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J W Gibb

Publications and source records attributed to J W Gibb.

At least 91 records · Page 5Linked to original sources
PubMed1988

Effects of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine isomers on central serotonergic, dopaminergic and nigral neurotensin systems of the rat.

This study demonstrates that the isomers of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) are different in their ability to induce changes in serotonergic parameters and nigral concentrations of neurotensin-like immunoreactivity. With five successive doses (3.5 mg/kg) the d-MDA isomer was more potent than the l-MDA in its ability to decrease the concentrations of serotonin in the frontal cortex and hippocampus. The same difference occurred in the ability to decrease the hippocampal activity of tryptophan hydroxylase as well as the hippocampal and neostriatal 5-hydroxyindoleacetic acid concentrations. However, both isomers of MDMA were equipotent in their ability to decrease serotonergic parameters in the brain areas examined. When the doses were increased to 5 and 10 mg/kg, both isomers of MDA were equipotent in their effects on the serotonin system, whereas the l-MDMA was significantly less potent than its d isomeric counterpart in causing a decrease in serotonergic parameters of the different brain areas. In contrast, treatments with any of the isomers appeared to have a minimal impact on neostriatal dopaminergic parameters. However, treatment with MDA or MDMA caused increases in the nigral concentrations of neurotensin, with the d isomer of both compounds having substantially greater effects on this neuropeptide system. These increases are suspected to result from drug-released dopamine. This study demonstrates that at selected doses, the d isomers of MDA and MDMA are more potent than their l forms in affecting neurochemical systems, whereas high doses of either isomer of MDA share a common ability to induce changes in the serotonergic system that are likely associated with neuronal damage.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetamine.

Similar to other amphetamine analogs 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), a currently popular illicit drug, has been characterized recently as a serotonergic neurotoxin due to its ability to cause long-lasting deficits in markers of central serotonergic function in animals. Because the serotonergic toxicity associated with the MDMA analog methamphetamine has been linked previously to endogenous dopamine and because MDMA, like methamphetamine, elicits pronounced dopamine release in vitro, we have examined the role of endogenous dopamine in both the immediate (3 hr) and longer-term (3 days) central serotonergic deficits induced by systemic MDMA administration to rats. Depletion of central dopamine content with alpha-methyl-p-tyrosine or reserpine, or selective destruction of nigrostriatal dopamine projections with bilateral 6-hydroxydopamine-induced substantia nigral lesions, partially blocked the immediate MDMA-induced reduction in rat striatal tryptophan hydroxylase (TPH) activity. In addition, the longer-term TPH deficits caused by a high single dose of MDMA were completely prevented by prior alpha-methyl-p-tyrosine or reserpine, and attenuated significantly by inhibition of dopamine uptake with the selective dopamine-uptake blocker GBR 12909. These results implicate endogenous drug-released dopamine as a partial mediator of the initial decrease in TPH activity caused by MDMA and as an important prerequisite to the development of long-term MDMA-induced neurotoxicity. Potential mechanisms of dopamine-mediated toxicity are discussed.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Effects of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on central serotonergic and dopaminergic systems of the rat.

The influence of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on the central serotonergic and dopaminergic systems of the rat after a single or multiple injections was studied. MDE (10 mg/kg) produced a significant decrease in the concentration of 5-hydroxytryptamine (5-HT) 1 hr later in the frontal cortex and the hippocampus without affecting the concentration of 5-hydroxyindoleacetic acid (5-HIAA) or tryptophan hydroxylase (TPH) activity. Hypothalamic and neostriatal concentrations of 5-HT, 5-HIAA, dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) remained unaffected, as well as the neostriatal TPH and tyrosine hydroxylase (TH) activities. However, 3 hr after the MDE injection, the serotonergic variables including TPH activity were decreased in most of the brain areas examined. The dopaminergic system remained unaffected, except for a significant reduction in neostriatal DOPAC concentrations. The changes in transmitter concentrations after a single injection were dose dependent; the maximum depletion in TPH activity was reached with a 10 mg/kg dose. The administration of multiple doses of MDE caused greater decreases in TPH activity and 5-HT concentrations 3 hr after the treatment than did a single injection; in addition, a partial recovery from multiple administrations occurred by 18 hr. The effects of MDE on DA and its metabolites were transient, and neostriatal TH activity was not altered. This study demonstrates that MDE primarily affects the central serotonergic system, as reported for its congeners 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine. It does, however, produce less neurotoxicity as judged by its lower potency on the dopaminergic and the serotonergic systems as well as the recovery occurring in these systems.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Characterization of dopaminergic influence on striatal-nigral neurotensin systems.

