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. 2012 Jul;24(7):1398-405.
doi: 10.1016/j.cellsig.2012.03.001. Epub 2012 Mar 10.

Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice

Marjelo A Mines  1 , Richard S Jope
Affiliations

Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice

Marjelo A Mines et al. Cell Signal. 2012 Jul.

Abstract

Acute amphetamine administration activates glycogen synthase kinase-3 (GSK3) by reducing its inhibitory serine-phosphorylation in mouse striatum and cerebral cortex. This results from Akt inactivation and is required for certain behavioral effects of amphetamine, such as increased locomotor activity. Here we tested if regulation of Akt and GSK3 was similarly affected by longer-term administration of amphetamine, as well as of methylphenidate, since each of these is administered chronically in patients with attention deficit hyperactivity disorder (ADHD). Akt is activated by post-translational phosphorylation on Thr308, and modulated by Ser473 phosphorylation, whereas phosphorylation on Ser21/9 inhibits the two GSK3 isoforms, GSK3α and GSK3β. After eight days of amphetamine or methylphenidate treatment, striatal Akt and GSK3 were dephosphorylated similar to reported changes after acute amphetamine treatment. Oppositely, in the cerebral cortex and hippocampus Akt and GSK3 phosphorylation increased after eight days of amphetamine or methylphenidate treatment. These opposite brain region changes in Akt and GSK3 phosphorylation matched opposite changes in the association of Akt with β-arrestin and GSK3, which after eight days of amphetamine treatment were increased in the striatum and decreased in the cerebral cortex. Thus, whereas the acute dephosphorylating effect of stimulants on Akt and GSK3 in the striatum was maintained, the response switched in the cerebral cortex after eight days of amphetamine or methylphenidate treatment to cause increased phosphorylation of Akt and GSK3. These results demonstrate that prolonged administration of stimulants causes brain region-selective differences in the regulation of Akt and GSK3.

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Figures

FIGURE 1
FIGURE 1. Amphetamine treatment for eight days reduces phosphorylation of Akt and GSK3 in the striatum
A. Phosphorylation of Thr308-Akt and Ser473-Akt was reduced in the striatum of mice treated with 2 mg/kg amphetamine for eight days. B. Phosphorylation of Ser21-GSK3α and Ser9-GSK3β was reduced in mouse striatum after eight days of amphetamine treatment. Values are presented as percent of matched control mice. Means ± SEM. n=3. *, p≤0.05.
FIGURE 2
FIGURE 2. Amphetamine treatment for eight days increases phosphorylation of Akt and GSK3 in the cerebral cortex
A. Phosphorylation of Thr308-Akt was increased in the cerebral cortex of mice treated for eight days with 2 mg/kg amphetamine. B. Phosphorylation of Ser21-GSK3α and Ser9-GSK3β in the cerebral cortex was increased after amphetamine treatment for eight days. Values are presented as percent of matched control mice. Means ± SEM. n=3. *, p≤0.05.
FIGURE 3
FIGURE 3. Amphetamine treatment for eight days increases phosphorylation of Akt and reduces phosphorylation of GSK3 in the hippocampus
A. Hippocampal Thr308-Akt phosphorylation was increased after 2 mg/kg amphetamine treatment for eight days. B. Hippocampal Ser21-GSK3α and Ser9-GSK3β phosphorylation was increased after administration of amphetamine for eight days. Values are presented as percent of matched control mice. Means ± SEM. n=3. *, p≤0.05.
FIGURE 4
FIGURE 4. Methylphenidate treatment for eight days mimics amphetamine-induced alterations in phosphorylation of Akt and GSK3 in the striatum
A. Treatment with 20 mg/kg methylphenidate for eight days reduced striatal phosphorylation of Thr308-Akt and Ser473-Akt. B. Phospho-Ser21-GSK3α and phospho-Ser9-GSK3β were reduced in striatum after methylphenidate treatment for eight days. Values are presented as percent of matched control mice. Means ± SEM. n=3. *, p≤0.05.
FIGURE 5
FIGURE 5. Methylphenidate treatment for eight days increases phosphorylation of Akt and reduces phosphorylation of GSK3 in the cerebral cortex
A. Phospho-Thr308-Akt and phospho-Ser473-Akt were increased in the cerebral cortex after 20 mg/kg methylphenidate treatment for eight days. B. Phospho-Ser21-GSK3α and phospho-Ser9-GSK3β were increased in the cerebral cortex after methylphenidate treatment for eight days. Values are presented as percent of matched control mice. Means ± SEM. n=3. *, p≤0.05.
FIGURE 6
FIGURE 6. Methylphenidate treatment for eight days increases phosphorylation of Akt and reduces phosphorylation of GSK3 in the hippocampus
A. Phospho-Ser473-Akt was increased in hippocampus from mice treated with 20 mg/kg methylphenidate for eight days. B. Phospho-Ser21-GSK3α and phospho-Ser9-GSK3β were increased in the cerebral cortex after methylphenidate treatment for eight days. Values are presented as percent of matched control mice. Means ± SEM. n=3. *, p≤0.05.
FIGURE 7
FIGURE 7. Regulation of the β-arrestin/Akt/GSK3 signaling complex
Akt was immunoprecipitated, followed by immunoblotting for GSK3 and β-arrestin, from (A) striatum after eight days of amphetamine treatment, (B) striatum after eight days of methylphenidate treatment, (C) cerebral cortex after eight days of amphetamine treatment, and (D) cerebral cortex after eight days of methylphenidate treatment. Values are normalized to results from stimulant-free control mice. Means ± SEM. n=4. *, p≤0.05.
FIGURE 7
FIGURE 7. Regulation of the β-arrestin/Akt/GSK3 signaling complex
Akt was immunoprecipitated, followed by immunoblotting for GSK3 and β-arrestin, from (A) striatum after eight days of amphetamine treatment, (B) striatum after eight days of methylphenidate treatment, (C) cerebral cortex after eight days of amphetamine treatment, and (D) cerebral cortex after eight days of methylphenidate treatment. Values are normalized to results from stimulant-free control mice. Means ± SEM. n=4. *, p≤0.05.
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