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Selective vulnerability in striosomes and in the nigrostriatal dopaminergic pathway after methamphetamine administration : early loss of TH in striosomes after methamphetamine.

Granado N, Ares-Santos S, O'Shea E, Vicario-Abejón C, Colado MI, Moratalla R - Neurotox Res (2009)

Bottom Line: In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals.Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix.In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens.

View Article: PubMed Central - PubMed

Affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Avda. Dr. Arce 37, 28002, Madrid, Spain.

ABSTRACT
Methamphetamine (METH), a commonly abused psychostimulant, causes dopamine neurotoxicity in humans, rodents, and nonhuman primates. This study examined the selective neuroanatomical pattern of dopaminergic neurotoxicity induced by METH in the mouse striatum. We examined the effect of METH on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the different compartments of the striatum and in the nucleus accumbens. The levels of dopamine and its metabolites, 3,4-dihidroxyphenylacetic acid and homovanillic acid, as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid, were also quantified in the striatum. Mice were given three injections of METH (4 mg/kg, i.p.) at 3 h intervals and sacrificed 7 days later. This repeated METH injection induced a hyperthermic response and a decrease in striatal concentrations of dopamine and its metabolites without affecting 5-HT concentrations. In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals. Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix. The predominant loss of dopaminergic terminals in the striosomes occurred along the rostrocaudal axis of the striatum. In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens. These results provide the first evidence that compartments of the mouse striatum, striosomes and matrix, and mesolimbic and nigrostriatal pathways have different vulnerability to METH. This pattern is similar to that observed with other neurotoxins such as MPTP, the most widely used model of Parkinson's disease, in early Huntington's disease and hypoxic/ischemic injury, suggesting that these conditions might share mechanisms of neurotoxicity.

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METH produces a decrease in DAT-immunoreactivity in the striatum. Photomicrographs of striatal sections from mice sacrificed 7 days after treatment with saline (a–c) or METH (d–f) stained for DAT. Note the DAT-ir loss in the METH-treated mice along the rostrocaudal axis of the striatum. (g) Histograms show the proportional stained area of DAT-immunoreactivity. METH (4 mg/kg, i.p., every 3 h, 3×) produced a reduction in DAT-immunoreactivity levels. Data represent mean ± S.E.M., n = 6 animals/group; * P < 0.001 vs. saline, one-way ANOVA. Bar 500 μm
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Fig3: METH produces a decrease in DAT-immunoreactivity in the striatum. Photomicrographs of striatal sections from mice sacrificed 7 days after treatment with saline (a–c) or METH (d–f) stained for DAT. Note the DAT-ir loss in the METH-treated mice along the rostrocaudal axis of the striatum. (g) Histograms show the proportional stained area of DAT-immunoreactivity. METH (4 mg/kg, i.p., every 3 h, 3×) produced a reduction in DAT-immunoreactivity levels. Data represent mean ± S.E.M., n = 6 animals/group; * P < 0.001 vs. saline, one-way ANOVA. Bar 500 μm

Mentions: To confirm that TH fiber loss reflected terminal damage and not just a reduction in TH synthesis, we used immunohistochemistry to evaluate the expression of dopamine transporter (DAT). DAT is located on dopaminergic terminals and is expressed independently of TH synthesis or accumulation. METH also produced a significant loss of striatal DAT-positive fibers 7 days after injection compared with saline-treated mice (Fig. 3). As expected, the pattern of DAT-ir loss paralleled the pattern of TH-ir loss, with a similar decrease in DAT-ir fibers along the rostrocaudal axis, and a greater loss of DAT-ir fibers in striosomes and in the lateral striatum (Fig. 3a–f). Quantification of DAT-ir by image analysis revealed a significant decrease of 67% in METH-treated mice compared to saline-treated animals (P < 0.001) (Fig. 3g).Fig. 3


Selective vulnerability in striosomes and in the nigrostriatal dopaminergic pathway after methamphetamine administration : early loss of TH in striosomes after methamphetamine.

