Abstract
Rationale
Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D-aspartate receptor function. Our previous findings demonstrated that the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and the antagonist 2-methyl-6-(phenylethynyl)-pyridine can reduce and enhance the ketamine anesthesia, respectively.
Objective
The purpose of this study was to examine whether CHPG and positive allosteric modulator 3,3′-difluorobenzaldazine (DFB) can reverse ketamine-induced behavioral responses including locomotor hyperactivity, motor incoordination, sensorimotor gating deficit, and learning impairment.
Methods
Mice were pretreated with CHPG (5–50 nmol,) or DFB (40–100 nmol) followed by ketamine administration. Locomotor activity, rotarod test, prepulse inhibition (PPI) of acoustic startle test, and novel object recognition test were examined.
Results
CHPG and DFB had no effect on these behaviors when administered alone. Both of them attenuated the locomotor hyperactivity, motor incoordination, and cognitive impairment induced by ketamine. However, the ketamine-induced PPI deficit was reversed by CHPG (50 nmol) but not by DFB (up to 100 nmol). CHPG and DFB have distinct potency and efficacy in attenuating ketamine-induced behavioral response.
Conclusions
These behavioral data extend previous findings and further suggest that positive modulation of mGluR5 may provide a novel approach for development of antipsychotic agents.
Similar content being viewed by others
References
Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A (1998) Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers. Biol Psychiatry 43:811–816
Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649
Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ (2000) Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 20:7871–7879
Balschun D, Zuschratter W, Wetzel W (2006) Allosteric enhancement of metabotropic glutamate receptor 5 function promotes spatial memory. Neuroscience 142:691–702
Berthele A, Platzer S, Laurie DJ, Weis S, Sommer B, Zieglgansberger W, Conrad B, Tolle TR (1999) Expression of metabotropic glutamate receptor subtype mRNA (mGluR1-8) in human cerebellum. Neuroreport 10:3861–3867
Campbell UC, Lalwani K, Hernandez L, Kinney GG, Conn PJ, Bristow LJ (2004) The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats. Psychopharmacology (Berl) 175:310–318
Carter AJ (1994) Many agents that antagonize the NMDA receptor-channel complex in vivo also cause disturbances of motor coordination. J Pharmacol Exp Ther 269:573–580
Choe ES, Shin EH, Wang JQ (2006) Regulation of phosphorylation of NMDA receptor NR1 subunits in the rat neostriatum by group I metabotropic glutamate receptors in vivo. Neurosci Lett 394:246–251
de Lima MN, Laranja DC, Bromberg E, Roesler R, Schroder N (2005) Pre- or post-training administration of the NMDA receptor blocker MK-801 impairs object recognition memory in rats. Behav Brain Res 156:139–143
Fitzjohn SM, Irving AJ, Palmer MJ, Harvey J, Lodge D, Collingridge GL (1996) Activation of group I mGluRs potentiates NMDA responses in rat hippocampal slices. Neurosci Lett 203:211–213
Henry SA, Lehmann-Masten V, Gasparini F, Geyer MA, Markou A (2002) The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology 43:1199–1209
Homayoun H, Stefani MR, Adams BW, Tamagan GD, Moghaddam B (2004) Functional Interaction Between NMDA and mGlu5 Receptors: effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology 29:1259–1269
Irifune M, Shimizu T, Nomoto M (1991) Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice. Pharmacol Biochem Behav 40:399–407
Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225
Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M, Takahashi K, Kobayashi K, Yoshida S, Maeda K, Takuma K, Nabeshima T, Yamada K (2006) Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice. Biol Psychiatry 59:75–84
Kinney GG, Burno M, Campbell UC, Hernandez LM, Rodriguez D, Bristow LJ, Conn PJ (2003) Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther 306:116–123
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214
Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467
Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE (2005) Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry 62:1196–1204
Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, Chen PW, Tsai G (2006) Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 60:645–649
Lindsley CW, Wisnoski DD, Leister WH, O’Brien JA, Lemaire W, Williams DL Jr, Burno M, Sur C, Kinney GG, Pettibone DJ, Tiller PR, Smith S, Duggan ME, Hartman GD, Conn PJ, Huff JR (2004) Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides that potentiate receptor function in vivo. J Med Chem 47:5825–5828
Lindsley CW, Shipe WD, Wolkenberg SE, Theberge CR, Williams DL Jr, Sur C, Kinney GG (2006) Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Curr Top Med Chem 6:771–785
Lipina T, Labrie V, Weiner I, Roder J (2005) Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. Psychopharmacology (Berl) 179:54–67
Liu F, Zhang G, Hornby G, Vasylyev D, Bowlby M, Park K, Gilbert A, Marquis K, Andree TH (2006) The effect of mGlu5 receptor positive allosteric modulators on signaling molecules in brain slices. Eur J Pharmacol 536:262–268
Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150
Martin G, Nie Z, Siggins GR (1997) Metabotropic glutamate receptors regulate N-methyl-D-aspartate-mediated synaptic transmission in nucleus accumbens. J Neurophysiol 78:3028–3038
Nilsson M, Hansson S, Carlsson A, Carlsson ML (2007) Differential effects of the N-methyl-d-aspartate receptor antagonist MK-801 on different stages of object recognition memory in mice. Neuroscience 149:123–130
O’Brien JA, Lemaire W, Chen TB, Chang RS, Jacobson MA, Ha SN, Lindsley CW, Schaffhauser HJ, Sur C, Pettibone DJ, Conn PJ, Williams DL Jr (2003) A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol Pharmacol 64:731–740
O’Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL Jr (2004) A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. J Pharmacol Exp Ther 309:568–577
Pietraszek M, Gravius A, Schafer D, Weil T, Trifanova D, Danysz W (2005) mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition. Neuropharmacology 49:73–85
Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D, Bernardi G, Calabresi P (2001) Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 106:579–587
Sou JH, Chan MH, Chen HH (2006) Ketamine, but not propofol, anaesthesia is regulated by metabotropic glutamate 5 receptors. Br J Anaesth 96:597–601
Swerdlow NR, Bakshi V, Waikar M, Taaid N, Geyer MA (1998) Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats. Psychopharmacology (Berl) 140:75–80
Acknowledgements
This work was supported by a grant from National Scientific Council, Taiwan (NSC 95-2745-B-320-003-URD).
Author information
Authors and Affiliations
Corresponding author
Additional information
Ming-Huan Chan and Pao-Hsiang Chiu contributed equally to this work.
Rights and permissions
About this article
Cite this article
Chan, MH., Chiu, PH., Sou, JH. et al. Attenuation of ketamine-evoked behavioral responses by mGluR5 positive modulators in mice. Psychopharmacology 198, 141–148 (2008). https://doi.org/10.1007/s00213-008-1103-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-008-1103-1