Advances in Clinical and Experimental Medicine
2011, vol. 20, nr 5, September-October, p. 559–565
Publication type: original article
Language: English
The Effects of a New Derivative of Phencyclidine on Anxiety- and Depression-Like Behaviors in Mice
Wpływ nowej pochodnej fencyklidyny na występowanie objawów lęku i depresji u myszy
1 Department of Biology, Islamic Azad University, Karaj Branch, Karaj, Iran
2 Departments of Chemistry, Islamic Azad University, Karaj Branch, Karaj, Iran
3 Young Researchers Club, Islamic Azad University, Karaj Branch, Karaj, Iran
Abstract
Objectives. Phencyclidine and its derivatives display analgesic, stimulant, anticonvulsant effects in animals, due to specific binding sites in the brain. The present study investigated the effects of phencyclidine (PCP) and a new derivative of it (PND) on anxietyand depression-like behaviors in animal models.
Material and Methods. Phencyclidine and it’s new derivative (PND) were synthesized and administered intraperitoneally to adult male NMRI mice in doses of 1, 5 and 10 mg/kg. The elevated plus maze (EPM) and forced swimming test (FST), which are useful models for the selective identification of anxiolytic and antidepressant-like effects of drugs, were used in the study.
Results. The results of the study demonstrated that intraperitoneal administration of PND (5 and 10 mg/kg) significantly increased the percentage of open-arm time (OAT %) and the percentage of open-arm entries (OAE %) in the elevated plus maze in comparison with PCP-treated mice and the saline-treated control group; at those doses PND also significantly decreased immobility times in the forced swimming test in comparison with the control group. However, the PCP-treated group showed less immobility time in the FST in comparison with the PND group.
Conclusion. It seems that intraperitoneal injection of this new derivative of phencyclidine was more effective than phencyclidine and than saline in modulating anxiety, but not in modulating depression-like behaviors in mice.
Streszczenie
Cel pracy. Fencyklidyna i jej pochodne wykazują działanie przeciwbólowe, pobudzające i przeciwdrgawkowe u zwierząt, z uwagi na specyficzne miejsca wiązania w mózgu. W niniejszym opracowaniu badano wpływ fencyklidyny (PCP) i jej nowej pochodnej (PND) na zachowania lękowo-depresyjne na modelach zwierzęcych.
Materiał i metody. Fencyklidyna i jej nowa pochodna (PND) zostały zsyntetyzowane i podane dootrzewnowo dorosłym samcom myszy NMRI w dawkach 1, 5 i 10 mg/kg. W badaniu wykorzystano uniesiony labirynt krzyżowy (EPM) i test wymuszonego pływania (FST), które są przydatnym modelami do selektywnej identyfikacji przeciwlękowego i przeciwdepresyjnego działania leków.
Wyniki. Badanie wykazało, że dootrzewnowe podanie PND (5 i 10 mg/kg) znacznie zwiększyło czas przebywania na otwartych ramionach krzyża (% OAT) oraz liczbę wejść na otwarte ramiona krzyża (% OAE) w teście uniesionego labiryntu krzyżowego w porównaniu z myszami, którym podawano PCP i sól fizjologiczną (grupa kontrolna); w tych dawkach PND znacznie skróciła czas bezruchu w teście wymuszonego pływania w porównaniu z grupą kontrolną. Jednak myszy, którym podawano PCP miały krótszy czas bezruchu w FST w porównaniu z myszami, którym podawano PND.
Wnioski. Wydaje się, że dootrzewnowe podanie nowej pochodnej fencyklidyny było bardziej skuteczne niż podanie fencyklidyny i soli w modulowaniu niepokoju, ale nie w modulowaniu zachowań depresyjnych u myszy.
Key words
phencyclidine, new derivative of phencyclidine, anxiety, depression, NMDA
Słowa kluczowe
fencyklidyna, nowe pochodne fencyklidyny, niepokój, depresja, NMDA
References (37)
- Pin J, Duvoisin R: The metabotropic glutamate receptors: Structure and functions 1. Neuropharmacology 1995, 34, 1–26.
- Javitt D: Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004, 9, 984–997.
- Poleszak E, Wlaz P, Kedzierska E, Nieoczym D, Wróbel A, Fidecka S: NMDA/glutamate mechanism of antidepressantlike action of magnesium in forced swim test in mice. Pharmacol Biochem Behav 2007, 88, 158–164.
- Baba A, Yamamoto T, Kawai N, Yamamoto H, Suzuki T, Moroji T: Behavioral effects of phencyclidine and its major metabolite,(trans) 4-phenyl-4-(1-piperidinyl) cyclohexanol, in mice. Behav Brain Res 1994, 65, 75–81.
- Hajikhani R, Solati J, Ahmadi A, Salari A: The Effect of Phencyclidine New Derivatives on Anxiety Behaviors in Rats. Iran J Basic Med Sci 2010.
- Ahmadi A, Solati J, Hajikhani R, Onagh M, Javadi M: Synthesis and analgesic effects of 1-[1-(2-methylphenyl) (cyclohexyl)]-3-piperidinol as a new derivative of phencyclidine in mice. Arzneimittel-Forschung 2010, 60, 492.
- Mori A, Noda Y, Mamiya T, Miyamoto Y, Nakajima A, Furukawa H: Phencyclidine-induced discriminative stimulus is mediated via phencyclidine binding sites on the N-methyl-aspartate receptor-ion channel complex, not via sigma1 receptors. Behav Brain Res 2001, 119, 33–40.
