Further pharmacological characterization of eltoprazine: focus on its anxiolytic, anorexic, and adverse - effect potential

• Autorzy: Gravius A. , Dekundy A. , Vanaga A. , Franke L. , Danysz W.
• Języki publikacji: EN

Abstrakty

EN

Eltoprazine, a drug that had previously been developed for aggression, has recently been investigated for L‑DOPA‑induced dyskinesia in animal models of Parkinson´s disease (PD) and in dyskinetic PD patients. Much less is known about effects of eltoprazine in other therapeutic indications. Indeed, the pharmacological profile of eltoprazine might suggest its effects on anxiety and food intake, but also adverse effect potential, which is the focus of the present study. Given for 2 weeks either as infusion or as twice‑daily treatment, eltoprazine produced a decrease in food intake and body weight at doses leading to 200–500 nM plasma concentrations. In the elevated plus maze eltoprazine increased anxiety‑like behavior. On the other hand, it induced a clear‑cut anxiolytic effect in context fear conditioning test starting at ca. 0.3 mg/kg, and failed to produce any significant effect in fear potentiated startle test. Regarding adverse effects, eltoprazine was found to produce hypothermia starting from 1 mg/kg. At similar doses it also increased locomotion in the open field. However, eltoprazine failed to affect acquisition in context fear conditioning paradigm, which may indicate lack of its detrimental effect on learning at the doses tested (i.e., up to 5 mg/kg). In summary, effects of eltoprazine in different anxiety tests were equivocal while its effect on body weight seems robust and requires further investigation. It is to be determined whether these effects can be expected at the doses free of adverse effects.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: 1
• Opis fizyczny: p.77-85,fig.,ref.

Twórcy

autor

Gravius A.

• Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany

autor

Dekundy A.

• Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany

autor

Vanaga A.

• Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany

autor

Franke L.

• Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany

autor

Danysz W.

• Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany

Bibliografia

• Bezard E, Tronci E, Pioli EY, Li Q, Porras G, Bjorklund A, Carta  M (2013) Study of the antidyskinetic effect of eltoprazine in animal models of levodopa‑induced dyskinesia. Mov Disord 28(8): 1088–1096.
• Brashier DB, Sharma AK, Dahiya N, Singh SK, Khadka A (2014) Lorcaserin: A novel antiobesity drug. J  Pharmacol Pharmacother 5(2): 175–178.
• de Boer SF, Lesourd  M, Mocaer E, Koolhaas JM (1999) Selective antiaggressive effects of alnespirone in resident‑intruder test are mediated via 5‑hydroxytryptamine1A receptors: A comparative pharmacological study with 8‑hydroxy‑2‑dipropylaminotetralin, ipsapirone, buspirone, eltoprazine, and WAY‑100635. J Pharmacol Exp Ther 288(3): 1125–1133.
• de Koning P, Mak M, de Vries MH, Allsopp LF, Stevens RB, Verbruggen R, Van den Borre R, van Peteghem P, Kohen D, Arumainayagam  M, et al. (1994) Eltoprazine in aggressive mentally handicapped patients: a  double‑blind, placebo‑ and baseline‑controlled multi‑centre study. The Eltoprazine Aggression Research Group. Int Clin Psychopharmacol 9(3): 187–194.
• Joels M, Pennartz CM, Sijbesma H, Schipper J (1990) Eltoprazine suppresses hyperpolarizing responses to serotonin in rat hippocampus. J Pharmacol Exp Ther 253(1): 284–289.
• Marston OJ, Heisler LK (2009) Targeting the serotonin 2C receptor for the treatment of obesity and type 2 diabetes. Neuropsychopharmacology 34(1): 252–253.
• Millan MJ, Rivet JM, Canton H, Le Marouille‑Girardon S, Gobert A (1993) Induction of hypothermia as a  model of 5‑hydroxytryptamine1A receptor‑mediated activity in the rat: a pharmacological characterization of the actions of novel agonists and antagonists. J Pharmacol Exp Ther 264(3): 1364–1376.
• Miller KJ (2005) Serotonin 5‑HT2c receptor agonists: potential for the treatment of obesity. Mol Interv 5(5): 282–291.
• Olivier B, Mos J, Rasmussen D (1990) Behavioural pharmacology of the serenic, eltoprazine. Drug Metabol Drug Interact 8(1–2): 31–83.
• Paolone G, Brugnoli A, Arcuri L, Mercatelli D, Morari M (2015) Eltoprazine prevents levodopa‑induced dyskinesias by reducing striatal glutamate and direct pathway activity. Mov Disord 30(13): 1728–1738.
• Rocha B, Di Scala G, Jenck F, Moreau JL, Sandner G (1993) Conditioned place aversion induced by 5‑HT(1C) receptor antagonists. Behav Pharmacol 4(2): 101–106.
• Rocha B, Rigo M, Di Scala G, Sandner G, Hoyer D (1994) Chronic mianserin or eltoprazine treatment in rats: effects on the elevated plus‑maze test and on limbic 5‑HT2C receptor levels. Eur J Pharmacol 262(1–2): 125–131.
• Rodgers RJ, Cole JC, Cobain MR, Daly P, Doran PJ, Eells JR, Wallis P (1992) Anxiogenic‑like effects of fluprazine and eltoprazine in the mouse elevated plus‑maze: profile comparisons with 8‑OH‑DPAT, CGS 12066B, TFMPP and mCPP. Behav Pharmacol 3(6): 621–634.
• Sanchez C (1993) Effect of serotonergic drugs on footshock‑induced ultrasonic vocalization in adult male rats. Behav Pharmacol 4(3): 269–277.
• Sanchez C (1997) Acute stress enhances anxiolytic‑like drug responses of mice tested in a black and white test box. Eur Neuropsychopharmacol 7(4): 283–288.
• Schipper J, Tulp MT, Sijbesma H (1990) Neurochemical profile of eltoprazine. Drug Metabol Drug Interact 8(1–2): 85–114.
• Svenningsson P, Rosenblad C, Af Edholm Arvidsson K, Wictorin K, Keywood  C, Shankar B, Lowe DA, Bjorklund A, Widner H (2015) Eltoprazine counteracts l‑DOPA‑induced dyskinesias in Parkinson’s disease: a dose‑finding study. Brain 138(Pt 4): 963–973.
• Zethof TJ, Van der Heyden JA, Tolboom JT, Olivier B (1995) Stress‑induced hyperthermia as a  putative anxiety model. Eur J  Pharmacol 294(1): 125–135.