Neurochemical and Physiological Effects of Chronic Stress on Methamphetamine Toxicity

Chronic stress precipitates drug seeking behavior and relapse to drug taking. Therefore, the overall scope of this research was to determine how chronic unpredictable stress alters the neurochemical and physiological effects of the drug of abuse methamphetamine. In this regard, the effects of chronic stress on markers of dopamine uptake in the nucleus accumbens, glutamate transmission in the dorsal hippocampus, and serotonin 2A receptors in the hypothalamus were investigated. It was determined that chronic stress increases vesicular monoamine transporter 2 in the nucleus accumbens, increases excitatory amino acid transporter 2, vesicular glutamate transporter 1, and vesicular glutamate content in the dorsal hippocampus, and increases and decreases serotonin 2A receptor mRNA in the medial preoptic nucleus and paraventricular nucleus of the hypothalamus respectively. These chronic stress induced increases in vesicular monoamine transporter 2 within the nucleus accumbens were accompanied by a potentiation of dopamine release in response to methamphetamine. Similarly, stress-induced increases in markers of glutamate transmission resulted in a potentiated glutamate response to methamphetamine in the dorsal hippocampus. Additionally, chronic stress induced alterations in hypothalamic serotonin 2A receptors were accompanied by a potentiation of methamphetamine-induced increases in corticosterone and body temperature. Finally, the combination of chronic stress and methamphetamine produced a long-term decrease in serotonin tissue content in the hippocampus. The roles of glutamate, corticosterone, and hyperthermia in mediating this toxicity to serotonin in the hippocampus were investigated. It was determined that the potentiation of methamphetamine-induced increases in body temperature by stress was the key mediator in the toxicity to serotonin terminals within the hippocampus. The role of hyperthermia in mediating toxicity was independent of increases in oxidative stress and energy dysregulation as the combination of stress and methamphetamine did not alter protein carbonyl formation or mitochondrial function and antioxidant pre-administration failed to block serotonin depletions in the hippocampus. Overall, these studies illustrate an acute neurochemical mechanism via which chronic stress may enhance vulnerability to drug taking and demonstrate a mechanism via which chronic stress renders serotonin terminals in the hippocampus more vulnerable to the toxicity of methamphetamine.