Effects of the mGluR5 antagonist MPEP on ethanol withdrawal induced anxiety-like syndrome in rats

Behavioral and Brain Functions

Jaya Kumar¹  Hermizi Hapidin²  Yvonne-Tee Get Bee²  Zalina Ismail¹ 

[1] BRAINetwork Centre for Neurocognitive Science, School of Health Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan 16150, Malaysia

[2] School of Health Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan 16150, Malaysia

关键词: mGluR5;    MPEP;    Ethanol withdrawal induced anxiety;   

Others  :  811200
DOI  :  10.1186/1744-9081-9-43

 received in 2013-06-03, accepted in 2013-11-23,  发布年份 2013

【 摘 要 】

Abstinence from chronic ethanol consumption leads to the manifestation of a variety of symptoms attributed to central nervous system hyperexcitability, such as increased irritability, anxiety, and restlessness. Recent studies have demonstrated the importance of metabotropic glutamate receptor 5 (mGluR5) in addictive behaviours. This study investigates the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on ethanol withdrawal induced anxiety using two behavioural paradigms. Male Wistar rats were fed a Modified Liquid Diet (MLD) containing low fat cow milk, sucrose, and maltodextrin with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days. Six hours into ethanol withdrawal, the rats were intraperitoneally injected with normal saline and MPEP (2.5, 5.0, 10, 20, 30 mg/kg) and were assessed for ethanol withdrawal induced anxiety-like syndrome using an automated elevated plus maze and an open field. MPEP at 10 mg/kg significantly attenuated ethanol withdrawal induced anxiety without any compromising effects on locomotor activities. Despite reversing several indices of ethanol withdrawal induced anxiety in both the elevated plus maze and the open field, low doses of MPEP (2.5, 5 mg/kg) significantly compromised the locomotor activities of ethanol withdrawn rats. High doses of MPEP (20 and 30 mg/kg) significantly attenuated withdrawal anxiety when tested in the elevated plus maze but not in the open field. Administration of MPEP (2.5, 5, 10, 20, 30 mg/kg) has no significant compromising effect on the locomotor activities of ethanol naïve rats. Despite significantly reducing withdrawal anxiety in both behavioural paradigms at 10 mg/kg, the compromising effects of low and high doses of MPEP must be further explored along with the therapeutic efficiency of this drug for relieving withdrawal induced anxiety.