Granado N, Ares-Santos S, O'Shea E, Vicario-Abejón C, Colado MI, Moratalla R - Neurotox Res (2009)

METH produces a decrease in DAT-immunoreactivity in the striatum. Photomicrographs of striatal sections from mice sacrificed 7 days after treatment with saline (a–c) or METH (d–f) stained for DAT. Note the DAT-ir loss in the METH-treated mice along the rostrocaudal axis of the striatum. (g) Histograms show the proportional stained area of DAT-immunoreactivity. METH (4 mg/kg, i.p., every 3 h, 3×) produced a reduction in DAT-immunoreactivity levels. Data represent mean ± S.E.M., n = 6 animals/group; * P < 0.001 vs. saline, one-way ANOVA. Bar 500 μm
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2875475&req=5

Fig3: METH produces a decrease in DAT-immunoreactivity in the striatum. Photomicrographs of striatal sections from mice sacrificed 7 days after treatment with saline (a–c) or METH (d–f) stained for DAT. Note the DAT-ir loss in the METH-treated mice along the rostrocaudal axis of the striatum. (g) Histograms show the proportional stained area of DAT-immunoreactivity. METH (4 mg/kg, i.p., every 3 h, 3×) produced a reduction in DAT-immunoreactivity levels. Data represent mean ± S.E.M., n = 6 animals/group; * P < 0.001 vs. saline, one-way ANOVA. Bar 500 μm
Mentions: To confirm that TH fiber loss reflected terminal damage and not just a reduction in TH synthesis, we used immunohistochemistry to evaluate the expression of dopamine transporter (DAT). DAT is located on dopaminergic terminals and is expressed independently of TH synthesis or accumulation. METH also produced a significant loss of striatal DAT-positive fibers 7 days after injection compared with saline-treated mice (Fig. 3). As expected, the pattern of DAT-ir loss paralleled the pattern of TH-ir loss, with a similar decrease in DAT-ir fibers along the rostrocaudal axis, and a greater loss of DAT-ir fibers in striosomes and in the lateral striatum (Fig. 3a–f). Quantification of DAT-ir by image analysis revealed a significant decrease of 67% in METH-treated mice compared to saline-treated animals (P < 0.001) (Fig. 3g).Fig. 3

Bottom Line: In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals.Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix.In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens.

View Article: PubMed Central - PubMed

Affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Avda. Dr. Arce 37, 28002, Madrid, Spain.

ABSTRACT
Methamphetamine (METH), a commonly abused psychostimulant, causes dopamine neurotoxicity in humans, rodents, and nonhuman primates. This study examined the selective neuroanatomical pattern of dopaminergic neurotoxicity induced by METH in the mouse striatum. We examined the effect of METH on tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity in the different compartments of the striatum and in the nucleus accumbens. The levels of dopamine and its metabolites, 3,4-dihidroxyphenylacetic acid and homovanillic acid, as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid, were also quantified in the striatum. Mice were given three injections of METH (4 mg/kg, i.p.) at 3 h intervals and sacrificed 7 days later. This repeated METH injection induced a hyperthermic response and a decrease in striatal concentrations of dopamine and its metabolites without affecting 5-HT concentrations. In addition, the drug caused a reduction in TH- and DAT-immunoreactivity when compared to saline-treated animals. Interestingly, there was a significantly greater loss of TH- and DAT-immunoreactivity in striosomes than in the matrix. The predominant loss of dopaminergic terminals in the striosomes occurred along the rostrocaudal axis of the striatum. In contrast, METH did not decrease TH- or DAT-immunoreactivity in the nucleus accumbens. These results provide the first evidence that compartments of the mouse striatum, striosomes and matrix, and mesolimbic and nigrostriatal pathways have different vulnerability to METH. This pattern is similar to that observed with other neurotoxins such as MPTP, the most widely used model of Parkinson's disease, in early Huntington's disease and hypoxic/ischemic injury, suggesting that these conditions might share mechanisms of neurotoxicity.

Show MeSH
Related in: MedlinePlus