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J W Gibb

Publications and source records attributed to J W Gibb.

At least 73 records · Page 4Linked to original sources
PubMed1990

Neurotensin-dopamine interactions in the substantia nigra of the rat brain.

Single or multiple doses of the potent dopamine releaser, methamphetamine (METH), increases the content of neurotensin (NT)-like immunoreactivity (NTLI) in the substantia nigra of the rat brain by 2- to 3-fold. Concurrent blockade of D-1 receptors with METH treatment completely antagonized the increase in nigral NTLI content induced by this drug. These results suggest that activation of D-1 receptors by endogenous dopamine results in an increase in the level of NTLI in the substantia nigra. The present study was performed to characterize further the mechanisms underlying dopaminergic regulation of nigral NT systems. Prior selective destruction of the nigrostriatal dopamine pathway completely prevented the increase in nigral NTLI content induced by treatment with METH, which suggests that the effects of METH on nigral NT systems are mediated by the nigrostriatal dopamine projections. However, unlike METH, treatment of rats with the direct-acting, D-1-selective agonist, SKF 38393, did not alter nigral NTLI content but when combined with stimulation of D-2 receptors, a significant increase in the level of NTLI occurred. Surprisingly, activation of only D-2 receptors caused a significant decrease in nigral NTLI content. These data suggest that although activation of D-2 receptors alone has an effect opposite to that of the D-1 subtype, in combination with D-1 stimulation they facilitate the effect of D-1 receptors on nigral NT systems. In addition to the effects of direct or indirect stimulation of dopamine activity on nigral NT levels, basally released dopamine also appeared to regulate the level of NTLI in the substantia nigra. Thus, interruption of tonic dopamine activity by reserpine-induced depletion of dopamine significantly reduced the level of NTLI in the substantia nigra. The role of D-1 receptors in this tonic dopaminergic regulation of nigral NT systems was evident when concurrent activation of D-1, but not D-2, receptors with reserpine treatment prevented or reversed the decrease in NTLI content caused by dopamine depletion. Additional evidence for the D-1-mediated tonic regulation of NT systems in the substantia nigra was that blockade of D-1 receptors with SCH 23390 decreased the nigral NTLI content but blockade of D-2 receptors with sulpiride had no effect.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Characterization of acute N-ethyl-3,4-methylenedioxyamphetamine (MDE) action on the central serotonergic system.

The effect of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on the central serotonergic system was studied. Within 1 hr after administration of MDE (10 mg/kg), the concentration of 5-hydroxytryptamine (5-HT) and the activity of tryptophan hydroxylase (TPH) had declined significantly in the hippocampus but returned to control within 12 hr. Hippocampal 5-hydroxyindoleacetic acid (5-HIAA) content decreased within 2 hr, rebounded to 22% above control by 12 hr, and returned to control by 24 hr. Blockade of the 5-HT uptake carrier with fluoxetine (10 mg/kg) prevented or attenuated the MDE-induced changes in 5-HT content and TPH activity, except for neostriatal TPH activity which remained unresponsive to the fluoxetine treatment. The MDE-induced decline in TPH activity could be reversed by incubating the TPH preparation with dithiothreitol and Fe2+ under nitrogen for 24 hr. This suggests that the loss in TPH activity induced by MDE results from an alteration of the oxidation-reduction state of a sulfhydryl group located on the enzyme. The inhibition of monoamine oxidase (MAO) by the administration of pargyline (75 mg/kg) failed to protect the neostriatal TPH activity from the MDE-induced decline while potentiating the MDE-induced decrease in cortical TPH activity. This suggests that H2O2 generated by MAO in vivo is not responsible for oxidation of the sulfhydryl site located on TPH during the MDE treatment.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain.

Blockade of dopamine D2 receptors with either the selective antagonist, sulpiride, or the non-selective antagonist, haloperidol, induces 2- to 3-fold increases in the content of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens of the rat brain. Quantitatively similar increases were also observed (a) in the striatum following selective degeneration of more than 85% of the nigrostriatal dopamine pathway with 6-hydroxydopamine and (b) in both the striatum and the nucleus accumbens after non-selective depletion of brain dopamine using reserpine plus alpha-methyl-p-tyrosine. Interestingly, treatment of animals with sulpiride or haloperidol, following the depletion of dopamine by either 6-hydroxydopamine or reserpine plus alpha-methyl-p-tyrosine, did not add to the elevation in neurotensin content of either structure caused by the dopamine depletion alone. These data suggest that an intact dopamine system is required for the neuroleptics to exert their effects on individual neurotensin systems. In addition, the same mechanism appears to underlie the responses of the neurotensin pathways to treatments with the neuroleptics or dopamine-depleting drugs. A likely explanation for the effects of neuroleptics and dopamine-depleting drugs is that they eliminate tonic activity on D2 receptors by basally released dopamine in the striatum and the nucleus accumbens. Supportive evidence for this hypothesis is that concurrent administration of the D2 receptor agonist, LY 171555, with reserpine, completely blocked the effects of reserpine-induced dopamine depletion on neurotensin systems of the striatum and the nucleus accumbens.

