Methamphetamine Self-Administration Differential Effects on Mesolimbic Glutathione Levels, Mitochondrial Respiration, and Dopamine Neuron Firing Activity

Abstract

Acute and neurotoxic regimens of METH are known to increase reactive oxygen species (ROS), affect redox homeostasis, and lead to cellular damage in dopamine neurons. However, functional changes induced by long-term METH self-administration on mitochondrial respiratory metabolism and redox homeostasis are less known. To fill this gap in our knowledge, we implanted adult mice with a jugular catheter and trained them to nose poke for METH infusions in operant chambers. After completing several weeks of METH self-administration exposure, we collected samples of the ventral striatum (vSTR) and the ventral midbrain (vMB), containing the nucleus accumbens (NAc) and the ventral tegmental area (VTA), respectively. We used HPLC to determine the levels of the ROS scavenger glutathione in its reduced (GSH) and oxidized (GSSG) forms. Then, we used high-resolution respirometry to determine the oxygen consumption rate (OCR) of mitochondrial complexes under several substrates and inhibitors. Finally, we used in vivo single-unit extracellular recordings to assess changes in dopamine neuron firing activity in the VTA. METH self-administration produces a progressive decrease of the GSH pool in vST, which correlates with METH lifetime intake. We observed increased mitochondrial respiration across the two mesolimbic regions, but only vMB OCR correlates with METH lifetime intake. We recorded an increased number of spontaneously active dopamine neurons with decreased firing rate and burst activity in the VTA. METH lifetime intake inversely correlates with firing rate, the percentage of spikes in a burst, and directly correlates with the number of neurons per track. We conclude that METH self-administration progressively decreased the antioxidant pool in sites of higher dopamine release and produced an increased 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 in response to the prolonged effects of METH on dopamine release and circuitry feedback.