- Geller E, Adler L, Wojno C, Adler M: The anticonvulsant effect of phencyclidine in rats. Psychopharmacology 1981, 74, 97–98.
- Olney J, Labruyere J, Wang G, Wozniak D, Price M, Sesma M: NMDA antagonist neurotoxicity: mechanism and prevention. Science 1991, 254, 1515.
- Hori T, Subramaniam S, Srivastava L, Quirion R: Behavioral and neurochemical alterations following repeated phencyclidine administration in rats with neonatal ventral hippocampal lesions. Neuropharmacology 2000, 39, 2478–2491.
- Porter J, Wiley J, Balster R: Effects of phencyclidine-like drugs on punished behavior in rats. J Pharmacol Exp Ther 1989, 248, 997.
- Guimarães F, Carobrez A, Aguiar J, Graeff F: Anxiolytic effect in the elevated plus-maze of the NMDA receptor antagonist AP7 microinjected into the dorsal periaqueductal grey. Psychopharmacology 1991, 103, 91–94.
- Plaznik A, Palejko W, Nazar M, Jessa M: Effects of antagonists at the NMDA receptor complex in two models of anxiety. Eur Neuropsychopharmacol 1994, 4, 503–512.
- Woolverton W, Balster R: Tolerance to the behavioral effects of phencyclidine: The importance of behavioral and pharmacological variables. Psychopharmacology 1979, 64, 19–24.
- Solati J, Asiaei M, Salari A: Prenatal exposure to lps leads to long-lasting physiological consequences in male offspring. Dev Psychobiol 2011, DOI: 10.1002/dev.20568.
- Pellow S, Chopin P, File SE, Briley M: Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Meth 1985, 14, 149–167.
- Pellow S: Anxiolytic and anxiogenic drug effects in a novel test of anxiety: are exploratory models of anxiety in rodents valid? Meth Find Exp Clin Pharmacol 1986, 8, 557–565.
- Solati J, Zarrindast M, Salari A: Dorsal hippocampal opioidergic system modulates anxiety-like behaviors in adult male Wistar rats. Psychiatry Clin Neurosci 2010, 248, 997.
- Zarrindast M, Solati J, Oryan S, Parivar K: Effect of intra-amygdala injection of nicotine and GABA receptor agents on anxiety-like behaviour in rats. Pharmacology 2008, 82, 276–284.
- Bourin M, Chenu F, Prica C, Hascoët M: Augmentation effect of combination therapy of aripiprazole and antidepressants on forced swimming test in mice. Psychopharmacology 2009, 206, 97–107.
- Maddox V, Godefroi E, Parcell R: The synthesis of phencyclidine and other 1-arylcyclohexylamines. J Med Chem 1965, 8, 230–235.
- Ahmadi A, Khalili M, Abbassi S, Javadi M, Mahmoudi A, Hajikhani R: Synthesis and study on analgesic effects of 1-[1-(4-methylphenyl)(cyclohexyl)] 4-piperidinol and 1-[1-(4-methoxyphenyl)(cyclohexyl)] 4-piperidinol as two new phencyclidine derivatives. Arzneimittel-Forschung 2009, 59, 202–206.
- Kapur S, Seeman P: NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors: Implications for models of schizophrenia. Mol Psychiatry 2002, 7, 837–844.
- Honey C, Miljkovic Z, MacDonald J: Ketamine and phencyclidine cause a voltage-dependent block of responses to L-aspartic acid. Neurosci Lett 1985, 61, 135–139.
- Bergink V, van Megen H: Glutamate and anxiety. Eur Neuropsychopharmacol 2004, 14, 175–183.
- Swanson C, Bures M, Johnson M, Linden A, Monn J, Schoepp D: Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Dis 2005, 4, 131–144.
- Amiel J, Mathew S: Glutamate and anxiety disorders. Current Psychiatry Reports 2007, 9, 278–83.
- Tzschentke T: Glutamatergic mechanisms in different disease states: overview and therapeutical implications – an introduction. Amino Acids 2002, 23, 147–52.
- Maeng S, Zarate C: The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Current Psychiatry Reports 2007, 9, 467–474.
- Berman R, Cappiello A, Anand A, Oren D, Heninger G, Charney D: Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000, 47, 351–354.
- Fryer J, Lukas R: Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther 1999, 288, 88.
- MJ E: M2 mutations of the nicotinic acetylcholine receptor increase the potency of the non-competitive inhibitor phencyclidine. J Neurosci Res 2000, 61, 44–51.
- Martin P, Carlsson M, Hjorth S: Systemic PCP treatment elevates brain extracellular 5-HT: a microdialysis study in awake rats. Neuroreport 1998, 9, 2985.
- Svensson T, Mathe J, Andersson J, Nomikos G, Hildebrand B, Marcus M: Mode of action of atypical neuroleptics in relation to the phencyclidine model of schizophrenia: role of 5-HT2 receptor and -adrenoreceptor antagonism. J Clin Psychopharmacol 1995, 15, 11S–8S.
- Graeff F, Guimarães F, De Andrade T, Deakin J: Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav 1996, 54, 129–141.
- Shulgin A, MacLean D: Illicit synthesis of phencyclidine (PCP) and several of its analogs. Clin Toxicol 1976, 9, 553–560.
- Shebley M, Jushchyshyn M, Hollenberg P: Selective pathways for the metabolism of phencyclidine by cytochrome p450 2b enzymes: identification of electrophilic metabolites, glutathione, and N-acetyl cysteine adducts. Drug Metab Dis 2006, 34, 375.