Animals↗
PubMed1989

Effect of MK-801 on the decrease in tryptophan hydroxylase induced by methamphetamine and its methylenedioxy analog.

The role of N-methyl-D-aspartate (NMDA) receptors in the decrease in neostriatal tryptophan hydroxylase (TPH) activity induced by repeated high doses of methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA) was evaluated. Rats received 4 injections of methamphetamine (15 mg/kg) or MDMA (10 mg/kg) at 6 h intervals, and were killed 18-20 h after the last administration. These treatments with methamphetamine or MDMA reduced neostriatal TPH activity to 26 and 34% of control, respectively. Coadministration of MK-801 (2.5 mg/kg) significantly attenuated the methamphetamine-induced decrease in TPH activity (66% of control), but did not alter the effect of MDMA. This study suggests that excitatory amino acids may participate in the methamphetamine-induced decline in central TPH activity, and that the mechanism by which MDMA and methamphetamine decreases TPH activity may differ.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Acute inactivation of tryptophan hydroxylase by amphetamine analogs involves the oxidation of sulfhydryl sites.

The activity of rat hippocampal tryptophan hydroxylase was reduced from 30-60% 3 h after the administration of a 10-15 mg/kg dose of either fenfluramine, methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Tryptophan hydroxylase inactivated by these drug treatments could be reconstituted by a prolonged anaerobic incubation in the presence of 5 mM dithiothreitol and 50 microM Fe2+. Drug-inactivated enzyme obtained from rats killed 18 h after multiple doses of either D(+)- or L(-)-MDMA could not be similarly restored. These observations suggest that the rapid decrease in central tryptophan hydroxylase activity induced by amphetamine analogs results from the reversible oxidation of a sulfhydryl site(s) within the enzyme molecule, whereas the irreversible decrease in enzymatic activity measured 18 h after multiple-dose MDMA treatment may reflect serotonergic toxicity.

Amphetamines↗
PubMed1989

Glucocorticoids and 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity.

The present study was carried out in order to explore the role of glucocorticoids in 3,4-methylenedio-xymethamphetamine (MDMA)-induced neurotoxicity of the central serotonergic system. The activity of tryptophan hydroxylase (TPH) was used as an index of this drug-induced neuronal degeneration. One week after a single high dose of MDMA (20 mg/kg), a significant decrease in the enzyme activity was measured in both the frontal cortex and hippocampus. Adrenalectomy (ADX) attenuated or blocked this decrease in TPH activity in the hippocampus but not in the frontal cortex. This protective effect of ADX on hippocampal serotonergic neurons disappeared with concurrent administration of corticosterone (CORT) and MDMA administration. The long-term MDMA-induced decreases in hippocampal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were similarly affected by CORT replacement. However, ADX did not alter the short-term decline in hippocampal TPH activity and 5-HT concentrations measured 3 h after a single dose of MDMA (10 mg/kg s.c.). This study suggests that CORT play a role in the development of neurotoxicity induced by MDMA in the hippocampal serotonergic system, but may be less important in other brain structures.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Role of dopamine D-1 and D-2 receptors in the regulation of neurotensin systems of the neostriatum and the nucleus accumbens.

Activation of dopamine D-1 receptors with multiple administrations of SKF 38393 significantly increased the level of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens. However, a similar treatment with the D-2 receptor-selective agonist, LY 171555, decreased the same in both structures; when the two drugs were administered concurrently, their individual effects were blocked. These results suggest that dopamine D-1 and D-2 receptors antagonistically regulate neurotensin systems of the striatum and nucleus accumbens. On the other hand, blockade of D-2 receptors (with sulpiride) elevated, while D-1 receptors blockade (with SCH 23390) caused no change in the level of neurotensin in both these structures. Dopamine D-1 receptors did not appear to contribute to the sulpiride-mediated effect as concurrent administration of SCH 23390 did not alter the response.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Response by the neurotensin systems of the basal ganglia to cocaine treatment.

