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Effects of Chronic Administration of THC on MDMA-Induced Physiological, Behavioral, and Neurochemical Alterations

Most recreational users of 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down, such as agitation and insomnia. Although previous animal studies have explored the acute effects of co-administering MDMA and Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. The four experiments included in the current dissertation were designed to provide a wide breadth of information on the physiological, behavioral, and neurochemical effects of intermittent MDMA administration combined with daily THC exposure using a dosing regimen designed to reflect a clinically-relevant pattern of human ecstasy and cannabis co-usage. Because ecstasy and cannabis abuse usually starts during human adolescence, drug treatment was administered from postnatal day (PD) 35 to 60 in order to target the period of rat development lasting from approximately mid-adolescence to early adulthood. In addition, the dosing regimen in rats was also chosen to best correlate to patterns of human ecstasy and marijuana use. Drug-treated rats received two subcutaneous (s.c.) injections of 10 mg/kg of (±) MDMA-HCL every fifth day and/or a single daily intraperitoneal (i.p.) injection of 5 mg/kg of THC every day. The twice every fifth day MDMA dosing regimen was designed to simulate the intermittent weekend usage of ecstasy at "rave" parties and the "boosting" behavior (taking additional doses of MDMA in the same session to maintain desired effects) that has been noted in human users. THC was administered daily to simulate heavy cannabis usage in humans, which has been defined to mean using cannabis more than seven times per week. While THC helped to alleviate MDMA-induced anxiety-like, impulsivity-like, and exploratory behavior, co-administration of MDMA and THC additively produced depressive-like behavior and deficits in spatial memory. Furthermore, our experiments provide physiological and neurochemical evidence that helps to explain the behavioral outcomes, specifically as THC failed to protect against MDMA-induced neurotoxicity in the hippocampus, the brain region that is responsible for processing of spatial memory information, in both the SERT binding assay and in SERT autoradiography. Finally, our data suggested that male rats are more susceptible to MDMA-induced damages than females--which has significant implications for assessing the risks of recreational ecstasy and cannabis co-usage in humans.
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