Dopamine depletion by treatment with alpha-methyl-p-tyrosine had no effect on methamphetamine-mediated increases in striatal neurotensin (NT) concentrations but significantly attenuated nigral increases; the attenuation in the nigral response was reversed by L-DOPA. Blockade of D2-receptors, with sulpiride, by itself increased striatal NT levels, while having no effect on the nigral NT system or its response to methamphetamine. In contrast, D1 blockade with SCH 23390 had no effect of its own on NT levels but significantly blocked the methamphetamine-induced actions in both the striatal and nigral NT systems.

Animals↗
PubMed1987

Effects of amphetamine analogs on neurotensin concentrations in rat brain.

The present study investigates the effects of amphetamine-like analogs on neurotensin systems and compares the same to those of methamphetamine. Like methamphetamine, multiple high doses of each of the analogs examined significantly increased the concentrations of neurotensin-like immunoreactivity in the striatum, substantia nigra and nucleus accumbens; these effects were reversible and specific. The changes in the neurotensin systems developed rapidly and were evident within 6 h following a single administration of two of the analogs studied.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Role of the dopaminergic nigrostriatal pathway in methamphetamine-induced depression of the neostriatal serotonergic system.

The prevention of the decrease in neostriatal tryptophan hydroxylase (TPH) activity with a single dose of methamphetamine (MA) was attempted by lesioning the nigrostriatal dopaminergic projections with bilateral nigral injections of 6-hydroxydopamine (6-OHDA). The rats were injected with MA (10 mg/kg) 11 days later, and killed 3 h after the injection. The 6-OHDA lesions prevented the decrease of TPH activity in the neostriatum, while the decrease of enzyme activity was slightly attenuated in the hippocampus and unaffected in the frontal cortex. This study demonstrates: that the attenuation of TPH activity can be prevented in a selected brain area by destroying its dopaminergic afferents, and implicates central dopamine (DA), or its metabolite, in the decrease in central TPH activity observed after a single injection of MA.

Animals↗
PubMed1987

A comparison of the neurotoxic potential of methylenedioxyamphetamine (MDA) and its N-methylated and N-ethylated derivatives.

Three psychoactive amphetamine congeners were evaluated for their ability to cause long-term changes in several neurochemical parameters indicative of central serotonergic function. Two weeks after multiple doses (10 mg/kg) of 3,4-methylenedioxyamphetamine (MDA) or its N-methylated derivative, 3,4-methylenedioxymethamphetamine (MDMA), selective and dramatic decreases were observed in regional brain tryptophan hydroxylase (TPH) activities, and in corresponding concentrations of 5-hydroxytryptamine (5-HT) and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA). However, the N-ethylated derivative of MDA, N-ethyl-3,4-methylenedioxyamphetamine (MDE), was much less potent in its ability to lower brain hydroxyindoles, and in most regions examined did not significantly affect TPH activity. The neurotoxic implications of these results are discussed.

3,4-Dihydroxyphenylacetic Acid↗
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

Differences in the central serotonergic effects of methylenedioxymethamphetamine (MDMA) in mice and rats.

The effects of subcutaneous injection of 3,4-methylenedioxymethamphetamine (MDMA), a psychoactive amphetamine congener, on mouse central monoaminergic systems were assessed and compared to effects in rats. Whereas neostriatal concentrations of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in mouse were transiently decreased after a single moderately high dose of MDMA (15 mg/kg), mouse neostriatal or hippocampal tryptophan hydroxylase activity was not significantly affected, even after a dose of 60 mg/kg. These results are in contrast to effects in rats, in which a single 10 mg/kg dose of MDMA induced immediate and prolonged decreases in both central tryptophan hydroxylase activity and 5-hydroxyindole concentrations. Decreases in mouse central tryptophan hydroxylase activity, and prolonged decreases in mouse 5-hydroxyindole concentrations, were observed only after multiple doses of MDMA, suggesting that the duration of exposure may be an important determinant of toxic effects. These results show mice to be less susceptible than rats to MDMA-induced neurotoxicity, and are discussed in terms of possible interspecies differences in MDMA pharmacokinetics.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Immediate and long-term effects of 3,4-methylenedioxymethamphetamine on serotonin pathways in brain of rat.

