Methamphetamine (METH) is an illicit toxic psychostimulant which is widely abused. Its toxic effects depend on the release of excessive levels of dopamine (DA) that activates striatal DA receptors. Inhibition of DA-mediated neurotransmission by the DA D1 receptor antagonist, SCH23390, protects against METH-induced neuronal apoptosis. The initial purpose of the present study was to investigate, using microarray analyses, the influence of SCH23390 on transcriptional responses in the rat striatum caused by a single METH injection at 2 and 4 hours after drug administration. We identified 545 out of a total of 22,227 genes as METH-responsive. These include genes which are involved in apoptotic pathways, endoplasmic reticulum (ER) stress, and in transcription regulation, among others. Of these, a total of 172 genes showed SCH23390-induced inhibition of METH-mediated changes. Among these SCH23390-responsive genes were several genes that are regulated during ER stress, namely ATF3, HSP27, Hmox1, HSP40, and CHOP/Gadd153. The secondary goal of the study was to investigate the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events. We thus used quantitative PCR to confirm changes in the METH-responsive ER genes identified by the microarray analyses. We also measured the expression of these genes and of ATF4, ATF6, BiP/GRP78, and of GADD34 over a more extended time course. SCH23390 attenuated or blocked METH-induced increases in the expression of the majority of these genes. Western blot analysis revealed METH-induced increases in the expression of the antioxidant protein, Hmox1, which lasted for about 24 hours after the METH injection. Additionally, METH caused DA D1 receptor-dependent transit of the Hmox1 regulator protein, Nrf2, from cytosolic into nuclear fractions where the protein exerts its regulatory functions. When taken together, these findings indicate that SCH23390 can provide protection against neuronal apoptosis by inhibiting METH-mediated DA D1 receptor-mediated ER stress in the rat striatum. Our data also suggest that METH-induced toxicity might be a useful model to dissect molecular mechanisms involved in ER stress-dependent events in the rodent brain. Therapies that interefere with actvitation of these receptors might be helpful to combat neurotxicity in human addicts.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$231,548
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
Krasnova, Irina N; Chiflikyan, Margarit; Justinova, Zuzana et al. (2013) CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat. Neurobiol Dis 58:132-43
Saint-Preux, F; Bores, L R; Tulloch, I et al. (2013) Chronic co-administration of nicotine and methamphetamine causes differential expression of immediate early genes in the dorsal striatum and nucleus accumbens of rats. Neuroscience 243:89-96
Cadet, Jean Lud; Jayanthi, Subramaniam (2013) Epigenetics of methamphetamine-induced changes in glutamate function. Neuropsychopharmacology 38:248-9
Jayanthi, Subramaniam; McCoy, Michael T; Beauvais, Genevieve et al. (2009) Methamphetamine induces dopamine D1 receptor-dependent endoplasmic reticulum stress-related molecular events in the rat striatum. PLoS One 4:e6092
Xi, Z-X; Kleitz, H K; Deng, X et al. (2009) A single high dose of methamphetamine increases cocaine self-administration by depletion of striatal dopamine in rats. Neuroscience 161:392-402
Krasnova, Irina N; Hodges, Amber B; Ladenheim, Bruce et al. (2009) Methamphetamine treatment causes delayed decrease in novelty-induced locomotor activity in mice. Neurosci Res 65:160-5