Chronic Fluoxetine Treatment Partly Attenuates the Long-Term Anxiety and Depressive Symptoms Induced by MDMA (‘Ecstasy’) in Rats

Abstract

Use of the drug 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') can have long-term adverse effects on emotion in both humans and laboratory animals. The present study examined whether chronic treatment with the antidepressant drug fluoxetine could reverse such effects. Male Wistar rats were briefly exposed to MDMA (4 Â 5 mg/kg over 4 h) or vehicle on 2 consecutive days. Approximately 9-12 weeks later, half of the rats received a dose of approximately 6 mg/kg/day fluoxetine in their drinking water for a 5-week period. Fluoxetine administration reduced fluid intake and body weight in MDMA and vehicle pretreated rats. After several weeks of fluoxetine treatment, rats were assessed on the social interaction test, the emergence test of anxiety and the forced swim model of depression. MDMA pretreated rats showed reduced social interaction, increased anxiety on the emergence test, and increased immobility and decreased active responses in the forced swim test. Fluoxetine treatment reversed MDMA-induced anxiety in the emergence test and depressive-like effects in the forced swim test, yet exhibited no effects on the social interaction test. MDMA pretreated rats had decreased 5-HT and 5-HIAA levels in limbic and cortical regions, and decreased density of serotonin transporter sites in the cortex. Fluoxetine treatment did not greatly affect 5-HT levels in MDMA pretreated rats, but significantly decreased 5-HIAA levels in all brain sites examined. Postmortem blood serum levels of fluoxetine and norfluoxetine did not differ in MDMA and vehicle pretreated rats. These results indicate that fluoxetine may provide a treatment option for some of the deleterious long-term effects resulting from MDMA exposure.

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

“…First, although the assessments of cognitive function and some measures of anxiety-like behavior were similar to those employed by McGregor's group (eg Gurtman et al, 2002;McGregor et al, 2003a, b;Thompson et al, 2004), the profile of MDMA-induced functional alterations was not identical. These discrepancies in outcome are likely due to a combination of factors, including differences in MDMA dosing regimen, rat strain, and possibly the intervals between drug administration and behavioral tests.…”

“…Nevertheless, Aguirre et al (1998) demonstrated that fluoxetine pretreatment prevented MDMA-induced enhancement of the hypothermic response to a subsequent challenge with 8-hydroxy-2-(di-n-propylamino)tetralin. Moreover, a recent study by Thompson et al (2004) found that chronic fluoxetine treatment following a neurotoxic dosing regimen of MDMA ameliorated many (though not all) of the behavioral changes observed in the MDMAtreated rats. In conjunction with the present results, these findings are consistent with the view that at least some of the short-and long-term functional consequences of MDMA administration are indeed mediated by altered serotonergic activity.…”

“…As both members of the pair provide data in the social-interaction paradigm, each rat was tested twice on two consecutive days with different partners. The average score of the two tests was used in all analyses (see Thompson et al, 2004).…”

“…These investigators have identified a constellation of changes, which they refer to as the MDMA syndrome, that includes a reduction in cognitive function in the object recognition test, increased anxiety-like behavior in the emergence test, and decreased social behavior in the social interaction test (Gurtman et al, 2002;McGregor et al, 2003a, b;Morley et al, 2001Morley et al, , 2004. The same group also determined that depressive-like behaviors were augmented following MDMA (McGregor et al, 2003b;Thompson et al, 2004). Other measures of complex behavior have yielded variable results with respect to the influence of MDMA treatment.…”

MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment

“…In rodents, a serotonin-selective drug inhibits MDMA-induced effects on the immune system and partly attenuates anxiety and depressive-like behaviors (Pacifici et al 2004;Thompson et al 2004). In human users, the serotonin-selective transport inhibitor citalopram reportedly attenuates the acute psychological (heightened mood, increased self-confidence, and enhanced sensory perception) effects of MDMA (Liechti et al 2000).…”