Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking.
Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.
Tessari
Michela
M
Center of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Pharmaceuticals, Via A. Fleming 4, 37135 Verona, Italy. michela.2.tessari@gsk.com
Pilla
Maria
M
Andreoli
Michela
M
Hutcheson
Daniel M
DM
Heidbreder
Christian A
CA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000008:administration & dosage*; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055502:Secondary Prevention; D012646:Self Administration; D019966:Substance-Related Disorders / Q000517:prevention & control
D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D009538:Nicotine; C121465:6-methyl-2-(phenylethynyl)pyridine; D003042:Cocaine