【 授权许可】

   
2013 Kumar et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Benquet P, Gee CE, Gerber U: Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes. J Neurosci 2002, 22:9679-9686.
• [2]Pin JP, Duvoisin R: The metabotropic glutamate receptors: Structure and functions. Neuropharmacology 1995, 34:1-26.
• [3]Backstrom P, Bachteler D, Koch S, Hyytia P, Spanagel R: mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology 2004, 29:921-928.
• [4]Olive MF, McGeehan AJ, Kinder JR, McMahon T, Hodge CW, Janak PH, Messing RO: The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism. Mol Pharmacol 2005, 67:349-355.
• [5]Hodge CW, Miles MF, Sharko AC, Stevenson RA, Hillmann JR, Lepoutre V, Besheer J, Schroeder JP: The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6 J mice. Psychopharmacology (Berl) 2006, 183:429-438.
• [6]Gupta T, Syed YM, Revis AA, Miller SA, Martinez M, Cohn KA, Demeyer MR, Patel KY, Brzezinska WJ, Rhodes JS: Acute effects of acamprosate and MPEP on ethanol drinking-in-the-dark in male C57BL/6 J mice. Alcohol Clin Exp Res 2008, 32:1992-1998.
• [7]Chojnacka-Woajcik E, Tatarczynska E, PILC A: The anxiolytic-like effect of metabotropic glutamate receptor antagonists after intrahippocampal injection in rats. Eur J Pharmacol 1997, 319:153 ± 156.
• [8]Spooren WPJM, Gasparini F, Bergmann R, Kuhn R: Effect of the prototypical mGlu5 receptor antagonist 2-methyl-6-(phenylethyl)-pyridine (MPEP) on motor behaviour: Rotarod, locomotor activity and rotational responses in the unilateral 6-OHDA-lesioned rat. Eur J Pharm 2000, 406:403-410.
• [9]Tatarczyńska E, Klodzińska A, Chojnacka-Wójcik E, Palucha A, Gasparini F, Kuhn R, Pilc A: Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 2001, 132:1423-1430.
• [10]Dahchour A, De Witte P: Excitatory and inhibitory amino acid changes during repeated episodes of ethanol withdrawal: an in vivo microdialysis study. Eur J Pharmacol 2003, 459:171-178.
• [11]De Witte P, Pinto E, Ansseau M, Verbanck P: Alcohol and withdrawal: from animal research to clinical issues. Neurosci Biobehav Rev 2008, 27:189-197.
• [12]Kotlinska J, Bochenski M: The influence of various glutamate receptors antagonists on anxiety-like effect of ethanol withdrawal in a plus-maze test in rats. Eur J Pharmacol 2008, 598:57-63.
• [13]Popp RL, Lovinger DM: Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons. Eur J Pharmacol 2000, 394:221-231.
• [14]Rammes G, Mahal B, Putzke J, Parsons C, Spielmanns P, Pestel E, Spanagel R, Zieglgansberger W, Schadrack J: The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801. Neuropharmacology 2001, 40:749-760.
• [15]Harris BR, Prendergast MA, Gibson DA, Rogers DT, Blanchard JA, Holley RC, Fu MC, Hart SR, Pedigo NW, Littleton JM: Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. Alcohol Clin Exp Res 2002, 26:1779-1793.
• [16]Gasparini F, Lingenho¨hl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Verney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Velicelebi G, Kuhn R: 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 1999, 38:1493-1503.
• [17]Fraser LM, Brown RE, Hussin A, Fontana M, Whittaker A, O’Leary TP, Lederle L, Holmes A, Ramos A: Measuring anxiety- and locomotion-related behaviours in mice: a new way of using old tests. Psychopharmacology (Berl) 2010, 211:99-112.
• [18]Anderson JJ, Bradbury MJ, Giracello DR, Chapman DF, Holtz G, Roppe J, King C, Cosford ND, Varney MA: In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl) pyridine). Eur J Pharmacol 2003, 473:35-40.
• [19]Uzbay IT, Kayaalp SO: A modified liquid diet of chronic ethanol administration: validation by ethanol withdrawal syndrome in rats. Pharmacol Res 1995, 31:37-42.
• [20]Boje KM, Fung HL: Characterization of the pharmacokinetic interaction between nifedipine and ethanol in the rat. J Pharmacol Exp Ther 1989, 249(2):567-571.
• [21]Pellow S, Chopin P, File SE, Briley M: Validation of open: closed arm entries in the elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985, 14:149-67.
• [22]Asano Y: Characteristics of Open Field Behavior of Wistar and Sprague Dawley Rats. Exp Anim 1986, 35:505-508.
• [23]Crusio WE, Schwegler H, Van Abeeelen JHF: Behavioral responses to novelty and structural variation of hippocampus in mice. I. Quantitaive-Genetic Analysis of Behavior in the Open Field. Behav Brain Res 1989, 3:75-80.
• [24]Whimbey AE, Denenberg VH: Two independent behavioral dimensions in Open Field Performance. J Comp Psychiol 1967, 63:500-504.
• [25]Lister RG: Ethologically-based animal models of anxiety disorders. Pharmacol Ther 1990, 46:321-40.
