title: The antidepressant-like pharmacological profile of Yuanzhi-1, a novel serotonin, norepinephrine and dopamine reuptake inhibitor.
abstract: Triple reuptake inhibitors that block dopamine transporters (DATs), norepinephrine transporters (NETs), and serotonin transporters (SERTs) are being developed as a new class of antidepressants that might have better efficacy and fewer side effects than traditional antidepressants. In this study, we performed in vitro binding and uptake assays as well as in vivo behavioural tests to assess the pharmacological properties and antidepressant-like efficacy of Yuanzhi-1. In vitro, Yuanzhi-1 had a high affinity for SERTs, NETs, and DATs prepared from rat brain tissue (Ki=3.95, 4.52 and 0.87nM, respectively) and recombinant cells (Ki=2.87, 6.86 and 1.03nM, respectively). Moreover, Yuanzhi-1 potently inhibited the uptake of serotonin (5-hydroxytryptamine; 5-HT), norepinephrine (NE) and dopamine (DA) into rat brain synaptosomes (Ki=2.12, 4.85 and 1.08nM, respectively) and recombinant cells (Ki=1.65, 5.32 and 0.68nM, respectively). In vivo, Yuanzhi-1 decreased immobility in a dose-dependent manner, which was shown among rats via the forced-swim test (FST) and mice via the tail-suspension test (TST). The results observed in the behavioural tests did not appear to result from the stimulation of locomotor activity. Repeated Yuanzhi-1 treatment (2.5, 5 or 10mg/kg) significantly reversed depression-like behaviours in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis studies showed that 5- and 10-mg/kg administrations of Yuanzhi-1 significantly increased the extracellular concentrations of 5-HT, NE and DA in the frontal cortices of freely moving rats. Therefore, Yuanzhi-1 might represent a novel triple reuptake inhibitor and possess antidepressant-like activity.
authors: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Zeng-liang
authors: ZL
authors: Jin
authors: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Nana
authors: N
authors: Gao
authors: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Xiao-rong
authors: XR
authors: Li
authors: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Yu
authors: Y
authors: Tang
authors: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Jie
authors: J
authors: Xiong
authors: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China.
authors: Hong-xia
authors: HX
authors: Chen
authors: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China.
authors: Rui
authors: R
authors: Xue
authors: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China. Electronic address: lyf619@aliyun.com.
authors: Yun-Feng
authors: YF
authors: Li
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015283:Citalopram / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000166:cytology; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005518:Food Preferences / Q000187:drug effects; D005625:Frontal Lobe / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018377:Neurotransmitter Agents / Q000493:pharmacokinetics; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use; D013395:Sucrose / Q000008:administration & dosage; D013574:Synaptosomes / Q000187:drug effects*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000928:Antidepressive Agents; D004365:Drugs, Chinese Herbal; D018377:Neurotransmitter Agents; D014179:Neurotransmitter Uptake Inhibitors; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D012503:Saponins; C000604075:yuanzhi-1; D015283:Citalopram; D014316:Tritium; D013395:Sucrose
keywords: Animal models; Antidepressants; Triple reuptake inhibitors; Yuanzhi-1