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Updated: Jun 18, 2026
A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Methamphetamine preconditioning alters midbrain transcriptional responses to methamphetamine-induced injury in the
Jean Lud Cadet1, Michael T McCoy, Ning Sheng Cai
1Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, Baltimore, MD, USA. jcadet@intra.nida.nih.gov
Abstract:
Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Quantitative PCR confirmed METH-induced changes in genes of interest and identified additional genes that were differentially impacted by the toxic METH challenge in the presence of METH preconditioning. These genes include small heat shock 27 kD 27 protein 2 (HspB2), thyrotropin-releasing hormone (TRH), brain derived neurotrophic factor (BDNF), c-fos, and some encoding antioxidant proteins including CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx)-1, and heme oxygenase-1 (Hmox-1). These observations are consistent, in part, with the transcriptional alterations reported in models of lethal ischemic injuries which are preceded by ischemic or pharmacological preconditioning. Our findings suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. Further analysis of the molecular and cellular pathways regulated by these genes should help to provide some insight into the neuroadaptive potentials of the brain when repeatedly exposed to drugs of abuse.
Insights
Repeated low doses of methamphetamine (METH) protect the brain against METH toxicity by altering gene expression. This METH preconditioning enhances neuroprotection against dopamine depletion.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Methamphetamine (METH) is a neurotoxic illicit drug causing dopamine and serotonin depletion.
- Low-dose METH preconditioning can protect against high-dose METH toxicity.
- The underlying transcriptional changes are not fully understood.
Purpose of the Study:
- To investigate transcriptional changes associated with METH preconditioning.
- To determine if preconditioning renders the nigrostriatal dopaminergic system resistant to METH toxicity.
- To identify specific genes involved in this neuroprotective effect.
Main Methods:
- Animal models exposed to METH preconditioning followed by a toxic METH challenge.
- Quantitative PCR (qPCR) to measure gene expression changes.
- Analysis of gene expression differences between preconditioned and non-preconditioned groups.
Main Results:
- METH preconditioning significantly protected against striatal dopamine depletion.
- Substantial differences in gene expression were observed between preconditioned and non-preconditioned groups after toxic METH challenge.
- Key genes identified include HspB2, TRH, BDNF, c-fos, CuZnSOD, GPx-1, and Hmox-1.
Conclusions:
- METH preconditioning induces protective transcriptional changes in the nigrostriatal dopaminergic system.
- Multiple molecular pathways, including those involving heat shock proteins, neurotrophic factors, and antioxidants, contribute to neuroprotection.
- These findings offer insights into the brain's adaptive responses to repeated drug exposure and potential therapeutic strategies.