Multiple administrations of high doses of cocaine had profound effects on the neurotensin (NT) systems of the basal ganglia. Approximately 200-300% increases in striatal content of neurotensin-like immunoreactivity (NTLI) were observed 1-8 h following five doses of 30 mg/kg per dose of cocaine. The effect subsided by 48 h after treatment. Significant changes in striatal NTLI levels were not observed after a single dose of this stimulant. The nigral NT systems appeared to be even more sensitive to cocaine administration. Compared to striatal changes, increases in nigral NTLI content were greater (as much as 455% of control), required lower cocaine doses (20 mg/kg per dose), lasted longer (still elevated to 200% of control after 48 h) and were significant following a single cocaine exposure. The response of the striatal NT systems to cocaine appeared to be mediated principally by dopamine D-1 receptors, while both D-1 and D-2 receptors contributed to the response by the nigral NT projections. Specific dopamine, but not serotonin, uptake blockers caused increases in striatal and nigral NTLI concentrations similar to that seen with cocaine treatments, suggesting that interference with the dopamine uptake carrier complex by cocaine was responsible for its actions on extrapyramidal NT systems.

Animals↗
PubMed1989

In vitro reactivation of rat cortical tryptophan hydroxylase following in vivo inactivation by methylenedioxymethamphetamine.

The activity of tryptophan hydroxylase (EC 1.14.16.4) from rat brain was significantly decreased 1 h following a single systemic injection of 3,4-methylenedioxymethamphetamine (MDMA) when assessed ex vivo by radioenzymatic assay or in vivo by the quantitation of 5-hydroxytryptophan accumulation following central L-aromatic amino acid decarboxylase inhibition. Recovery of enzymatic activity in vivo, which occurred within 24 h of low-dose MDMA treatment, appeared not to involve synthesis of new enzyme protein, because the return of enzymatic activity was not prevented by prior cycloheximide. Acutely MDMA-depressed cortical tryptophan hydroxylase activity could be completely restored in vitro by a prolonged (20-24 h) anaerobic incubation in the presence of dithiothreitol and Fe2+ at 25 degrees C; partial reconstitution occurred when 2-mercapto-ethanol was substituted for dithiothreitol. Cortical tryptophan hydroxylase acutely inactivated by methamphetamine or p-chloroamphetamine could be similarly reactivated. MDMA-inactivated cortical tryptophan hydroxylase derived from rats killed later than 3 days after drug treatment could not be significantly reactivated under the conditions described above, indicating the development of irreversible enzymatic damage. Kinetic analysis of enzyme reactivation revealed an approximate doubling of enzyme Vmax with no change in enzyme affinity for either substrate, tryptophan, or pterin cofactor. These studies suggest that MDMA and its congeners inactivate central tryptophan hydroxylase by inducing oxidation of key enzyme sulfhydryl groups. The reactivation capacity of drug-inactivated enzyme at various times after MDMA treatment may provide a means of assessing the development of MDMA-induced neurotoxicity.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems.

Intrastriatal administration of the hydroxylated metabolites of amphetamine, p-hydroxyamphetamine (p-OHA) or p-hydroxy-norephedrine (p-OHNor), decreased local concentrations of dopamine and serotonin in a dose-dependent manner. Although both compounds reduced concentrations of the metabolites of dopamine, 5-hydroxyindoleacetic acid concentrations were elevated. After systemic treatment with p-OHA, striatal dopamine was also reduced. In contrast, only hypothalamic and hippocampal serotonin stores were altered significantly in rats treated with p-OHA systemically. Neither compound decreased the activities of tryptophan hydroxylase or tyrosine hydroxylase. Because p-OHA is metabolized to p-OHNor via dopamine beta-hydroxylase present in noradrenergic neurons, the direct effects of these compounds on dopaminergic and serotonergic variables can be observed in rats which receive intrastriatal drug treatment. p-OHA and p-OHNor were equally potent in decreasing dopamine concentrations. However, p-OHNor was more potent than p-OHA in decreasing serotonin concentrations. Both compounds more readily depleted dopamine compared to serotonin stores. Complete recovery of p-OHA-induced decreases in striatal dopamine occurred within 48 hr of intrastriatal administration and concurrent treatment with the dopamine uptake blocker, amfonelic acid, significantly attenuated the p-OHA-induced effects on dopamine.

Amphetamine↗
PubMed1988

Characterization of methamphetamine effects on the striatal-nigral dynorphin system.

