Striatal dopamine and glutamate receptors modulate methamphetamine-induced cortical Fos expression

Abstract

Methamphetamine (mAMPH) is a psychostimulant drug that increases extracellular levels of monoamines throughout the brain. It has previously been observed that a single injection of mAMPH increases immediate early gene (IEG) expression in both the striatum and cerebral cortex. Moreover, this effect is modulated by dopamine and glutamate receptors since systemic administration of dopamine or glutamate antagonists has been found to alter mAMPH-induced striatal and cortical IEG expression. However, because dopamine and glutamate receptors are found in extra-striatal as well as striatal brain regions, studies employing systemic injection of dopamine or glutamate antagonists fail to localize the effects of mAMPH-induced activation. In the present experiments, the roles of striatal dopamine and glutamate receptors in mAMPH-induced gene expression in the striatum and cerebral cortex were examined. The nuclear expression of Fos, the protein product of the IEG c-fos, was quantified in both the striatum and the cortex of animals receiving intrastriatal dopamine or glutamate antagonist administration. Intrastriatal infusion of dopamine (D1 or D2) or glutamate [N-methyl-D-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)] antagonists affected not only mAMPH-induced striatal, but also cortical, Fos expression. Overall, the effects of the antagonists occurred dose-dependently, in both the infused and non-infused hemispheres, with greater influences occurring in the infused hemisphere. Finally, unilateral intrastriatal infusion of dopamine or glutamate antagonists changed the behavior of the rats from characteristic mAMPH-induced stereotypy to rotation ipsilateral to the infusion. These results demonstrate that mAMPH's actions on striatal dopamine and glutamate receptors modulate the widespread cortical activation induced by mAMPH. It is hypothesized that dopamine release from nigrostriatal terminals modulates activity within striatal efferent pathways, thereby disinhibiting thalamo-cortical circuits. By extension, these results suggest processes through which repeated exposure to mAMPH might influence cortical function in mAMPH abusers.

Figure 1

Schematic diagrams depicting cannula track and sampling areas in which Fos protein expression was measured. A.) Schematic diagram depicting guide cannula and infusion cannula placement. Tips of infusion cannula are denoted by “*” and illustrate the representative distribution of infusion tips from multiple treatment groups that were verified by cresyl violet histological examination. B.) A representative cresyl violet-stained coronal section depicting cannula placement in the right striatum at a middle striatal level (0.4 mm anterior to Bregma, Paxinos and Watson, 2003). C.) Schematic diagram of a coronal section depicting approximate sampling areas used for Fos quantification. Fos protein expression was measured in the cingulate (1), motor (2), somatosensory (3), insular (4) and piriform (5) cortices, and the striatum (6) at a rostral striatal level ( ca. 2.0 mm anterior to Bregma). For panel B, background staining brightness/contrast were adjusted to optimize visualization of corpus collosum and infusion site (Adobe Photoshop CS2, Adobe Systems, Inc.).

Figure 2

Representative Fos photomicrographs (100x magnification) depicting Fos+ immunoreactive nuclei in the striatum, motor cortex, insular cortex, and cingulate cortex in rats that received an intrastriatal infusion of saline (1 µl; left column), SCH23390 (2 µg/µl; middle column), or AP5 (5 µg/µl; right column) followed by a systemic injection of mAMPH (4 mg/kg). Scale bar = 200 µm. Fos immunoreactive images were adjusted for brightness and contrast to normalize background and enhance visualization of Fos-positive nuclei (Adobe Photoshop CS2, Adobe Systems, Inc.).

Figure 3

Fos protein expression levels in the striatum and cerebral cortex after intrastriatal infusion of the D1 receptor antagonist SCH23390, or the D2 receptor antagonist sulpiride, followed by mAMPH injection. Mean (± SEM) proportional area (x 100) measured in the striatum, the cingulate cortex, motor cortex, somatosensory cortex, piriform cortex, and insular cortex, in the infused (left panels) and non-infused (right panels) hemispheres. Rats received an intrastriatal infusion of saline (1µl), SCH23390 (1 µg/µl or 2 µg/µl; top panels), or sulpiride (75 ng/µl or 200 ng/µl; lower panels), before an injection of mAMPH (1 injection x 4 mg/kg). SCH23390 treatment groups include (intrastriatal infusion/systemic injection): saline/saline (n=4), SCH23390 (2 µg/µl)/saline(n=5), saline/mAMPH (n=8), SCH23390 (1 µg/µl)/mAMPH (n=5), SCH23390(2 µg/µl)/mAMPH (n=13); sulpiride treatment groups include: saline/saline (n=4), sulpiride(200 ng/µl)/saline (n=4), saline/mAMPH (n=8), sulpiride(75 ng/µl)/mAMPH (n=6), sulpiride(200 ng/1µl)/mAMPH (n=6). *p < .05, **p < .01, ***p < .001.

Figure 4

Fos protein expression levels in the striatum and cerebral cortex after intrastriatal infusion of the NMDA receptor antagonist AP5, or the AMPA receptor antagonist DNQX, followed by mAMPH injection. Mean (± SEM) proportional area (x 100) measured in the striatum, the cingulate cortex, the motor cortex, sensory cortex, piriform cortex, and insular cortex, in the infused (left panels) and non-infused (right panels) hemispheres. Rats received an intrastriatal infusion of saline (1µl), AP5 (2 µg/µl or 5 µg/µl; top panels), or DNQX (0.5 µg/µl or 1.5 µg/µl; lower panels), before an injection of mAMPH (1 injection x 4 mg/kg). AP5 treatment groups include: saline/saline (n=4), AP5 (5 µg/µl)/saline (n=5), saline/mAMPH (n=8), AP5 (2 µg/µl)/mAMPH (n=5), AP5(5 µg/µl)/mAMPH (n=5); DNQX treatment groups include: PBS/saline (n=3), DNQX (1.5 µg/µl)/saline (n=3), PBS/mAMPH (n=6), DNQX (0.5 µg/µl)/mAMPH (n=4), DNQX (1.5 µg/µl)/mAMPH (n=6). *p < .05, **p < .01, ***p < .001.