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Biomedical subjects

J W Gibb

Publications and source records attributed to J W Gibb.

At least 19 recordsLinked to original sources
PubMed1998

Methamphetamine treatment rapidly inhibits serotonin, but not glutamate, transporters in rat brain.

Previous studies have demonstrated that multiple methamphetamine (METH) administrations rapidly and reversibly decrease dopamine transporter activity assessed in striatal synaptosomes. A role for reactive oxygen species was suggested by findings that: (1) METH treatment increases the formation of oxygen radicals in vivo; and (2) oxygen radicals, generated by the enzyme xanthine oxidase, attenuate dopamine uptake in vitro. To test the selectivity of transporter responses, the present study examined effects of METH and xanthine oxidase on [3H]serotonin ([3H]5HT) and [3H]glutamate transport into striatal synaptosomes. Multiple doses of METH, or incubation with xanthine oxidase, rapidly attenuated [3H]5HT transport; an effect attributable to a decrease in Vmax. The METH-induced decrease in transport activity completely recovered by 24 h, but was decreased again 1 week later. In contrast, [3H]glutamate transport was essentially unchanged after METH treatment or incubation with xanthine oxidase. These findings indicate that: (1) METH causes a rapid and reversible decrease in 5HT transporter activity; and (2) glutamate transporters are less susceptible than 5HT transporters to effects of reactive species or METH treatment.

ATP-Binding Cassette Transporters↗
PubMed1998

Methamphetamine-induced rapid and reversible reduction in the activities of tryptophan hydroxylase and dopamine transporters: oxidative consequences?

Treatment with high doses of methamphetamine (METH) results in dramatic changes in extrapyramidal monoaminergic systems. Elevated concentrations of extracellular dopamine (DA), caused by METH administration, are thought to contribute to these effects due to the oxidative potential of this reactive catecholamine. According to this hypothesis monoaminergic cellular elements, which are vulnerable to oxidative modification, may be especially sensitive to high-dose METH treatments. We confirmed this possibility by observing that both tryptophan hydroxylase (the synthesizing enzyme for serotonin) and the DA transporter, proteins particularly susceptible to oxidative modification, were rapidly (within 30 min), but reversibly (returned to control levels by 36 hr) inactivated by a single administration of METH. These findings suggest that there also may be other cellular elements similarly altered by METH treatment due to oxidative mechanisms.

Animals↗
PubMed1998

3-4-Methylenedioxymethamphetamine-induced acute changes in dopamine transporter function.

The acute effects of the amphetamine designer drug, 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'), on dopamine transporter function in rat striatum were investigated and compared to other psychostimulants known to influence monoaminergic systems. A single MDMA injection (10-20 mg/kg; s.c.) caused a dose-related decrease in [3H]dopamine uptake into striatal synaptosomes prepared 1 h after MDMA administration. This rapid effect on [3H]dopamine uptake returned to control levels 24 h after treatment. A single administration of other amphetamine analogs, such as methamphetamine (15 mg/kg; s.c.), p-chloroamphetamine (10 mg/kg; i.p.) or methcathinone (30 mg/kg; s.c.), also rapidly decreased striatal [3H]dopamine uptake. In contrast, a single or multiple administrations of cocaine (30 mg/kg; i.p.) had no effect on [3H]dopamine transport into striatal synaptosomes. These changes in dopamine transporter activity by the amphetamine analogs may occur via reactive oxygen species-mediated mechanisms.

Animals↗
PubMed1997

Oxygen radicals diminish dopamine transporter function in rat striatum.

Incubation of striatal synaptosomes with the oxygen radical generating enzyme, xanthine oxidase, decreased [3H]dopamine uptake: an effect attributable to a decreased Vmax. Concurrent incubation with the superoxide radical scavenger, superoxide dismutase, abolished the xanthine oxidase-induced decrease. These results indicate that, like methamphetamine administration in vivo, reactive oxygen species diminish dopamine transporter function in vitro. The significance of these findings to mechanisms responsible for effects of methamphetamine is discussed.

Animals↗
PubMed1997

Methamphetamine-induced decrease in tryptophan hydroxylase activity: role of 5-hydroxytryptaminergic transporters.

