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Biomedical subjects

J W Gibb

Publications and source records attributed to J W Gibb.

At least 109 records · Page 6Linked to original sources
PubMed1986

Nigrostriatal dopamine actions on the D2 receptors mediate methamphetamine effects on the striatonigral substance P system.

Multiple administrations of methamphetamine to rats produced elevated concentrations of substance P-like immunoreactivity within the substantia nigra, an effect which is believed to be mediated by increases in dopaminergic activity induced by methamphetamine. The results reported here demonstrate that the effect of methamphetamine is mediated specifically by the dopamine pathway in the nigrostriatum. Thus, extensive destruction of dopamine neurons in the nigrostriatum by lesions induced by 6-hydroxydopamine or blockade of synthesis of dopamine with alpha-methyl-p-tyrosine prevented the increases in substance P-like immunoreactivity in the nigra, induced by methamphetamine. Similarly, the concurrent administration of the D2 receptor antagonist, sulpiride, also prevented the effects of methamphetamine on substance P-like immunoreactivity in a dose-dependent way. In addition, multiple administrations of the D2 agonist, RU24926, elevated, whereas the DI agonist, SKF38393, decreased the content of substance P-like immunoreactivity in the nigra. The effects of methamphetamine were not altered in rats with lesions induced by 5,7-dihydroxytryptamine. Thus, these findings suggest that the effect of methamphetamine on the striatonigral substance P pathway is mediated by nigrostriatal dopaminergic actions on D2 receptors.

5,7-Dihydroxytryptamine↗
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

Roles of D1 and D2 dopamine receptor subtypes in mediating the methamphetamine-induced changes in monoamine systems.

Previous studies have demonstrated that the effects of methamphetamine (METH) on dopaminergic and serotonergic systems are likely related to METH-induced increases in dopamine release. The ability of haloperidol to prevent these effects of METH suggests that dopamine receptor activation is involved in mediating these METH actions. The present studies were undertaken to determine what role the dopamine receptor subtype(s) might have in such METH effects. We found that the D1 antagonist, SCH23390, attenuated or blocked the effects of METH on dopaminergic and serotonergic systems, whereas the D2 antagonist, sulpiride, blocked the effects of METH on only the dopaminergic system. The results of the present studies suggest that METH-induced increases in dopaminergic action on both D1 and D2 receptors are associated with the effects of METH on the dopaminergic system. In contrast, dopamine action on D1, but not on D2, receptors appears to be involved in the effects of METH on the serotonergic systems of the neostriatum and the cerebral cortex.

Animals↗
PubMed1985

The acute effects of methamphetamine, amphetamine and p-chloroamphetamine on the cortical serotonergic system of the rat brain: evidence for differences in the effects of methamphetamine and amphetamine.

Cortical tryptophan hydroxylase (TPH) activity was reduced 3 h after a 10 or 15 mg/kg i.p. dose of either amphetamine (AMP), methamphetamine (METH), or p-chloroamphetamine (PCA). These injections of METH or PCA also decreased cortical serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations; none of the four doses of AMP decreased indoleamine concentrations. The time course of the effects following a 15 mg/kg dose of each amine was also different. Cortical TPH activity was reduced by all three amines for periods up to 24 h, whereas only METH and PCA significantly decreased 5-HT and 5-HIAA concentrations for long periods. These data suggest that each of the amphetamines may inhibit TPH activity, whereas only METH and PCA produced long-lasting decreases in indoleamine concentrations, reflecting either varying degrees of toxicity or differential effects of AMP on enzyme activity and neurotransmitter concentrations.

Amphetamine↗
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

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↗
PubMed1984

Opposite responses in the striato-nigral substance P system to D1 and D2 receptor activation.

The roles of different dopamine receptors in mediating the responses of the striato-nigral substance P (SP) feedback loop were investigated. Subacute treatment of rats with the D1 agonist, SK&F 38393, produced a significant decrease in SP content in the substantia nigra whereas treatment with the D2 agonist, RU 24926, elevated nigral SP concentrations. Consequently, the elevation in nigral SP content which occurs following treatment with methamphetamine is likely a D2-mediated event. This conclusion is supported by our observation that the D2 antagonist, sulpiride, totally blocked the methamphetamine effect. These findings suggest that D1 and D2 receptors mediate opposing influences on the SP feedback system.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1984

In vitro release of tritiated monoamines from rat CNS tissue by the neurotoxic compound 1-methyl-phenyl-tetrahydropyridine.

