Chronic Stress Enhances the Corticosterone Response and Neurotoxicity to +3,4-Methylenedioxymethamphetamine (MDMA): The Role of Ambient Temperature
Journal of Pharmacology and Experimental Therapeutics – July 16, 2010
Source: OpenAlex
Summary
Chronic unpredictable stress significantly amplifies the harmful effects of MDMA, a popular psychostimulant. In a study involving rats subjected to 10 days of stress, MDMA administration (5 mg/kg) led to heightened hyperthermia and increased plasma corticosterone levels. Notably, serotonin levels dropped by over 50% in key brain areas, such as the striatum and hippocampus. Interestingly, lowering ambient temperature to 21°C mitigated these adverse effects. While blocking corticosterone synthesis with metyrapone reduced its secretion, it did not impact serotonin or dopamine depletions, highlighting hyperthermia's critical role in stress-related drug responses.
Abstract
Stress facilitates drug abuse by humans. In rodents, stress enhances the neurochemical, neuroendocrine, and behavioral responses to psychostimulants. Although chronic unpredictable stress (CUS) enhances the acute hyperthermic and long-term monoamine-depleting effects of the psychostimulant +3,4-methylenedioxymethamphetamine (MDMA), the roles of hyperthermia and corticosterone (CORT) in mediating the stress-induced enhancement of MDMA-induced serotonin (5-HT) and dopamine (DA) depletions are unknown. Rats were exposed to 10 days of CUS and then challenged with MDMA (5 mg/kg i.p. once every 2 h for a total of four injections). Prior exposure to CUS augmented MDMA-induced hyperthermia and plasma CORT secretion and the long-term depletions in 5-HT content in striatum, hippocampus, and frontal cortex and DA content in striatum. A reduced ambient temperature of 21°C attenuated the hyperthermia, CORT secretion, and 5-HT decreases after MDMA in nonstressed rats. The lower ambient temperature also prevented the augmented hyperthermia, CORT secretion, and enhanced 5-HT and DA depletions after MDMA in chronically stressed rats to levels exhibited by nonstressed, MDMA-treated rats. To investigate the role of CORT on monoamine depletions in response to MDMA, stressed and nonstressed rats were treated with the CORT synthesis inhibitor metyrapone during exposure to MDMA. Metyrapone prevented CORT secretion in both stressed and nonstressed rats but did not modify 5-HT or DA depletions in any brain region examined. This study suggests that enhanced CORT is a consequence of enhanced hyperthermia and the CUS-induced enhancements of MDMA-induced monoamine depletions may be mediated by hyperthermia but not CORT.