Multiple high doses of methamphetamine (METH) induced 200-300% increases in the concentration of striatal and nigral dynorphin-like immunoreactivity (DLI). Increases in striatal and nigral DLI levels also were seen within 6 h following a single administration. The changes in the striatal-nigral dynorphin system had subsided 48 h after either acute or multiple treatments with METH. Selective lesioning of the nigral-striatal dopamine pathway blocked the effects; thus, the METH-induced changes appeared to be mediated by dopamine released from the nigral-striatal dopamine projection. Administration of the METH analog, 3,4-methylenedioxymethamphetamine, appeared to alter striatal and nigral DLI concentrations in a manner similar to that of METH.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Effects of methamphetamine on central monoaminergic systems in normal and ascorbic acid-deficient guinea pigs.

Repeated injections (s.c.) of methamphetamine (METH) were administered to normal and ascorbic acid-deficient (scorbutic) guinea pigs to assess a potential role for ascorbic acid in the METH-induced effects in central monoaminergic systems. The ascorbic acid-deficient condition differentially influenced the METH-induced responses of dopaminergic and serotonergic variables in the striatum: drug-induced changes in dopaminergic variables were identical in normal and scorbutic animals; METH-induced decreases in serotonergic variables [tryptophan hydroxylase activity, serotonin (5-HT) and 5-hydroxyindoleacetic acid concentrations], however, were prevented in scorbutic animals. The scorbutic condition did not alter significantly the distribution of METH in the brain, nor were striatal concentrations of dopamine (DA) or 5-HT affected. In vitro, ascorbic acid increased significantly DA-mediated [3H]5-HT release from striatal slices, thus suggesting a potential role for ascorbate in DA-mediated actions of METH on serotonergic systems. Although supplemental ascorbate failed to restore the METH-induced serotonergic effects in scorbutic guinea pigs, these data suggest that, in a normal animal, the effects of multiple injections of METH, on serotonergic systems, involve ascorbic acid.

Amphetamine↗
PubMed1988

Changes in the limbic neurotensin systems induced by dopaminergic drugs.

Single or multiple high doses of the dopamine-releasing drug, methamphetamine, induced 100-150% increases in the content of neurotensin-like immunoreactivity (NTLI) in the nucleus accumbens, but was without effect on the NTLI level in the ventral tegmental area. The increases in NTLI content in the nucleus accumbens were selectively blocked by the dopamine D-1 receptor antagonist, SCH 23390, which failed to exert any significant effect of its own in the same area. In contrast, haloperidol or the selective dopamine D-2 antagonist, sulpiride, when administered alone, significantly raised the NTLI level in the nucleus accumbens and when given concomitantly with methamphetamine, their effects on the amount of NTLI appeared to be additive. Very different patterns of response were observed in neurotensin systems associated with the mesocortical dopaminergic terminal fields of the frontal cortex and olfactory bulbs. Changes in NTLI contents occurred following only multiple doses of methamphetamine and consisted of decreases in levels of this peptide. However, like the nucleus accumbens, these methamphetamine-induced alterations were blocked completely by D-1 antagonism, while D-2 blockade appeared to be additive with the effects of methamphetamine.

Animals↗
PubMed1988

Effects of dopaminergic and serotonergic receptor blockade on neurochemical changes induced by acute administration of methamphetamine and 3,4-methylenedioxymethamphetamine.

As dopamine (DA) causes neurochemical changes in the central serotonergic system after an acute injection of methamphetamine, the present study examined the possibility that this response is mediated through dopaminergic receptors. Pretreatment with the DA receptor antagonist, haloperidol, failed to prevent the decreases in the activity of tryptophan hydroxylase and the concentration of serotonin (5-HT) in the frontal cortex, hippocampus and neostriatum 1 hr after a single administration of methamphetamine. Because methamphetamine is also a potent releaser of 5-HT, the possibility that 5-HT receptors mediate the effects of methamphetamine was evaluated. Pretreatment with methiothepin an antagonist of both DA and 5-HT receptors, failed to prevent the decline in activity of tryptophan hydroxylase but did attenuate the decreases in concentrations of 5-HT measured in the frontal cortex and hippocampus. This attenuation is not mediated through 5-HT2 receptors, as ritanserin failed to interfere with the changes induced by methamphetamine. In addition, DA or 5-HT receptors were apparently not involved in the changes in activity of tryptophan hydroxylase and concentrations of 5-HT induced by another analogue of amphetamine, 3,4-methylenedioxymethamphetamine (MDMA). This study suggests different mechanisms are responsible for the acute and long-term changes observed in the central serotonergic system following a single or multiple doses of methamphetamine.

3,4-Methylenedioxyamphetamine↗