Chronic stress precipitates drug seeking behavior and alters the effects of drugs of abuse. Although it is known that chronic stress potentiates acute neurochemical and hyperthermic responses to the drug of abuse methamphetamine, no studies have investigated if and how chronic stress alters other physiological responses to methamphetamine. Therefore the objective of these studies was to determine if 10 days of chronic unpredictable stress modulates corticosterone (CORT) responses to methamphetamine and furthermore how chronic stress may modulate methamphetamine-induced increases in hyperthermia and CORT. As chronic stress potentiates hyperthermic responses to serotonin 2 (5-HT2) stimulation and 5-HT2 receptors are important in mediating both hyperthermic and CORT responses, we also investigated if 5-HT2 antagonism would block hyperthermia and CORT secretion by the serial exposure to stress and methamphetamine (stress/methamphetamine). The results of these studies illustrate that stress potentiates methamphetamine-induced increases in body temperature and CORT secretion and that these increases are blocked by the 5-HT2 antagonist ketanserin. Furthermore, the combination of stress and methamphetamine depletes 5-HT content in the hippocampus 7 days after methamphetamine administration which is blocked by the 5-HT2 antagonist ketanserin. Overall, these results indicate a pharmacological mechanism for the depletion of hippocampal 5-HT by the serial exposure to stress and methamphetamine and further illustrate the deleterious interactions between chronic stress and methamphetamine use.
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