• [26]Vendruscolo LF, Takahashi RN, Bruske GR: Evaluation of the anxiolytic-like effect of NKP608, a NK1-receptor antagonist, in two rat strains that differ in anxiety-related behaviors. Psychopharmacology (Berl) 2003, 170:287-293.
• [27]Ramos A: Animal models of anxiety: do I need multiple tests? Trends Pharmacol Sci 2008, 29:493-498.
• [28]Olive MF, Becker HC: Effects of the mGluR2/3 agonist LY379268 and the mGluR5 antagonist MPEP on handling-induced convulsions during ethanol withdrawal in mice. Alcohol 2008, 42:191-197.
• [29]Simonyi A, Christian MR, Sun AY, Sun GY: Chronic ethanol-induced subtype- and subregion-specific decrease in the mRNA expression of metabotropic glutamate receptors in rat hippocampus. Alcohol Clin Exp Res 2004, 28:1419-1423.
• [30]Harris BR, Gibson DA, Prendergast MA, Blanchard JA, Holley RC, Hart SR, Scotland RL, Pedigo NW, Littleton JM: The neurotoxicity induced by ethanol withdrawal in mature organotypic hippocampal slices might involve cross-talk between Metabotropic Glutamate Type 5 Receptors and N-Methyl-D-Aspartate Receptors. Alcohol Clin Exp Res 2003, 27:1724-1735.
• [31]Obara I, Bell RL, Goulding SP, Reyes CM, Larson LA, Ary AW, Truitt WA, Szumlinski KK: Differential effects of chronic ethanol consumption and withdrawal on Homer/Glutamate receptor expression in subregions of the accumbens and amygdale of P rats. Alcohol Clin Exp Res 2009, 33:11.
• [32]Läck AK, Diaz MR, Chappell A, DuBois DW, McCool BA: Chronic ethanol and withdrawal differentially modulate pre- and postsynaptic function at glutamatergic synapses in rat basolateral amygdale. J Neurophysiol 2007, 98:3185-3196.
• [33]Roberto M, Schweitzer P, Madamba SG, Stouffer DG, Parsons LH, Siggins GR: Acute and chronic ethanol alter glutamatergic transmission in rat central amygdala: an in vitro and in vivo analysis. J Neurosci 2004, 24:1594-1603.
• [34]Szumlinski KK, Ary AW, Lominac KD, Klugmann M, Kippin TE: Accumbens Homer2 overexpression facilitates alcohol-induced neuroplasticity in C57BL⁄6 J mice. Neuropsychopharmacology 2008, 33:1365-1378.
• [35]File ES, Zharkowsky A, Hitchcott PK: Effects of nitrendipine, chlordiazepoxide, flumazenil and baclofen on the increase anxiety resulting from alcohol withdrawal. Prog Neuro-Psychopharmacol Biol Psychiat 1992, 16:87-93.
• [36]Ramos A, Mormede P: Stress and emotionality: a multidimensional and genetic approach. Neurosci Biobehav Rev 1998, 22:33-57.
• [37]O’Leary DM, Movsesyan V, Vicini S, Faden AI: Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism. Br J Pharmacol 2000, 131:1429-1437.
• [38]Lea PM IV, Movsesyan VA, Faden AI: Neuroprotective activity of the mGluR5 antagonists MPEP andMTEP against acute excitotoxicity differs and does not reflect actions at mGluR5 receptors. Br J Pharmacol 2005, 145:527-534.
• [39]Olive MF: Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev 2009, 2:83-98.
• [40]Overstreet DH, Knapp DJ, Moy SS, Breese GR: A 5-HT1A agonistanda5-HT2c antagonist reduce social interaction deficit induced by multiple ethanol withdrawals in rats. Psychopharmacology (Berl) 2003, 167:344-352.
• [41]Rasmussen DD, Mitton DR, Green J, Puchalski S: Chronic daily ethanol and withdrawal:2. Behavioral changes during prolonged abstinence. Alcohol Clin Exp 2001, Res 25:999-1005.
• [42]Pietraszek M, Rogoz Z, Wolfarth S, Ossowska K: Opposite influence of MPEP, an mGluR5 antagonist, on the locomotor hyperactivity induced by PCP and amphetamine. J Physiol Pharmacol 2004, 55(3):587-93.
• [43]Herzig V, Schmidt WJ: Effects of MPEP on locomotion, sensitization and conditioned reward induced by cocaine or morphine. Neuropharmacology 2004, 47:973-984.
• [44]Testa CM, Standaert DG, Young AB, Penney JJB: Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat. J Neurosci 1994, 14:3005-3018.
• [45]Romano C, Sesma MA, McDonald CT, O’Malley K, Van den Pol AN, Olney JW: Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J Comp Neurol 1995, 355:455-469.
• [46]Hope BT, Simmons DE, Mitchell TB, Kresuter JD, Mattson BJ: Cocaine-induced locomotor activity and Fos expression in nucleus accumbens are sensitized for 6 months after repeated cocaine administration outside the home cage. Eur J Neurosci 2006, 24(3):867-75.
• [47]Ikemoto S: Ventral striatal anatomy of locomotor activity induced by cocaine, D-amphetamine, dopamine and D1/D2 agonists. Neuroscience 2002, 113(4):939-55.
• [48]Mikulecka A, Mares P: Effects of mGluR5 and mGluR1 antagonists on anxiety-like behavior and learning in developing rats. Behav Brain Res 2009, 204:133-139.