serotonin synthesis was examined. In vivo, coadministration of citalopram or chlorimipramine with methamphetamine blocked the irreversible depression of tryptophan hydroxylase activity observed in the neostriatum and cerebral cortex after repeated administration of high doses of methamphetamine. The methamphetamine-induced reduction of neostriatal serotonin and 5-hydroxyindoleacetic acid was also attenuated by the two uptake inhibitors. In contrast, neither drug antagonized the depression of neostriatal tyrosine hydroxylase activity observed after methamphetamine administration. Citalopram also blocked the reversible inhibition of tryptophan hydroxylase activity observed after the acute administration of methamphetamine. In vitro, citalopram significantly inhibited methamphetamine-induced [3H]serotonin release from neostriatal slices. The results demonstrate that inhibitors of the serotonin uptake carrier can antagonize both the in vivo and in vitro effects of methamphetamine on serotonergic neurons. Furthermore, the methamphetamine-induced depression of serotonin synthesis is dependent upon a functional serotonin uptake system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Methamphetamine-induced depression of monoamine synthesis in the rat: development of tolerance.

Animals treated with high doses of amphetamines have been used as a model of schizophrenia due to the similarities between the psychosis associated with this mental disorder and that induced by chronic amphetamine abuse. When administered to naive rats in high doses, the amphetamine-like CNS stimulant methamphetamine produces drastic alterations in the neurochemical parameters of the neostriatal monoaminergic systems. These alterations are characterized by a decrease in the activities of the rate-limiting enzymes for dopamine and serotonin synthesis, as well as a decrease in the concentrations of both neurotransmitters and their metabolites. However, tolerance develops to these neurochemical effects when drug administration occurs in a pattern similar to that encountered during chronic amphetamine abuse. The results indicate that the neurochemical alterations produced by amphetamines in naive and tolerant animals differ widely. This suggests that the administration of high doses of amphetamine-like central stimulants to naive rats may not be an appropriate model for studying the neurochemical changes associated with psychosis and amphetamine abuse.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Role of dopamine in the neurotoxic effects of methamphetamine.

Multiple administrations of high doses of methamphetamine to rats cause long-term depression of both dopamine and serotonin synthesis. Coadministration of the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, antagonizes this effect of methamphetamine on both neurotransmitter systems. However, when catecholamine synthesis was maintained by the administration of L-dopa and the peripheral decarboxylase inhibitor R04-4602, alpha-methyl-p-tyrosine no longer prevented the effects of methamphetamine on either dopamine or serotonin synthesis. In addition, the administration of the specific dopamine uptake blocker, amfonelic acid, significantly attenuated the changes in the serotonin synthesizing enzyme, tryptophan hydroxylase, resulting from multiple high doses of methamphetamine. The ability of a single administration of methamphetamine to depress tryptophan hydroxylase was also dependent on catecholamine synthesis. These results suggest that dopamine plays an important role in the changes mediated by the administration of methamphetamine in both the dopaminergic and serotonergic systems.

Animals↗