, Volume 187, Issue 4, pp 397–404

Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats

  • Olga A. Dravolina
  • Wojciech Danysz
  • Anton Y. Bespalov
Original Investigation



Metabotropic glutamate receptors (mGluRs) were reported to regulate various behavioral effects of addictive drugs.


The present study evaluated the role of group I mGluRs in the progressive augmentation (“sensitization”) of the behavioral effects observed after repeated, intermittent cocaine exposure.

Materials and methods

After habituation to handling and baseline activity measurement (days 1–2), rats received eight injections of cocaine (10 mg/kg) or saline on days 3–6, 8–11, and then, were tested twice with acute saline and cocaine given in a counterbalanced manner on days 13 and 15. Before the test sessions, subjects were pretreated with mGluR1 antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine).


Pretreatment with EMQMCM (2.5–10 mg/kg) but not MTEP (2.5–10 mg/kg) significantly reduced expression of the sensitized ambulatory motor activity of the cocaine-experienced animals acutely challenged with cocaine. Both EMQMCM and MTEP significantly reduced vertical motor activity across all cocaine/saline treatment conditions.


These findings indicate that the expression of behavioral sensitization to cocaine-induced stimulation of locomotor activity may be modulated by group I mGluR antagonists (mGluR1 rather than mGluR5), but these effects occur at the dose levels that attenuate vertical activity.


Cocaine Motor activity Sensitization Conditioning Metabotropic glutamate receptor antagonist Rat 


