Biomedical subjects

B Ladenheim

Publications and source records attributed to B Ladenheim.

27 records · Page 2Linked to original sources

PubMed1996

Autoradiographic evidence for methamphetamine-induced striatal dopaminergic loss in mouse brain: attenuation in CuZn-superoxide dismutase transgenic mice.

Methamphetamine (METH) has long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system of rodents. METH-induced neurotoxicity is thought to involve release of DA in presynaptic DA terminals, which is associated with increased formation of oxygen-based free radicals. We have recently shown that METH-induced striatal DA depletion is attenuated in transgenic (Tg) mice that express the human CuZn-superoxide dismutase (SOD) enzyme. That study did not specifically address the issue of loss of DA terminals. In the present study, we have used receptor autoradiographic studies of [(125)I]RTI-121-labeled DA uptake sites to evaluate the effects of several doses of METH on striatal DA terminals of Non-Tg as well as of heterozygous and homozygous SOD-Tg mice. In Non-Tg mice, METH caused decreases in striatal DA uptake sites in a dose-dependent fashion. The loss of DA terminals was more prominent in the lateral region than in the medial subdivisions of the striatum. In SOD-Tg mice, the loss of DA terminals caused by METH was attenuated in a gene dosage-dependent fashion, with the homozygous mice showing the greatest protection. Female mice were somewhat more resistant than male mice against these deleterious effects of METH. These results provide further evidence for a role of superoxide radicals in the long-term effects of METH. They also suggest the notion of a gender-specific handling of oxidative stress.

Animals↗

PubMed1996

AP-1 DNA-binding activation by methamphetamine involves oxidative stress.

Methamphetamine (METH) caused dose-dependent increases in AP-1 DNA-binding activity in both nontransgenic (Non-Tg) and CuZn-SOD transgenic (SOD-Tg) mice. However, the increases in SOD-Tg mice were less prominent than those observed in Non-Tg animals. The time-course of METH-induced AP-1 changes was similar in both strains of mice. AP-1 binding activity showed an initial increase at 1 h, peaked at 3 h, and then gradually declined. AP-1 binding activity was back to normal by the 72-h time point. Regional analyses of METH effects revealed increases in the caudate putamen and cerebellum, with the striatum showing relatively higher METH-induced AP-1 DNA-binding activation. These regional effects were also attenuated in the SOD-Tg mice. These data indicate that METH-induced stimulation of AP-1 DNA-binding depends on cellular redox status. These results are consistent with in vitro studies that have reported that several transcription factors are regulated through redox mechanisms.

Animals↗

PubMed1996

Methamphetamine-induced neurotoxicity is associated with increased striatal AP-1 DNA-binding activity in mice.

Multiple injections of methamphetamine (METH) produce long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system. The drug also causes increases in AP-1 DNA-binding activity in mice. In the present study, we tested the idea that toxic doses of METH might cause long-term increases in AP-1 DNA-binding. Mice were given 10 mg/kg of METH 2, 3 or 4 times at a 2 h interval in 1 day. Striatal DA levels were markedly decreased at 3 h and 24 h in all injection groups. After 1 week, striatal DA level recovered to near control in the METH x2 group, but were still significantly decreased in the METH x3 and x4 groups. Similar drug administration schedules caused increases in AP-1 DNA-binding activity at the 3 h time point in all groups. The AP-1-binding activity almost returned back to control level in the x2 and x3 injection groups at the 24 h and 1 week time point, but there were still increased levels of AP-1-binding activity in the METH x4 group. These findings raise the possibility that METH-induced neurotoxicity might involve prolonged activation of AP-1 transcription factor. This might be related to the report that c-fos or c-jun activation may be important in some models of neurodegeneration.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Transgenic mice with high levels of superoxide dismutase activity are protected from the neurotoxic effects of 2'-NH2-MPTP on serotonergic and noradrenergic nerve terminals.

Administration of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analog 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP; 4 x 15 mg/kg) to CD-1 mice was found to cause substantial decreases in cortical and hippocampal 5-hydroxytryptamine (5-HT) and norepinephrine (NE) to 20-30% of control 3 weeks after treatment. The magnitude of these depletions was similar to those reported previously in Swiss Webster and C57BL/6 mice given 4 x 20 mg/kg 2'-NH2-MPTP, and in keeping with these prior studies, striatal dopamine levels were unchanged by 2'-NH2-MPTP treatment in CD-1 mice. Subsequently, transgenic CD-1 mice producing high levels of human cytosolic Cu-Zn superoxide dismutase (SOD) were studied to assess the role of oxygen radicals in the mechanism of action of 2'-NH2-MPTP. In contrast to the results described above, 5-HT and NE levels were almost completely unaffected by 2'-NH2-MPTP treatment in homozygous SOD mice bearing 5-fold increases in brain SOD activity. In 2'-NH2-MPTP-treated heterozygous SOD mice, which showed an average 3-fold increase in brain SOD activity, only moderate depletions in cortical and hippocampal 5-HT (50-60% of control) and NE (30-40% of control) were observed. Additionally, the density of [125I]RTI-55-labeled 5-HT uptake sites was studied to further assess possible 5-HT terminal loss. In various cortical and hippocampal subregions of nontransgenic mice, 5-HT uptake sites were reduced to 20-35% of control after 2'-NH2-MPTP treatment, in comparison with homozygous SOD mice, which were affected only minimally by 2'-NH2-MPTP administration, and heterozygous SOD mice, which showed intermediate reductions in 5-HT uptake site density on the order of 55-80% of control. Together, these data indicate that mice genetically endowed with increased SOD activity are protected from 2'-NH2-MPTP-induced toxicity, thereby implicating superoxide radicals in the mechanism of action of a neurotoxin that selectively depletes 5-HT and NE without affecting dopamine.

