title: The dual orexin receptor antagonist almorexant, alone and in combination with morphine, cocaine and amphetamine, on conditioned place preference and locomotor sensitization in the rat.
abstract: Dual orexin receptor (OXR) antagonists emerge as a novel therapeutic class to treat insomnia that, based on anti-addictive effects of selective OXR type 1 antagonists in rats, might be associated with less abuse liability than commonly used γ-aminobutyric acid (GABA) receptor modulators. Here, we studied the effects of the sleep-enabling dual OXR antagonist almorexant on conditioned place preference (CPP) and locomotor sensitization in rats. First, we compared almorexant to the GABA metabolite γ-hydroxybutyrate (GHB), which is clinically used as a sleep-inducing drug and which is associated with mild abuse liability. Whereas conditioning with GHB induced significant place preference, conditioning with almorexant did not. Second, we tested the potential of almorexant to interfere with the conditioned rewarding or locomotor sensitizing effects related to psychostimulants or opiates. Almorexant attenuated the expression of CPP to high doses of cocaine (15 mg/kg) and d.l-amphetamine (2 mg/kg), but not to high dose of morphine (10 mg/kg). Conversely, almorexant interfered with the expression of locomotor sensitization to morphine, but not with that to cocaine and d.l-amphetamine. Third, we observed that chronic almorexant (12 d) treatment in morphine, cocaine or amphetamine pre-conditioned and locomotor-sensitized rats had no influence on the maintenance of CPP and locomotor sensitization when tested after almorexant washout. Our findings suggest that almorexant itself does not exert conditioned rewarding effects in the rat and that it may acutely interfere with the expression of CPP or locomotor sensitization in a drug-dependent manner (monoaminergic psychostimulants vs. opiates).
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. michel.steiner@actelion.com
authors.forename: Michel Alexander
authors.initials: MA
authors.lastname: Steiner
authors.forename: Hugues
authors.initials: H
authors.lastname: Lecourt
authors.forename: François
authors.initials: F
authors.lastname: Jenck
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology*; D004347:Drug Interactions; D000074623:Dual Oxidases; D005420:Flavoproteins / Q000819:agonists*; D007546:Isoquinolines / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward
chemical_list: D000081:Acetamides; D000777:Anesthetics; D015259:Dopamine Agents; D005420:Flavoproteins; D007546:Isoquinolines; D009020:Morphine; C519150:almorexant; D000661:Amphetamine; D000074623:Dual Oxidases; C486611:Duox2 protein, rat; D003042:Cocaine