In the rat, administration of the psychoactive analog of amphetamine 3,4-methylenedioxymethamphetamine (MDMA), causes selective, pronounced decreases in markers of central serotonergic function. The time course of these neurochemical changes was examined in several serotonergic nerve terminal regions of the brain. Fifteen min after subcutaneous injection of MDMA (10 mg/kg), the enzymatic activity of tryptophan hydroxylase (the rate-limiting enzyme for the biosynthesis of serotonin) was significantly decreased in the frontal cortex; by 1 hr after the injection, the activity of tryptophan hydroxylase had significantly declined in the neostriatum, hippocampus and hypothalamus as well. Although extensive recovery had occurred by 2 weeks, the activity of the enzyme remained significantly depressed in most regions. Decline of the regional content of 5-hydroxytryptamine (5-HT) closely paralleled, but was usually preceded by, that of the enzyme. Concentrations of the primary metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), were less responsive: in most regions levels of 5-HIAA had significantly decreased by 3 hr, but not by 1 hr, following treatment. Markers of dopamine function were altered transiently but had returned to control values by 24 hr. Administration of multiple doses of MDMA (5 doses over a 24-hr period) resulted in significant decreases in serotonergic parameters for up to 110 days after treatment. The rate and extent of recovery varied according to both the dose administered and the region examined. The persistence of these serotonergic deficits suggests that MDMA induced the destruction of serotonin-containing axon terminals.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Methamphetamine-induced reduction in D1 and D2 dopamine receptors as evidenced by autoradiography: comparison with tyrosine hydroxylase activity.

As determined by autoradiographic techniques, multiple high doses of methamphetamine elicited a reduction in dopamine receptor population (both D1 and D2) in several areas of the rat central nervous system. D1 receptors were labeled with the D1-selective antagonist, [3H]SCH 23390, and D2 receptors were labeled with the D2-selective neuroleptic, [3H]sulpiride. Scatchard analysis, obtained from saturation data in caudate-putamen, indicated that the receptor alterations were due to a decrease in the number of receptors (Bmax) without an apparent change in affinity (Kd). A time course demonstrated that five doses of methamphetamine were required to elicit significant changes in receptors in most brain areas examined. The onset of the receptor alterations in various brain regions correlated with the development of methamphetamine-induced depression of striatal tyrosine hydroxylase activity. In most brain areas, the dopamine receptors returned to normal within 7 days following methamphetamine.

Animals↗
PubMed1987

Autoradiographic analysis of muscarinic cholinergic and serotonergic receptor alterations following methamphetamine treatment.

Autoradiographic examination of the response of muscarinic cholinergic (M1 and M2) receptors to multiple doses of methamphetamine has been performed in several regions of the rat brain. Both muscarinic receptor subtypes were identified with [3H]-N-methylscopolamine, while M1 receptors were specifically labeled with [3H]-pirenzepine. No change in muscarinic receptors labeled with [3H]-pirenzepine was found in any of the brain regions examined following methamphetamine treatment; however, [3H]-N-methylscopolamine binding was significantly reduced (24-40%). These results indicate that M1 receptors remained unchanged after the drug treatment, while M2 receptors were reduced in many areas of the rat central nervous system following multiple high doses of methamphetamine. Five doses of methamphetamine (6-hour interval between doses) were required to elicit the receptor changes in all brain regions analyzed. Within 7 days after drug treatment, the receptor number returned to control values in the affected brain areas. Additionally, the response of serotonin (5-HT1 and 5-HT2) receptors to methamphetamine was examined and found to be reduced in a few brain areas analyzed. The receptor changes were accompanied by METH-induced decreases in tyrosine hydroxylase and tryptophan hydroxylase activities.

Animals↗
PubMed1987

The effects of amphetamine-like designer drugs on monoaminergic systems in rat brain.