  1. Attucci S, Clodfelter GV, Thibault O, Staton J, Moroni F, Landfield PW, Porter NM (2002) Group I metabotropic glutamate receptor inhibition selectively blocks a prolonged Ca(2+) elevation associated with age-dependent excitotoxicity. Neuroscience 112:183–194PubMedCrossRefGoogle Scholar
  2. Balster RL, Willetts J (1996) Phencyclidine: a drug of abuse and a tool for neuroscience research. In: Schuster CR, Kuhar MJ (eds) Pharmacological aspects of drug dependence: towards an integrated neurobehavioral approach. Handbook of Experimental Pharmacology, vol. 118. Springer Berlin Heidelberg, New York, pp 233–262Google Scholar
  3. Beardsley PM, Hayes BA, Balster RL (1990) The self-administration of MK-801 can depend upon drug-reinforcement history, and its discriminative stimulus properties are phencyclidine-like in rhesus monkeys. J Pharmacol Exp Ther 252:53–959Google Scholar
  4. Bespalov AY, Dravolina OA, Zvartau EE, Beardsley PM, Balster RL (2000) Effects of NMDA receptor antagonists on cocaine-conditioned motor activity in rats. Eur J Pharmacol 390:303–311PubMedCrossRefGoogle Scholar
  5. Bespalov AY, Dravolina OA, Sukhanov I, Zakharova E, Blokhina E, Zvartau E, Danysz W, van Heeke G, Markou A (2005) Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats. Neuropharmacology 49:167–178PubMedCrossRefGoogle Scholar
  6. Blaabjerg M, Fang L, Zimmer J, Baskys A (2003) Neuroprotection against NMDA excitotoxicity by group I metabotropic glutamate receptors is associated with reduction of NMDA stimulated currents. Exp Neurol 183:573–580PubMedCrossRefGoogle Scholar
  7. Brown EE, Fibiger HC (1992) Cocaine-induced conditioned locomotion: absence of associated increases in dopamine release. Neuroscience 48:621–629PubMedCrossRefGoogle Scholar
  8. Busse CS, Brodkin J, Tattersall D, Anderson JJ, Warren N, Tehrani L, Bristow LJ, Varney MA, Cosford ND (2004) The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology 29:1971–1979PubMedCrossRefGoogle Scholar
  9. Carey RJ, DePalma G, Damianopoulos E (2003) Cocaine-conditioned behavioral effects: a role for habituation processes. Pharmacol Biochem Behav 74:701–712PubMedCrossRefGoogle Scholar
  10. Carlezon WA Jr, Wise RA (1996) Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward. Psychopharmacology 128:413–420PubMedCrossRefGoogle Scholar
  11. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 4:873–874PubMedCrossRefGoogle Scholar
  12. Corbett D (1989) Possible abuse potential of the NMDA antagonist MK-801. Behav Brain Res 34:239–246PubMedCrossRefGoogle Scholar
  13. Cosford ND, Tehrani L, Roppe J, Schweiger E, Smith ND, Anderson J, Bristow L, Brodkin J, Jiang X, McDonald I, Rao S, Washburn M, Varney MA (2003) 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J Med Chem 46:204–206PubMedCrossRefGoogle Scholar
  14. David HN, Abraini JH (2003) Blockade of the locomotor stimulant effects of amphetamine by group I, group II, and group III metabotropic glutamate receptor ligands in the rat nucleus accumbens: possible interactions with dopamine receptors. Neuropharmacology 44:717–727PubMedCrossRefGoogle Scholar
  15. De Vries TJ, Schoffelmeer AN, Binnekade R, Mulder AH, Vanderschuren LJ (1998) Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization. Eur J Neurosci 10:3565–3571PubMedCrossRefGoogle Scholar
  16. De Vries TJ, Schoffelmeer AN, Binnekade R, Raaso H, Vanderschuren LJ (2002) Relapse to cocaine- and heroin-seeking behavior mediated by dopamine D2 receptors is time-dependent and associated with behavioral sensitization. Neuropsychopharmacology 26:18–26PubMedCrossRefGoogle Scholar
  17. Doherty AJ, Palmer MJ, Henley JM, Collingridge GL, Jane DE (1997) (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) activates mGlu5, but no mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology 36:265–267PubMedCrossRefGoogle Scholar
  18. Ghasemzadeh MB, Nelson LC, Lu XY, Kalivas PW (1999) Neuroadaptations in ionotropic and metabotropic glutamate receptor mRNA produced by cocaine treatment. J Neurochem 72:157–165PubMedCrossRefGoogle Scholar
  19. Heidbreder CA, Bianchi M, Lacroix LP, Faedo S, Perdona E, Remelli R, Cavanni P, Crespi F (2003) Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo. Synapse 50:269–276PubMedCrossRefGoogle Scholar
  20. 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 43:1199–1209PubMedCrossRefGoogle Scholar
  21. Herzig V, Schmidt WJ (2004) Effects of MPEP on locomotion, sensitization and conditioned reward induced by cocaine or morphine. Neuropharmacology 47:973–984PubMedCrossRefGoogle Scholar
  22. Herzig V, Capuani EM, Kovar KA, Schmidt WJ (2005) Effects of MPEP on expression of food-, MDMA- or amphetamine-conditioned place preference in rats. Addict Biol 10:243–249PubMedCrossRefGoogle Scholar
  23. 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 29:1259–1269PubMedCrossRefGoogle Scholar
  24. Lesage ASJ, Bischoff F, Van Beijsterveldt L, Meert T, Steckler T, Ashton D (2002) Novel, centrally active mGluR1 antagonists: in vitro and in vivo pharmacology. Neuropharmacology 43:295Google Scholar
  25. Mao L, Wang JQ (2001) Differentially altered mGluR1 and mGluR5 mRNA expression in rat caudate nucleus and nucleus accumbens in the development and expression of behavioral sensitization to repeated amphetamine administration. Synapse 41:230–240PubMedCrossRefGoogle Scholar
