Adolescent users of 3,4-methylenedioxymethamphetamine (
MDMA, Ecstasy) may escalate their dose because of the development of tolerance. We examined the influence of intermittent adolescent
MDMA exposure on the behavioral, physiological, and neurochemical responses to a subsequent
MDMA "binge" or to a 5-hydroxytryptamine(1A) (5-HT(1A)) receptor challenge. Male Sprague-Dawley rats were given
MDMA (10 mg/kg b.i.d.) or saline every 5th day on postnatal days (PDs) 35 to 60. One week later on PD 67, animals were challenged with either multiple doses of
MDMA (four 5 or 10 mg/kg doses) or a single dose of the 5-HT(1A) agonist
8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.1 or 0.5 mg/kg). Adolescent
MDMA exposure partially attenuated the hyperthermic effects of the PD 67
MDMA challenge, completely blocked the locomotor hypoactivity otherwise observed on the day after the challenge, and also prevented
MDMA-induced
serotonin neurotoxicity assessed on PD 74 by measuring regional [(3)H]
citalopram binding to the
serotonin transporter (SERT). Adolescent
MDMA-treated animals also showed a partial attenuation of the
serotonin syndrome but not the hypothermic response to the high dose of
8-OH-DPAT. However, there was no effect of
MDMA administration on regional [(3)H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) binding to 5-HT(1A) receptors in the brain or spinal cord. These results suggest that chronic, intermittent
MDMA exposure during adolescence induces neuroadaptive changes that can protect against the adverse consequences of a subsequent dose escalation. On the other hand, the same exposure pattern appears to produce a partial
5-HT(1A) receptor desensitization, which may negatively influence the therapeutic responses of chronic
MDMA users treated with
serotonergic agents for various affective or
anxiety disorders.