title: Differential substitution for the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and methylphenidate in rats.
abstract: Previous studies have demonstrated that methylphenidate, MDMA (3,4-methylenedioxymethamphetamine), and other psychostimulants exert stimulant-like subjective effects in humans. Furthermore, MDMA and methylphenidate substitute for the discriminative stimulus effects of psychostimulants, such as amphetamine and cocaine, in animals, which suggests that MDMA and methylphenidate may produce similar discriminative stimulus effects in rats. However, there is no evidence regarding the similarities between the discriminative stimulus effects of MDMA and methylphenidate. To explore this issue, cross-substitution, substitution, and combination tests were conducted in rats that had been trained to discriminate between MDMA (2.5 mg/kg) or methylphenidate (5.0 mg/kg) and saline. In the cross-substitution tests, MDMA and methylphenidate did not cross-substitute for each other. In the substitution test, methamphetamine substituted for the discriminative stimulus effects of methylphenidate, but not for those of MDMA. Furthermore, ephedrine and bupropion, which activate dopaminergic and noradrenergic systems, substituted for the discriminative stimulus effects of methylphenidate. On the other hand, serotonin (5-HT) receptor agonists 5-HT1A and 5-HT2 fully substituted for the discriminative stimulus effects of MDMA. These results suggest that activation of the noradrenergic and dopaminergic systems is important for the discriminative stimulus effects of methylphenidate, whereas activation of the serotonergic system is crucial for the discriminative stimulus effects of MDMA. Even though MDMA, like psychostimulants, exerts stimulant-like effects, our findings clearly indicate that the discriminative stimulus effects of MDMA are distinctly different from those of other psychostimulants in rats.
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.).
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Uzawa
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.).
authors.forename: Haruyo
authors.initials: H
authors.lastname: Kazawa
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.).
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.).
authors.forename: Ayano
authors.initials: A
authors.lastname: Mochizuki
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.).
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.).
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yoshizawa
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.).
authors.forename: Kimio
authors.initials: K
authors.lastname: Higashiyama
authors.affiliation: Department of Toxicology (T.M., N.U., H.K., H.W., A.M., M.S., T.S.) and Institute of Medicinal Chemistry (K.H.), Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan; and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan (K.Y.) suzuki@hoshi.ac.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D044348:Receptors, Serotonin, 5-HT2 / Q000502:physiology; D017480:Receptors, sigma / Q000502:physiology; D000097605:Sigma-1 Receptor
chemical_list: D001552:Benzazepines; D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D044282:Receptor, Serotonin, 5-HT1A; D044348:Receptors, Serotonin, 5-HT2; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C534628:SCH 23390