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

PubMed1995

Transgenic superoxide dismutase mice differ in opioid-induced analgesia.

Autoradiographic data from transgenic mice carrying the human Cu/Zn-superoxide dismutase gene demonstrate an increase in mu-opioid receptor concentration in dopaminergic-related areas and the central grey area. The relative potencies of mu-, delta- and kappa-opioid receptor agonists to induce antinociception in heterozygous and homozygous superoxide dismutase transgenic mice as well as four inbred strains were assessed to determine the functional significance of the increased receptor concentration. Increased superoxide dismutase activity results in an increased sensitivity to mu-agonists in a gene dosage-dependent manner. SOD/Tg/hom mice were less sensitive to the delta-agonist than were SOD/Tg/het mice. The superoxide dismutase transgene did not affect kappa-opioid receptor agonist sensitivity. These data suggest that delta-opioid receptors are not regulated in the same manner as mu-opioid receptors and that kappa-opioid receptors are unaffected by superoxide dismutase activity.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1995

Methamphetamine-induced serotonin neurotoxicity is mediated by superoxide radicals.

Methamphetamine (METH) causes deleterious effects in brain monoaminergic systems. Evidence has accumulated to suggest that these effects may be mediated via the overproduction of the superoxide radicals. We have recently shown that METH-induced dopamine (DA) depletion is attenuated in copper-zinc superoxide dismutase (CuZnSOD) transgenic (Tg) mice. In the present study, we have used receptor autoradiographic studies of [125I]RTI-55 labeled serotonin (5-HT) uptake sites to evaluate the effect of a two dosing schedule (5 mg/kg or 10 mg/kg x 4) of METH on striatal 5-HT uptake sites in nontransgenic (Non-Tg), heterozygous (Hetero) and homozygous (Homo) SOD-Tg mice. The low dose caused no significant changes in striatal 5-HT uptake sites in any of the groups. The high dose caused marked decreases (-74%) in striatal 5-HT uptake sites in Non-Tg mice. In contrast, 5-HT uptake sites showed only a 31% decrease in homozygous SOD-Tg mice whereas heterozygous SOD-Tg mice showed 63% depletion. These results show that increased SOD activity can protect against METH-induced neurotoxicity in striatal serotonergic terminals. These data provide further evidence for a role of oxidative stress in the neurotoxic effects of METH.

Animals↗

PubMed1995

Superoxide radicals mediate the biochemical effects of methylenedioxymethamphetamine (MDMA): evidence from using CuZn-superoxide dismutase transgenic mice.

The subacute and long-term biochemical effects of methylenedioxymethamphetamine (MDMA) were assessed in homozygous and heterozygous transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) superoxide dismutase (SOD) gene. Non-transgenic (Non-Tg) mice showed significant decreased in striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels both at 24 h and at 2 weeks after a single injection of MDMA (50 mg/kg). Heterozygous SOD-Tg mice showed DA depletion only at the 24 h time point. In contrast, homozygous SOD-Tg mice show no DA or DOPAC depletion at either the 24 h or at the 2 week time points. Moreover, three injections of MDMA (50 mg/kg) given 24 h apart also caused marked reduction of striatal DA and DOPAC in Non-Tg mice when these substances were measured 2 weeks after the last MDMA injection. That injection schedule also caused small decreases in DA levels in the heterozygous animals but no changes in the homozygous mice; DOPAC levels were not affected in the heterozygous nor in the homozygous SOD-Tg mice. Furthermore, the multiple injection schedule caused significant decreases in DA and DOPAC in female Non-Tg mice but not in the two strains of transgenic mice. Neither the single dose nor the multiple dose schedule of MDMA injections affected striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in any of the three strains of mice. These results support previous observations that MDMA-induced biochemical effects are observed in the DA systems of mice, whereas these effects are seen in the 5-HT systems of rats. The present observations also document for the first time a role for the production of superoxide radicals in these effects of MDMA. These mice are an important tool for dissecting pathways involved in drug-induced neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Involvement of oxidative and L-arginine-NO pathways in the neurotoxicity of drugs of abuse in vitro.

1. Inhibitors of nitric oxide (NO) formation or ADP-ribosylation attenuate methamphetamine (METH)- and methylenedioxymetamphetamine (MDMA)-induced neurotoxicity on dopaminergic and serotonergic cells in primary cultures. 2. They also prevent METH-induced reactive gliosis in dopaminergic cultures. 3. Overexpression of superoxide dismutase (SOD) in cells obtained from SOD-transgenic mice also attenuates drug-induced toxicity. 4. These data indicate a role for oxygen-based and NO free radicals in the mechanisms of cell death associated with drugs of abuse in vitro.

Adenosine Diphosphate Ribose↗

PubMed1994

CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxymethamphetamine (MDMA).

We have used female and male transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) superoxide dismutase (SOD) gene in order to assess the lethal effects of methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA). In contrast to non-Tg mice, both heterozygous and homozygous SOD-Tg mice showed resistance to the lethal effects of both drugs. Females of both SOD-Tg and non-Tg strains were somewhat more resistant to the effects of these drugs in comparison to males. In general, homozygous animals show greater resistance to the effects of the two drugs. These results suggest that the acute lethal effects of amphetamine-substituted analogs might involve the intracellular overproduction of the superoxide radicals secondary to hypoxic injury. The gender differences suggest that there might be hormonal-free radical scavenger interactions that offer better protection to female mice. This might be related both to the lifespan of and to the lower prevalence of Parkinson's disease in women. Future studies will need to address these issues further.

3,4-Methylenedioxyamphetamine↗