3,4-Methylenedioxymethamphetamine (Ecstasy)-Induced Learning and Memory Impairments Depend on the Age of Exposure during Early Development

Abstract

Use of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has increased dramatically in recent years, yet little is known about its effects on the developing brain. Neonatal rats were administered MDMA on days 1-10 or 11-20 (analogous to early and late human third trimester brain development). MDMA exposure had no effect on survival but did affect body weight gain during treatment. After treatment, body weight largely recovered to 90-95% of controls. MDMA exposure on days 11-20 resulted in dose-related impairments of sequential learning and spatial learning and memory, whereas neonatal rats exposed on days 1-10 showed almost no effects. At neither stage of exposure did MDMA-treated offspring show effects on swimming ability or cued learning. Brain region-specific dopamine, serotonin, and norepinephrine changes were small and were not correlated to learning changes. These findings suggest that MDMA may pose a previously unrecognized risk to the developing brain by inducing long-term deleterious effects on learning and memory.

Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected

“…These results together strengthen the notion that 5HT suppletion after serotonergic drugs such as MDMA and fenfluramine produces spatial memory impairment. In addition, support for this serotonin hypothesis also comes from animal studies that have shown impairment of spatial memory after treatment with MDMA (Sprague et al 2003; Broening et al 2001) or d-fenfluramine (Morford et al 2002 as well. Sprague et al (2003) subsequently linked the MDMA-induced serotonergic lesions in the hippocampus to deficits seen in spatial memory.…”

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

“…Lower levels of dopamine metabolites were also detected in the caudate of squirrel monkeys and in the cerebral spinal fluid of women that used ecstasy [90,132]. Interestingly, either early or late neonatal (PD 1-10 or 11-20) MDMA caused subtle, yet significant, elevations in norepinephrine (7-15%) in the hippocampus of adult (PD 105) rats [11]. Even more striking, MDMA treatments to dams (GD 14 to 18) resulted in a five-fold increase in dopaminergic fiber density in the frontal cortex of offspring [76].…”

“…Neonatal MDMA (PD 11-20) diminished water maze learning and novel object exploration in adult-rats [27]. However, MDMA administration at earlier postnatal periods did not alter these endpoints [11,120]. Perhaps counter-intuitively, newborn rat offspring from mothers that received MDMA during pregnancy performed better on an olfactory discrimination task.…”

“…Perinatal exposure (PD 1-4, 20 mg/kg/day), decreased weight gain in male and female rat pups [99]. Treatments (10-40 mg/kg/day) during a longer period (PD 1-10 or 11-20) attenuated the body mass such that there were still small (5-10%) deficits in adulthood (PD 82) [11]. Importantly, as will also be discussed later, [166] determined that the amount of weight loss caused by MDMA was inadequate to affect learning and memory.…”

“…Similarly, adolescent rats lost over ten grams, 8% of pre-drug weight, only hours after MDMA treatments [121]. The molecular mechanisms of MDMA induced weight loss are incompletely understood but are quite likely to involve systemic norepinephrine release by this sympathomimetic and binding to alpha1 or beta3 adrenergic receptors followed by activation Body weight exhibits dose dependent reductions at all exposure ages tested [1,11,50,71,75,76,99,118,119,121,166,167]. Intermittent MDMA (20 mg/kg/day) delivery every fifth day from PD 35 to 60 to rats reduced the rate of weight gain [118,119].…”