Repeated Adolescent 3,4-Methylenedioxymethamphetamine (MDMA) Exposure in Rats Attenuates the Effects of a Subsequent Challenge with MDMA or a 5-Hydroxytryptamine_(1A) Receptor Agonist

摘要

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)te-tralin (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 hypo-activity otherwise observed on the day after the challenge,and also prevented MDMA-induced serotonin neurotoxicity as-sessed on PD 74 by measuring regional pHjcitalopram binding to the serotonin transporter (SERT).Adolescent MDMA-treated animals also showed a partial attenuation of the serotonin syndrome but not the hypothermia response to the high dose of 8-OH-DPAT.However,there was no effect of MDMA adminis-tration on regional [~3H]N-[2-[4-(2-methoxyphenyl)-1-piperazi-nyl]ethyl]-/V-(2-pyridinyl)cyclohexanecarboxamidetrihydrochlo-ride (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.