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A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Long-term methamphetamine self-administration increases mesolimbic mitochondrial oxygen consumption and decreases
Sergio Dominguez-Lopez1, Bumsoo Ahn2, Kavithalakshmi Sataranatarajan2
1Department of Anatomy and Neurobiology, University of Maryland, School of Medicine, Baltimore, MD, 21201, USA; Aging and Metabolism Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
Abstract:
Neurotoxic regimens of methamphetamine (METH) are known to increase reactive oxygen species (ROS), affect redox homeostasis, and lead to damage in dopamine neurons. Functional changes induced by long-term METH self-administration on mitochondrial respiratory metabolism and redox homeostasis are less known. To fill this gap, we implanted a jugular catheter into adult male mice and trained them to nose poke for METH infusions. After several weeks of METH exposure, we collected samples of the ventral striatum (vST) and the ventral midbrain (vMB). We used HPLC to determine the levels of the ROS scavenger glutathione in its reduced (GSH) and oxidized forms. Then, we used high-resolution respirometry to determine the oxygen consumption rate (OCR) of mitochondrial complexes. Finally, using in vivo electrophysiology, we assessed changes in dopamine neuron firing activity in the VTA. METH self-administration produced a decrease of the GSH pool in vST, correlating with lifetime METH intake. We observed increased mitochondrial respiration across the two mesolimbic regions. METH self-administration decreases firing rate and burst activity but increases the number of spontaneously active dopamine neurons per track. We conclude that METH self-administration progressively decreased the antioxidant pool in sites of higher dopamine release and produced an increase in mitochondrial metabolism in the mesolimbic areas, probably derived from the increased number of dopamine neurons actively firing. However, dopamine neuron firing activity is decreased by METH self-administration, reflecting a new basal level of dopamine neurotransmission.
Insights
Long-term methamphetamine (METH) use depletes antioxidants and increases mitochondrial metabolism in dopamine-rich brain areas. This study reveals how METH self-administration alters dopamine neuron function and brain redox balance.
Area of Science:
- Neuroscience
- Neuropharmacology
- Biochemistry
Background:
- Methamphetamine (METH) neurotoxicity is linked to increased reactive oxygen species (ROS) and dopamine neuron damage.
- The effects of chronic METH self-administration on mitochondrial respiration and redox homeostasis remain poorly understood.
Purpose of the Study:
- To investigate the functional changes in mitochondrial metabolism and redox balance in dopamine neurons following long-term METH self-administration.
- To assess alterations in dopamine neuron activity and antioxidant levels in specific mesolimbic regions.
Main Methods:
- Adult male mice underwent jugular catheterization for METH self-administration via nose-poking.
- High-performance liquid chromatography (HPLC) measured glutathione (GSH) levels.
- High-resolution respirometry assessed mitochondrial oxygen consumption rates (OCR).
- In vivo electrophysiology recorded dopamine neuron firing activity in the ventral tegmental area (VTA).
Main Results:
- METH self-administration decreased the reduced glutathione (GSH) pool in the ventral striatum (vST), correlating with METH intake.
- Mitochondrial respiration rates increased in both ventral striatum (vST) and ventral midbrain (vMB) regions.
- Dopamine neuron firing rate and burst activity decreased, while the number of spontaneously active neurons increased.
Conclusions:
- Chronic METH self-administration depletes the antioxidant pool (GSH) in dopamine release sites and enhances mitochondrial metabolism.
- Increased mitochondrial activity may be linked to a higher number of actively firing dopamine neurons.
- Overall dopamine neuron firing activity is reduced, indicating a recalibrated basal neurotransmission level.
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