Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats
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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.
KeywordsCocaine Motor activity Sensitization Conditioning Metabotropic glutamate receptor antagonist Rat
- 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
- 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
- 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
- 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
- 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
- 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