Adolescent 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') exposure in rats: Behavioral, neurochemical, and pharmocokinetic activity.

摘要

The drug +/-3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational substance among young people. Most prior research has not attempted to carefully emulate human ecstasy use patterns in animal investigations. The objectives of the present series of experiments were to develop a rat model of intermittent ecstasy use and to begin to characterize the acute and long-term physiological, behavioral, and neurochemical consequences of adolescent MDMA exposure. In Experiments I and II, male Sprague-Dawley rats received 20 mg/kg/day of MDMA on every fifth day from postnatal day 35 to 60. This regimen caused subtle reductions in cortical serotonin transporter (SERT) binding and dose dependently modified indices of attention, working memory, and anxiety-like behavior. Experiment III tested whether periadolescent MDMA exposure (10 mg/kg x 2) modified the responses to a MDMA binge (5 or 10 mg/kg x 4) in young adulthood. Adolescent MDMA completely blocked the hypoactivity and SERT reductions induced by adult MDMA treatments. Importantly, developmental MDMA exposure only partially reduced the hyperthermia evoked by the binge. The pharmacokinetic profile of early (PD 35) and late (PD 60) adolescent MDMA (10 mg/kg) treatments were compared in Experiment IV. Pharmacokinetic parameters (elimination half-life, peak concentration) did not differ by age for MDMA but PD 60 animals showed lower peak concentrations of the metabolite methylenedioxyamphetamine (MDA). Finally, the goal of Experiment V was to determine if MDMA induced decreases in SERT levels mediated the behavioral consequences. Rats received the binge (10 mg/kg x 4) in combination with pretreatment with the serotonin reuptake inhibitor citalopram (10 mg/kg). Citalopram blocked SERT reductions measured one week after dosing and prevented some of the MDMA induced alterations in complex behavior. These studies reveal that: (1) repeated exposure to a clinically relevant MDMA dose can reduce cognitive function and alter affective behavior, (2) adolescent MDMA can lead to MDMA tolerance in adulthood, (3) the behavioral toxicology of MDMA may not be exclusively mediated by decreases in SERT. Overall, these findings indicate that the enduring neurobiological consequences of MDMA may not be limited to the serotonergic system and have substantial public health implications for regular ecstasy users.; Keywords. Adolescence, Behavior, Memory, Serotonin transporter, Temperature, Weight