Search PubMed⌕ Search

Biomedical subjects

G R Hanson

Publications and source records attributed to G R Hanson.

At least 127 records · Page 7Linked to original sources
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↗
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↗