title: Evaluation of brain SERT occupancy by resveratrol against MDMA-induced neurobiological and behavioral changes in rats: A 4-[¹⁸F]-ADAM/small-animal PET study.
abstract: The misuse of 3,4-methylenedioxymethamphetamine (MDMA) has drawn a growing concern worldwide for its psychophysiological impacts on humans. MDMA abusers are often accompanied by long-term serotonergic neurotoxicity, which is associated with reduced density of cerebral serotonin transporters (SERT) and depressive disorders. Resveratrol (RSV) is a natural polyphenolic phytoalexin that has been known for its antidepressant and neuroprotective effects. However, biological targets of RSV as well as its neuroprotective effects against MDMA remained largely unknown. In this study, we examined binding potency of RSV and MDMA to SERT using small-animal positron emission tomography (PET) with the SERT radioligand, N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) and investigated the protection of RSV against the acute and long-term adverse effects of MDMA. We found that RSV exhibit binding potentials to SERT in vivo in a dose-dependent manner with variation among brain regions. When the MDMA-treated rats (10mg/kg, s.c.) were co-injected with RSV (20mg/kg, i.p.) twice daily for 4 consecutive days, MDMA-induced acute elevation in plasma corticosterone was significantly reduced. Further, 4-[(18)F]-ADAM PET imaging revealed that RSV protected against the MDMA-induced decrease in SERT availability in the midbrain and the thalamus 2 weeks following the co-treatment. The PET data were comparable to the observation from the forced swim test that RSV sufficiently ameliorated the depressive-like behaviors of the MDMA-treated rats. Together, these findings suggest that RSV is a potential antidepressant and may confer protection against neurobiological and behavioral changes induced by MDMA.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Jui-Hu
authors.initials: JH
authors.lastname: Shih
authors.affiliation: Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Kuo-Hsing
authors.initials: KH
authors.lastname: Ma
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chien-Fu F
authors.initials: CF
authors.lastname: Chen
authors.affiliation: Department of Nuclear Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Health-Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
authors.forename: Li-Heng
authors.initials: LH
authors.lastname: Pao
authors.affiliation: Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shao-Ju
authors.initials: SJ
authors.lastname: Weng
authors.affiliation: Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yuahn-Sieh
authors.initials: YS
authors.lastname: Huang
authors.affiliation: Department of Nuclear Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chyng-Yann
authors.initials: CY
authors.lastname: Shiue
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan; Ministry of Health and Welfare, Taiwan.
authors.forename: Ming-Kung
authors.initials: MK
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan. Electronic address: lhs01077@gmail.com.
authors.forename: I-Hsun
authors.initials: IH
authors.lastname: Li
mesh_terms: D000818:Animals; D001596:Benzylamines; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D001931:Brain Mapping; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D016601:RNA-Binding Proteins / Q000378:metabolism*; D019275:Radiopharmaceuticals; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D018490:Serotonin Agents / Q000633:toxicity; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D001596:Benzylamines; D005462:Fluorine Radioisotopes; C475911:N,N-dimethyl-2-(2-amino-4-fluorophenylthio)benzylamine; D018696:Neuroprotective Agents; D016601:RNA-Binding Proteins; D019275:Radiopharmaceuticals; D018490:Serotonin Agents; C482440:Sert1 protein, rat; D013267:Stilbenes; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D000077185:Resveratrol; D003345:Corticosterone
keywords: 4-[(18)F]-ADAM; MDMA; Occupancy; Resveratrol; Serotonin transporter; Small-animal PET