Methamphetamine-induced 5-hydroxytryptaminergic neuronal damage purportedly involves transport of newly released dopamine from extracellular spaces into 5-hydroxytryptaminergic terminals. This hypothesis is based primarily on findings that dopamine is required for, whereas 5-hydroxytryptamine (5-HT) uptake inhibitors prevent, methamphetamine-induced deficits in 5-hydroxytryptaminergic neuronal function. This hypothesis is not, however, supported by findings presented in this study that 5-hydroxytryptaminergic neuronal damage, induced by p-chloroamphetamine, does not decrease [3H]dopamine uptake into rat brain synaptosomes prepared from 5-HT-transporter-containing tissue. Moreover, despite having greater affinity for the 5-HT transporter, citalopram has an IC50 for [1H]dopamine transport into these synaptosomal preparations that is considerably greater than that of fluoxetine. These data suggest that 5-HT transporters may not effect dopamine uptake and thereby methamphetamine-induced 5-hydroxytryptaminergic neuronal damage. Other possible mechanisms related to 5-HT uptake inhibitor attenuation of methamphetamine-induced deficits were investigated. Fluoxetine pretreatment prevented the methamphetamine-induced decrease in tryptophan hydroxylase activity: this effect cannot be attributed to altered body temperatures or brain concentrations of methamphetamine which suggests that neither, per se, is sufficient to impair 5-hydroxytryptaminergic neuronal function.

Animals↗
PubMed1997

A rapid and reversible change in dopamine transporters induced by methamphetamine.

Because high doses of methamphetamine promote free radical formation, and striatal dopamine transporters are rapidly inactivated by oxidative events, we determined the effect of a single high dose of methamphetamine on dopamine transporter activity in striatal synaptosomes. One hour after methamphetamine administration, dopamine uptake decreased by 48%. This dramatic decline was totally reversed by 24 h after treatment. These findings suggest that methamphetamine reversibly decreases dopamine transporter activity by oxidative mechanisms.

Animals↗
PubMed1997

Role of dopamine D1- and NMDA receptors in regulating neurotensin release in the striatum and nucleus accumbens.

Stimulation of dopamine D1-receptors by SKF 82958 increased extracellular neurotensin (NT) levels in the striatum and nucleus accumbens as measured by in vivo microdialysis while blockade of D1-receptors had no effect. Antagonism of NMDA receptors with MK 801 completely prevented the increased NT release induced by D1-stimulation in both structures. Tissue content of striatal NT anterior and posterior to the microdialysis probe was oppositely altered by D1-stimulation: increases were observed in the anterior striatum with decreased NT levels in the posterior striatum.

Animals↗
PubMed1997

Comparison of neurotensin responses to MDL 100,907, a selective 5HT2A antagonist, with clozapine and haloperidol.

The unique pharmacological profile of atypical antipsychotics, such as clozapine, suggests that action on non-dopaminergic transmitter systems might contribute to the unique therapeutic benefits of these drugs. In order to test this possibility, the response of neurotensin systems to drugs with antipsychotic potential was examined because of this peptide's putative association with psychiatric disorders. The effects of treatments by haloperidol, clozapine, and MDL 100,907 (a selective 5HT2A antagonist thought to have antipsychotic activity) on NT pathways were determined in various extrapyramidal and limbic regions and compared. The response of neurotensin systems was determined by measuring neurotensin-like immunoreactivity after 1, 2, 4, and 5 drug administrations. It was observed that tissue content of this peptide in caudate and nucleus accumbens regions tended to be elevated after 1 or 2 drug administrations, but had either returned or was returning to control levels after 4 or 5 drug administrations. In general, the extrapyramidal and limbic neurotensin levels responded in a similar manner to clozapine and the 5HT2A antagonist, but differently for haloperidol in most regions examined. An important exception was in the nucleus accumbens, where all three drugs had similar effects on neurotensin tissue levels. These results suggest that 5HT2A receptors exert basal control over some extrapyramidal and limbic neurotensin systems and this interaction might contribute to the antipsychotic effects of these drugs.

Animals↗
PubMed1997

Rapid and reversible effects of methamphetamine on dopamine transporters.

