Development and Characterization of a Novel Animal Model of Intermittent MDMA (“Ecstasy”) Exposure during Adolescence

Abstract

Adult animals treated with high doses of MDMA ("ecstasy") either on a single day or for several consecutive days show numerous behavioral changes as well as persistent reductions in brain serotonin (5-HT) concentrations and 5-HT transporter (SERT) protein expression. However, such dosing regimens do not adequately mimic the intermittent use patterns commonly seen in adolescent recreational ecstasy users. We have developed and characterized a rat model of intermittent adolescent MDMA exposure that simulates many of the features of human weekend use. Animals treated with our dosing regimen experience only small increases in core body temperature, and their plasma MDMA levels compare favorably with the levels reported for heavy ecstasy users under naturalistic conditions when species differences in drug clearance rates are taken into account. Intermittent adolescent MDMA exposure causes later deficits in object-recognition memory, increased impulsivity in the elevated plus-maze, and reduced sensitivity to a 5-HT(1A) agonist challenge. SERT-immunoreactive fiber density is significantly reduced in the hippocampus but not the neocortex, suggesting that the hippocampus may be particularly vulnerable to moderate MDMA exposure during adolescence. Finally, adolescent MDMA-treated animals are protected (i.e., show tolerance) against the neurotoxic and depressant effects of a subsequent MDMA "binge" challenge. We believe that the present animal model has important clinical relevance based on the similarities between the model and the reported effects of regular ecstasy use.