  26. Mao L, Conquet F, Wang JQ (2001) Augmented motor activity and reduced striatal preprodynorphin mRNA induction in response to acute amphetamine administration in metabotropic glutamate receptor 1 knockout mice. Neuroscience 106:303–312PubMedCrossRefGoogle Scholar
  27. Martin-Iverson MT, Reimer AR (1994) Effects of nimodipine and/or haloperidol on the expression of conditioned locomotion and sensitization to cocaine in rats. Psychopharmacology (Berl) 114:315–320CrossRefGoogle Scholar
  28. McGeehan AJ, Olive MF (2003) The mGluR5 antagonist MPEP reduces the conditioned rewarding effects of cocaine but not other drugs of abuse. Synapse 47:240–242PubMedCrossRefGoogle Scholar
  29. McGeehan AJ, Janak PH, Olive MF (2004) Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, d-amphetamine, and the dopamine reuptake inhibitor GBR12909 in mice. Psychopharmacology (Berl) 174:266–273CrossRefGoogle Scholar
  30. O’Leary DM, Movsesyan V, Vicini S, Faden AI (2000) Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism. Br J Pharmacol 131:1429–1437PubMedCrossRefGoogle Scholar
  31. Pietraszek M, Sukhanov I, Maciejak P, Szyndler J, Gravius A, Wislowska A, Plaznik A, Bespalov AY, Danysz W (2005) Anxiolytic-like effects of mGlu1 and mGlu5 receptor antagonists in rats. Eur J Pharmacol 514:25–34PubMedCrossRefGoogle Scholar
  32. Popik P, Wrobel M (2002) Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist. Neuropharmacology 43:1210–1217PubMedCrossRefGoogle Scholar
  33. Ranaldi R, French E, Roberts DC (1996) Systemic pretreatment with MK-801 (dizocilpine) increases breaking points for self-administration of cocaine on a progressive-ratio schedule in rats. Psychopharmacology (Berl) 128:83–88CrossRefGoogle Scholar
  34. Ranaldi R, Bauco P, Wise RA (1997) Synergistic effects of cocaine and dizocilpine (MK-801) on brain stimulation reward. Brain Res 760:231–237PubMedCrossRefGoogle Scholar
  35. Ranaldi R, Munn E, Naklesa T, Wise RA (2000) Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK-801 (dizocilpine). Psychopharmacology (Berl) 151:192–201CrossRefGoogle Scholar
  36. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291PubMedCrossRefGoogle Scholar
  37. Spooren WP, Gasparini F, Bergmann R, Kuhn R (2000a) Effects of the prototypical mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. Eur J Pharmacol 406:403–410PubMedCrossRefGoogle Scholar
  38. Spooren WP, Vassout A, Neijt HC, Kuhn R, Gasparini F, Roux S, Porsolt RD, Gentsch C (2000b) Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents. J Pharmacol Exp Ther 295:1267–1275PubMedGoogle Scholar
  39. Steckler T, Lavreysen H, Oliveira AM, Aerts N, Van Craenendonck H, Prickaerts J, Megens A, Lesage AS (2005a) Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test. Psychopharmacology (Berl) 179:198–206CrossRefGoogle Scholar
  40. Steckler T, Oliveira AF, Van Dyck C, Van Craenendonck H, Mateus AM, Langlois X, Lesage AS, Prickaerts J (2005b) Metabotropic glutamate receptor 1 blockade impairs acquisition and retention in a spatial Water maze task. Behav Brain Res 164:52–60PubMedCrossRefGoogle Scholar
  41. Swanson CJ, Baker DA, Carson D, Worley PF, Kalivas PW (2001) Repeated cocaine administration attenuates group I metabotropic glutamate receptor-mediated glutamate release and behavioral activation: a potential role for Homer. J Neurosci 21:9043–9052PubMedGoogle Scholar
  42. Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E, Palucha A, Gasparini F, Kuhn R, Pilc A (2001) Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 132:1423–1430PubMedCrossRefGoogle Scholar
  43. Tessari M, Pilla M, Andreoli M, Hutcheson DM, Heidbreder CA (2004) Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. Eur J Pharmacol 499:121–133PubMedCrossRefGoogle Scholar
  44. Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology (Berl) 151:99–120CrossRefGoogle Scholar
  45. Vezina P, Kim JH (1999) Metabotropic glutamate receptors and the generation of locomotor activity: interactions with midbrain dopamine. Neurosci Biobehav Rev 23:577–589PubMedCrossRefGoogle Scholar
  46. Wise RA, Mendrek A, Carlezon WA Jr (1996) MK-801 (dizocilpine): synergist and conditioned stimulus in bromocriptine-induced psychomotor sensitization. Synapse 22:362–368PubMedCrossRefGoogle Scholar
  47. Wolf ME (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679–720PubMedCrossRefGoogle Scholar
  48. Yap JJ, Covington HE 3rd, Gale MC, Datta R, Miczek KA (2005) Behavioral sensitization due to social defeat stress in mice: antagonism at mGluR5 and NMDA receptors. Psychopharmacology (Berl) 179:230–239CrossRefGoogle Scholar
  49. Yu MF, Lin WW, Li LT, Yin HS (2003) Activation of metabotropic glutamate receptor 5 is associated with effect of amphetamine on brain neurons. Synapse 50:334–344PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Olga A. Dravolina
    • 1
  • Wojciech Danysz
    • 2
  • Anton Y. Bespalov
    • 1
  1. 1.Laboratory of Behavioral Pharmacology, Institute of PharmacologyPavlov Medical UniversitySt. PetersburgRussia
  2. 2.Preclinical R&DMerz PharmaceuticalsFrankfurt am MainGermany
  3. 3.CNS PharmacologyAbbott GmbH & Co. KGLudwigshafenGermany

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