title: Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test.
abstract: Kappa opioid (KOP) receptor antagonists and delta opioid (DOP) receptor agonists have antidepressant-like effects in animal tests and may be useful for treatment-resistant depression in humans. In this study, we examined whether the combination of a KOP receptor antagonist and a DOP receptor agonist would produce a better than additive effect (i.e. synergy). LY2444296 is a short-acting selective nonpeptide KOP receptor antagonist. ADL5859 is a selective nonpeptide DOP receptor agonist which does not produce seizures and EEG disturbances. Each compound and combinations of the two were examined in the forced swim test (FST) one h post injection, a screening test for antidepressant-like effect, in male adult C57BL/6J mice (Jackson Lab). LY2444296 [subcutaneous (s.c.) injection] at 10 and 30mg/kg, but not 3mg/kg, significantly decreased immobility time in a dose-dependent manner. Intraperitoneal (i.p.) injections of ADL5859 also reduced immobility time dose-dependently at doses of 3 and 10mg/kg, but not at 1mg/kg. An analysis was conducted using the method of Tallarida and Raffa (2010), which employed dose equivalence. The relative potency of the drugs was determined to be LY2444296: ADL5859=1:0.28, which was the dose ratio for combination studies. Six combinations of the two compounds were tested in mice at a fixed dose ratio. We found that LY2444296 and ADL5859 yielded significant synergistic effects for the antidepressant-like effect at the combined dose ranging from 3.84mg/kg to 9.0mg/kg. ADL5859 (10mg/kg), LY2444296 (30mg/kg) and their combined dose (3.84mg/kg) had no effects on locomotor activities. Since the two drugs have distinct pharmacological profiles, such a synergism will allow use of lower doses of both drugs to achieve desired antidepressant effects with fewer side effects.
authors.affiliation: Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Tunis
authors.affiliation: Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Parry
authors.affiliation: Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Tallarida
authors.affiliation: Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States. Electronic address: lliuche@temple.edu.
authors.forename: Lee-Yuan
authors.initials: LY
authors.lastname: Liu-Chen
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D001549:Benzamides; D001578:Benzopyrans; C000609058:LY 2444296; C532570:N,N-diethyl-4-(5-hydroxyspiro(chromene-2,4'-piperidine)-4-yl)benzamide; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa
keywords: Antidepressant; Delta opioid agonist; Forced swim test; Kappa opioid antagonist; Synergy