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Perinatal asphyxia reduces dentate granule cells and exacerbates methamphetamine-induced hyperlocomotion in adulthood.

Wakuda T, Matsuzaki H, Suzuki K, Iwata Y, Shinmura C, Suda S, Iwata K, Yamamoto S, Sugihara G, Tsuchiya KJ, Ueki T, Nakamura K, Nakahara D, Takei N, Mori N - PLoS ONE (2008)

Bottom Line: However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens.At the same age, we also found a reduction of the dentate granule cells of the hippocampus.These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Shizuoka, Japan.

ABSTRACT

Background: Obstetric complications have been regarded as a risk factor for schizophrenia later in life. One of the mechanisms underlying the association is postulated to be a hypoxic process in the brain in the offspring around the time of birth. Hippocampus is one of the brain regions implicated in the late-onset dopaminergic dysfunction associated with hypoxic obstetric complications.

Methodology/principal findings: We used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Cesarean section birth. At 6 and 12 weeks after birth, the behavior of the pups was assessed using a methamphetamine-induced locomotion test. In addition, the histopathology of the hippocampus was examined by means of stereology. At 6 weeks, there was no change in the methamphetamine-induced locomotion. However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens. At the same age, we also found a reduction of the dentate granule cells of the hippocampus.

Conclusions/significance: These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.

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Related in: MedlinePlus

Effects of C-section with global asphyxia on methamphetamine-induced dopamine release.(A) Illustration of the location of dialysis probes in the nucleus accumbens. Lines indicate probe tracks within the nucleus accumbens of animals from groups V (solid lines, n = 6), C (broken lines, n = 6), or A (dotted lines, n = 6). (B) Vehicle- or methamphetamine-evoked dopamine release in the nucleus accumbens in V (○), C (▵) and A (▴) group animals at 12 weeks after birth (n = 6 for each of the V, C, and A groups). The symbols and bars represent means±SEM. Dopamine release is expressed as the %change relative to the baseline. (C) The total amounts of methamphetamine-evoked dopamine release in the nucleus accumbens in the V (open column), C (hatched column), and A (closed column) groups during a 90-min period are summarized. Values are expressed as means+SEM. Significant differences: *p<0.05 and **p<0.01 vs. the V group; ††p<0.01 vs. the C group.
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pone-0003648-g002: Effects of C-section with global asphyxia on methamphetamine-induced dopamine release.(A) Illustration of the location of dialysis probes in the nucleus accumbens. Lines indicate probe tracks within the nucleus accumbens of animals from groups V (solid lines, n = 6), C (broken lines, n = 6), or A (dotted lines, n = 6). (B) Vehicle- or methamphetamine-evoked dopamine release in the nucleus accumbens in V (○), C (▵) and A (▴) group animals at 12 weeks after birth (n = 6 for each of the V, C, and A groups). The symbols and bars represent means±SEM. Dopamine release is expressed as the %change relative to the baseline. (C) The total amounts of methamphetamine-evoked dopamine release in the nucleus accumbens in the V (open column), C (hatched column), and A (closed column) groups during a 90-min period are summarized. Values are expressed as means+SEM. Significant differences: *p<0.05 and **p<0.01 vs. the V group; ††p<0.01 vs. the C group.

Mentions: We measured the extracellular amount of dopamine in the nucleus accumbens after the administration of 2.0 mg/kg methamphetamine to 12-week-old animals. It was verified that the dialysis probe had been correctly placed within the nucleus accumbens in all animals (Figure 2A). The basal level of extracellular dopamine was similar among the 3 birth groups [F(2 15) = 1.22, p = 0.31] (Figure 2B). Vehicle injection did not alter the dopamine levels [F(2 15) = 0.79, p = 0.46] (Figure 2B). One-way repeated measures ANOVA revealed a statistically significant interaction between Group and Time [F(14 91) = 2.51, p<0.01]. The post-hoc Bonferroni tests revealed that the elevation in dopamine release in animals from the A group was significantly larger than that of both the V and C groups (p<0.01 for both groups) during the 30-min period after the injection of methamphetamine, and the elevation in dopamine release was also greater in the A group than in the V group (p<0.05) in the period from 30 to 60 min after the injection of methamphetamine (Figure 2B). The total amount of dopamine within the 90-min methamphetamine post-injection period in the A group was significantly higher than that of the V and C groups (p<0.01 for both groups) (Figure 2C).


