The anxiolytic- and antidepressant-like effects of ATPM-ET, a novel κ agonist and μ partial agonist, in mice.
Opioid receptors are implicated in the regulation of motivation and emotion. However, animal studies show that activation of κ opioid receptor produces contrasting mood-altering effects in models of anxiety-like and depressive-like behaviors, and consequently, the role of κ receptor in mood control remains unsettled. The effect of κ/μ opioid combination in emotion regulation was unexplored.



The aim of the study was to investigate the effects of (-)-3-N-ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a novel κ agonist and μ partial agonist, in regulating emotional responses.



The emotional responses of ATPM-ET were detected in the elevated plus maze (EPM), open field test (OFT), forced swim test (FST), and tail suspension test (TST). Selective κ antagonist nor-binaltorphimine (nor-BNI) and μ antagonist β-funaltrexamine (β-FNA) were applied to determine the type of receptor involved. The conditioned place aversion model was used to evaluate the effects on aversive emotion.



In the EPM and OFT, ATPM-ET (1 and 2 mg/kg, s.c.) significantly increased the time spent in the open arm and in the central area, respectively. In the FST and TST, ATPM-ET (0.5 and 1 mg/kg, s.c.) significantly reduced the duration of immobility. These effects were prevented by nor-BNI (10 mg/kg, i.p., -24 h), but not by β-FNA (10 and20 mg/kg, i.p., -24 h) pretreatment. At the dose of 2 mg/kg, ATPM-ET did not induce conditioned place aversion.



ATPM-ET, at doses from 0.5 to 2 mg/kg, produced anxiolytic- and antidepressant-like effects without inducing aversive emotion. These effects were more closely mediated by activation of κ receptor than μ receptor.
College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
Qian
Q
Wang
College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
Yu
Y
Long
Pharmacology and Toxicology Department, Shanghai Institute for Food and Drug Control, Shanghai, 201203, China.
Ai
A
Hang
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, 201203, China.
Gui-Ying
GY
Zan
College of Pharmacy, Dalian Medical University, Dalian, 116044, China. schuxh@126.com.
Xiao-Hong
XH
Shu
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, 201203, China. yjwang@mail.simm.ac.cn.
Yu-Jun
YJ
Wang
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, 201203, China.
Jing-Gen
JG
Liu
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D001362:Avoidance Learning / Q000187:drug effects; D004644:Emotions / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension / Q000523:psychology; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D009019:Morphinans / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors
C557443:3-N-ethylaminothiazolo(5,4-b)-N-cyclopropylmethylmorphinan hydrochloride; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C051844:norbinaltorphimine; D009271:Naltrexone; C024524:beta-funaltrexamine
ATPM-ET; Emotional response; κ agonist; μ partial agonist