The effects of the neurotoxic compound, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1-MPTP), on monoamine release was determined using slices of rat corpus striatum or cerebral cortex preloaded with [3H]dopamine or [3H]serotonin, respectively. 1-MPTP released both monoamines in a concentration-dependent manner. [3H]Dopamine release was unaffected by tetrodotoxin, the absence of Ca2+, and nicotinic or muscarinic cholinergic antagonists. Dopamine uptake inhibitors had no effect on release from normal striatal slices but appeared to attenuate 1-MPTP-induced release from striatal slices of reserpine-pretreated rats.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

The effects of a single dose of amphetamine and iprindole on the serotonergic system of the rat brain.

Rats treated with iprindole (IPR) (10 mg/kg, i.p.) were given a single dose (15 mg/kg, i.p.) of amphetamine (AMP). Marked decreases in the activity of tryptophan hydroxylase (TPH) were observed in both the cerebral cortex and neostriatum after 6 hr, with maximum depression observed at 24 hr. Enzyme activity had returned to control levels in neostriatum after 3 days and in cerebral cortex after 7 days. Levels of serotonin (5-HT) in both the cerebral cortex and neostriatum were significantly lowered at 24 hr but had recovered by 72 hr. Levels of tryptophan (TRP) in the cortex were significantly elevated after 6 hr, recovering by 24 hr. In the neostriatum, the activity of tyrosine hydroxylase (TH) was significantly depressed by 24 hr and remained so for 7 days. Concentrations of dopamine (DA) were decreased at all times examined. This study clarifies the differences previously observed in the response of the serotonergic system to amphetamine or methamphetamine (METH) in iprindole-treated rats.

Animals↗
PubMed1984

Increases of substance P-like immunoreactivity within striatal-nigral structures after subacute methamphetamine treatment.

Substantial increases in the nigral concentration of substance P-like immunoreactivity (SPLI) were observed after subacute administration of the indirect dopamine agonist, methamphetamine (METH, 15 mg/kg every 6 hr; five doses). The effect was opposite, and thus consistent, with the reduction of SPLI levels previously reported in nigral tissue after pharmacological blockade of the nigrostriatal dopaminergic activity. In addition, subacute METH treatment increased SPLI concentrations in other structures associated with the basal ganglia, such as the striatum and entopeduncular nucleus, but not in the hypothalamus or dorsal raphe nucleus. Subacute treatment with d-amphetamine exerted METH-like effects on the substance P neurons of the basal ganglia, whereas haloperidol completely antagonized the METH effect. The possibility that monoaminergic systems help mediate the response of the substance P system to subacute METH treatment is examined.

Animals↗
PubMed1983

The effects of phencyclidine on glutamic acid decarboxylase activity in several regions of the rat brain.

Glutamic acid decarboxylase (GAD) activity in several regions of the rat brain were monitored after administration of phencyclidine. Sub-acute (4 injections over 12 h) treatment decreased cerebellar GAD activity 6 and 12 h after the last dose; recovery was noticed by 24 h. This effect occurred with doses of 5 and 10 mg/kg. GAD activity in other brain regions was not affected by this treatment. Acute and chronic treatments with phencyclidine caused no change in GAD activity in any of the brain regions examined.

Animals↗
PubMed1983

High-performance liquid chromatographic determination of indoleamines, dopamine, and norepinephrine in rat brain with fluorometric detection.

A high-performance liquid chromatography-fluorescence procedure for the determination of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, tryptophan, dopamine, and norepinephrine has been developed. The method uses an ion-pairing system on an Ultrasphere ODS (5-microns) column with detector wavelength settings of excitation at 290 nm and emission at 330 nm. The procedure has been used to quantitate these indoleamines and catecholamines in rat brain tissue after homogenization in a perchloric acid solution; an aliquot of this solution is injected directly onto the HPLC column. Column sensitivities range from 6.1 pmol for tryptophan to 1.1 pmol for 5-hydroxytryptamine.

Animals↗
PubMed1983

Effects of a single dose of methamphetamine and iprindole on the serotonergic and dopaminergic system of the rat brain.

A single dose (17.5 mg/kg i.p.) of methamphetamine was administered to iprindole-treated (10 mg/kg i.p.) rats. Forebrain concentrations of methamphetamine and amphetamine were significantly increased in iprindole-treated rats 1 and 6 hr after injection; in contrast to rats pretreated with saline, both amines were also detected after 18 hr. Three and 7 days after injection, significant decreases were seen in tryptophan hydroxylase (TPH) activity and serotonin concentrations in the cerebral cortex, neostriatum and hypothalamus. Hypothalamic TPH activity had recovered by 14 days. Neostriatal tyrosine hydroxylase activity and dopamine concentrations were significantly depressed at all time points examined. Iprindole alone produced a significant increase in cortical TPH activity after 1 day. After 3 days, TPH activity was significantly decreased when compared with control, whereas serotonin and 5-hydroxyindoleacetic acid concentrations were significantly increased. This study demonstrates that persistence of methamphetamine and/or amphetamine at the site of action is important for neurotoxicity.

Amphetamines↗