Reactive oxygen species decrease dopamine transporter (DAT) function in vitro. Because of this, and the finding that METH administration causes oxygen radical formation in vivo, the effects of METH administration on DAT activity in rat striatum were investigated. A single METH injection caused a dose-dependent (0-15 mg/kg) decrease in [3H]dopamine uptake into striatal synaptosomes prepared 1 h after METH administration; an effect attributable to a decreased Vmax of [3H]dopamine uptake. Similarly, multiple high-dose administrations of METH (10 mg/kg/dose; four doses at 2-h intervals) decreased DAT function. The decreases in DAT activity after either single or multiple METH administrations were reversed 24 h after treatment. [3H]5HT transport into striatal synaptosomes was also affected by METH treatment. Taken together, these data suggest that METH decreases DAT activity, perhaps through a reactive oxygen species-mediated mechanism. These findings may have important implications regarding the role of oxidative events in the physiological regulation of monoaminergic systems.

Animals↗
PubMed1997

Interaction between hyperthermia and oxygen radical formation in the 5-hydroxytryptaminergic response to a single methamphetamine administration.

Administration of a single high dose of methamphetamine (METH) causes a rapid and reversible decrease in the activity of the tryptophan hydroxylase (TPH), the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine. This effect can be reversed completely by exposing the METH-impaired enzyme to a reducing environment, which suggests that the decrease in TPH activity is a reversible oxidative consequence of free radical formation. Consistent with this hypothesis, a single METH administration to male rats increased oxygen radical formation, as demonstrated by increased striatal dihydroxybenzoic acid formation after coadministration of salicylate with METH. Prevention of METH-induced hyperthermia attenuated both the increase in dihydroxybenzoic acid formation and the decrease in TPH activity observed 1 h after METH administration. These data suggest that both reactive oxygen species and hyperthermia contribute to the acute decrease in TPH activity which results from a single METH administration.

Animals↗
PubMed1997

Exacerbation of methamphetamine-induced neurochemical deficits by melatonin.

Methamphetamine (METH), administered in large, repeated doses, compromises the dopaminergic and serotonergic systems as indicated by prolonged suppression of tyrosine hydroxylase and tryptophan hydroxylase activity and concurrent decreases in the content of dopamine and 5-hydroxytryptamine. Because dopamine is necessary for these dopaminergic and serotonergic deficits we postulated that dopamine and/or its reactive metabolites are responsible for these degenerative alterations. Because we previously demonstrated that in vitro reducing conditions reverse the decrease in tryptophan hydroxylase activity, we reasoned that melatonin, a purported endogenous antioxidant, may alter this response. Rats were treated with METH and/or melatonin and trytophan hydroxylase activity and 5-hydroxytryptamine content were assessed; tyrosine hydroxylase activity and dopamine content were also measured. Not only did melatonin not prevent METH-induced deficits in serotonergic and dopaminergic parameters, but coadministration of melatonin with METH actually enhanced most of the monoaminergic effects of METH. This enhancing effect could not be attributed to alteration of body temperature. Because METH abuse causes insomnia and melatonin is promoted in some countries for insomnia, the implications of the interaction between these two drugs could be clinically important.

Animals↗
PubMed1997

Role of endogenous dopamine in the neurochemical deficits induced by methcathinone.

Multiple administrations of methcathinone caused persistent deficits in monoaminergic systems, as reflected by decreases in dopamine and 5-hydroxytryptamine uptake capacity, tissue content and associated rate-limiting synthetic enzyme activities. Because dopamine has been implicated in mediating such effects after administration of related amphetamine analogs, its role in effecting methcathinone-induced monoaminergic neuronal impairment was assessed. A single high-dose administration of methcathinone increased striatal dopamine release, as measured by microdialysis in conscious rats and reflected by increases in striatal neurotensin-like immunoreactivity. Dopaminergic deficits observed 18 hr after a multiple-dose treatment with methcathinone were prevented by pretreatment with the selective D1 antagonist SCH23390 and D2 receptor antagonist eticlopride, but 5-hydroxytryptaminergic deficits were not altered. 5-Hydroxytryptaminergic changes did not occur in animals depleted of striatal dopamine by 6-hydroxydopamine lesions. These results indicate that dopaminergic systems are profoundly affected by methcathinone administration and that dopamine likely contributes to the monoaminergic effects of this stimulant.

Animals↗
PubMed1996

Dopamine D2-receptors regulate neurotensin release from nucleus accumbens and striatum as measured by in vivo microdialysis.