Perinatal asphyxia reduces dentate granule cells and exacerbates methamphetamine-induced hyperlocomotion in adulthood.

Wakuda T, Matsuzaki H, Suzuki K, Iwata Y, Shinmura C, Suda S, Iwata K, Yamamoto S, Sugihara G, Tsuchiya KJ, Ueki T, Nakamura K, Nakahara D, Takei N, Mori N - PLoS ONE (2008)

Effects of C-section with global asphyxia on methamphetamine-induced dopamine release.(A) Illustration of the location of dialysis probes in the nucleus accumbens. Lines indicate probe tracks within the nucleus accumbens of animals from groups V (solid lines, n = 6), C (broken lines, n = 6), or A (dotted lines, n = 6). (B) Vehicle- or methamphetamine-evoked dopamine release in the nucleus accumbens in V (○), C (▵) and A (▴) group animals at 12 weeks after birth (n = 6 for each of the V, C, and A groups). The symbols and bars represent means±SEM. Dopamine release is expressed as the %change relative to the baseline. (C) The total amounts of methamphetamine-evoked dopamine release in the nucleus accumbens in the V (open column), C (hatched column), and A (closed column) groups during a 90-min period are summarized. Values are expressed as means+SEM. Significant differences: *p<0.05 and **p<0.01 vs. the V group; ††p<0.01 vs. the C group.
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Related In: Results  -  Collection

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pone-0003648-g002: Effects of C-section with global asphyxia on methamphetamine-induced dopamine release.(A) Illustration of the location of dialysis probes in the nucleus accumbens. Lines indicate probe tracks within the nucleus accumbens of animals from groups V (solid lines, n = 6), C (broken lines, n = 6), or A (dotted lines, n = 6). (B) Vehicle- or methamphetamine-evoked dopamine release in the nucleus accumbens in V (○), C (▵) and A (▴) group animals at 12 weeks after birth (n = 6 for each of the V, C, and A groups). The symbols and bars represent means±SEM. Dopamine release is expressed as the %change relative to the baseline. (C) The total amounts of methamphetamine-evoked dopamine release in the nucleus accumbens in the V (open column), C (hatched column), and A (closed column) groups during a 90-min period are summarized. Values are expressed as means+SEM. Significant differences: *p<0.05 and **p<0.01 vs. the V group; ††p<0.01 vs. the C group.
Mentions: We measured the extracellular amount of dopamine in the nucleus accumbens after the administration of 2.0 mg/kg methamphetamine to 12-week-old animals. It was verified that the dialysis probe had been correctly placed within the nucleus accumbens in all animals (Figure 2A). The basal level of extracellular dopamine was similar among the 3 birth groups [F(2 15) = 1.22, p = 0.31] (Figure 2B). Vehicle injection did not alter the dopamine levels [F(2 15) = 0.79, p = 0.46] (Figure 2B). One-way repeated measures ANOVA revealed a statistically significant interaction between Group and Time [F(14 91) = 2.51, p<0.01]. The post-hoc Bonferroni tests revealed that the elevation in dopamine release in animals from the A group was significantly larger than that of both the V and C groups (p<0.01 for both groups) during the 30-min period after the injection of methamphetamine, and the elevation in dopamine release was also greater in the A group than in the V group (p<0.05) in the period from 30 to 60 min after the injection of methamphetamine (Figure 2B). The total amount of dopamine within the 90-min methamphetamine post-injection period in the A group was significantly higher than that of the V and C groups (p<0.01 for both groups) (Figure 2C).

Bottom Line: However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens.At the same age, we also found a reduction of the dentate granule cells of the hippocampus.These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Shizuoka, Japan.

ABSTRACT

Background: Obstetric complications have been regarded as a risk factor for schizophrenia later in life. One of the mechanisms underlying the association is postulated to be a hypoxic process in the brain in the offspring around the time of birth. Hippocampus is one of the brain regions implicated in the late-onset dopaminergic dysfunction associated with hypoxic obstetric complications.

Methodology/principal findings: We used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Cesarean section birth. At 6 and 12 weeks after birth, the behavior of the pups was assessed using a methamphetamine-induced locomotion test. In addition, the histopathology of the hippocampus was examined by means of stereology. At 6 weeks, there was no change in the methamphetamine-induced locomotion. However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens. At the same age, we also found a reduction of the dentate granule cells of the hippocampus.

Conclusions/significance: These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.

Show MeSH
Related in: MedlinePlus