The response of brain dopaminergic and serotonergic systems to the amphetamine-like designer drugs, 3,4-methylenedioxyamp amphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA), was investigated and compared to methamphetamine (METH). Like METH, single or multiple doses of either drug caused marked reductions in both tryptophan hydroxylase (TPH) activity and concentrations of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) in several brain regions. The reduction in 5HT content corresponded to the depression of TPH activity in all regions examined. In contrast to METH, which induced pronounced deficits in dopaminergic neuronal markers, repeated doses of MDA or MDMA did not alter striatal tyrosine hydroxylase (TH) activities or reduce striatal dopamine concentrations. A single dose of MDA or MDMA significantly elevated striatal dopamine content; however, after repeated drug administrations dopamine concentrations were comparable to control values. The effects of MDA or MDMA administration in the rat brain are reminiscent of those elicited by p-chloroamphetamine, a presumed serotonergic neurotoxin.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Effects of cocaine on methamphetamine-induced neurochemical changes: characterization of cocaine as a monoamine uptake blocker.

Many of the rewarding aspects of cocaine are thought to be due to the ability of this stimulant to block reuptake of monoamines. However, because of its ability also to cause transmitter release, it is difficult to examine the properties of cocaine as an uptake blocker using in vitro techniques such as tissue slices or synaptosomes. Thus, we have evaluated cocaine as a blocker of dopamine and 5-hydroxytryptamine uptake processes by determining the in vivo effect of concurrent administrations of cocaine on the neurochemical effects of methamphetamine treatments. These findings demonstrated that cocaine like 5-hydroxytryptamine uptake blockers such as citalopram, greatly attenuated or blocked decreases in striatal and cortical tryptophan hydroxylase activities and concentrations of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid induced by multiple and single methamphetamine administrations. In contrast to other dopamine uptake blockers, such as amfonelic acid, cocaine did not attenuate the methamphetamine effects on striatal tyrosine hydroxylase activity and the concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid. The neurochemical findings were correlated with behavioral analyses.

Animals↗
PubMed1987

Effect of methamphetamine on neurotensin concentrations in rat brain regions.

High doses of methamphetamine (METH) induced 200 to 300% increases in the neurotensin-like immunoreactivity (NTLI) concentrations of the substantia nigra and striatum in rats after a single or multiple drug doses; smaller but significant increases of 30 to 50% were observed in the hypothalamus and hippocampus after multiple, but not single, METH administrations whereas no measurable changes were detected in the NTLI levels of the periaqueductal gray area or the amygdala. These METH-induced increases in NTLI concentrations were attenuated by coadministration of haloperidol in the substantia nigra, hypothalamus and hippocampus, indicating a possible involvement of dopamine receptors in these tissues. In the striatum haloperidol alone produced significant increases in NTLI levels; these increases were additive with those induced by METH treatment demonstrating that the neurotensin pathways associated with the striatum are regulated differently from that of the other brain areas examined. The implications of these findings to the relationship between dopamine and neurotensin transmitter systems are discussed.

Animals↗
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

The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain.

The effects of two amphetamine-like designer drugs, 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA), on dopaminergic and serotonergic systems in the rat brain were investigated and compared to those of methamphetamine (METH). Like METH, single or multiple 10 mg/kg doses of either drug caused marked reductions in both tryptophan hydroxylase (TPH) activity and concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid, in several serotonergic nerve terminal regions. In all regions examined, the reduction in 5-HT content corresponded to the depression of TPH activity. Unlike multiple METH administrations, which induced pronounced deficits in dopaminergic neuronal markers, repeated doses of MDA or MDMA did not alter striatal tyrosine hydroxylase (TH) activities or reduce striatal dopamine concentrations. A single dose of MDA or MDMA significantly elevated striatal dopamine content; however, after repeated drug administrations dopamine concentrations were comparable to control values. At this time, striatal levels of homovanillic acid were significantly elevated suggesting that both drugs influence dopamine turnover. The effects of MDA or MDMA administration in the rat brain are reminiscent of those elicited by p-chloroamphetamine, a presumed serotonergic neurotoxin.

3,4-Dihydroxyphenylacetic Acid↗