The present study was undertaken to examine the role of dopamine D2-receptors in the regulation of neurotensin release. Through a modification of the methods described by Maidment et al. (Neuroscience, 45 (1991) 81-93), we have developed a highly reproducible method of measuring changes in extracellular NT in the striatum and nucleus accumbens by in vivo microdialysis in awake animals. It was observed that calcium-dependent release of NT was evoked in both structures by infusing a high concentration of potassium. In addition, systemic administration of the D2 agonist quinpirole (5 mg/kg) induced a rapid increase of approximately 200% in extracellular NT levels in the lateral caudate and 30-40% in the nucleus accumbens. Conversely, treatment with the D2 antagonist eticlopride (0.5 mg/kg) reduced extracellular NT in the medial anterior caudate and nucleus accumbens 20-30%, but had no effect in the lateral anterior caudate. These data demonstrate for the first time that D2-receptors are important in the dopaminergic regulation of extrapyramidal and limbic NT release in conscious animals.

Animals↗
PubMed1996

Mechanisms for tolerance to methamphetamine effects.

Pretreatment with incremental increases in methamphetamine causes tolerance to serotonergic effects caused by challenging with multiple high doses of methamphetamine (11.5 mg/kg/dose). The brain concentration of methamphetamine following this challenge was reduced in tolerant rats, yet the plasma concentration was elevated. The tolerance was selective for methamphetamine and did not occur when cocaine was used in the pretreatment. The possibility that tolerance affects the distribution of methamphetamine in or out of the brain through an active transport system was examined by combining the transport-blocking drug, probenecid, with a low dose of methamphetamine. The presence of probenecid enhanced methamphetamine-induced serotonergic changes in the hippocampus. The brain concentration of methamphetamine increased in the presence of probenecid; however, a similar increase in the plasma methamphetamine concentration suggests that the effects of probenecid on methamphetamine distribution are not related to the redistribution of methamphetamine that occurs in tolerant animals.

Animals↗
PubMed1996

Microdialysis assessment of methamphetamine-induced changes in extracellular neurotensin in the striatum and nucleus accumbens.

Stimulants of abuse such as cocaine and methamphetamine (METH) have dramatic effects on tissue neurotensin (NT) levels in the striatum and nucleus accumbens. Presumably these effects are due to the ability of such drugs to increase dopamine transmission. Because changes in dopamine activity appear to influence NT systems, we examined the effects of increasing doses of METH on extracellular NT levels in the medial striatum and nucleus accumbens using in vivo microdialysis in conscious rats. At the lowest dose tested (0.5 mg/kg), METH almost doubled the extracellular concentration of NT in both regions. When the dose of METH was increased to 5.0 mg/kg, extracellular NT concentration was elevated, but only to approximately 150% of control. At the highest dose examined (15.0 mg/kg), extracellular NT was not altered compared to pretreatment control levels. The role of DA D-1 and D-2 receptors in mediating these effects was determined by combining specific antagonists with the low dose of METH. The D-1 antagonist SCH 23390 blocked the METH-induced increase in extracellular NT levels in the striatum, but not in the nucleus accumbens. Pretreatment with the D-2 antagonist, eticlopride, blocked the increase in extracellular NT in both regions. Changes in striatal NT extracellular levels after a single METH injection were compared to the alterations in tissue NT levels following multiple administrations of the same doses of METH. Tissue levels were significantly elevated with 5 or 15 mg/kg METH in the medial, but not the lateral, striatum. There was not a clear correlation observed between the METH effects on striatal NT tissue levels and extracellular NT concentration.

Animals↗
PubMed1996

Methcathinone: an initial study of its effects on monoaminergic systems.

Methcathinone is a stimulant recently designated a Schedule I drug. Its use and popularity are growing; however, little data are available concerning its neurochemical properties. We investigated the effects of single and multiple doses of methcathinone on dopaminergic and serotonergic systems in the rat. Multiple doses of 30 mg/kg methcathinone caused dramatic decreases in neurochemical parameters associated with both dopaminergic and serotonergic systems in the striatum; corresponding decreases also occurred in serotonergic parameters in hippocampus and frontal cortex. These reductions in enzyme activity and concentrations of transmitters and their metabolites were apparent of 18 and 72 hr after drug administration. In addition, a single dose of methcathinone caused a significant decrease in the serotonergic enzyme activity in the striatum that was evident at 30 min and 2 hr after drug administration. We found that doses of 10 and 20 mg/kg causes no effect on striatal monoaminergic systems; however, doses higher that the 30 mg/kg dose caused significant lethality. In comparison with other stimulants of abuse, methcathinone appears to be most similar to methamphetamine with regard to its effects on monamine systems.

Amines↗