title: Involvement of metabotropic glutamate receptor 5 in the inhibition of methamphetamine-associated contextual memory after prolonged extinction training.
abstract: Addiction is thought to be a memory process between perception and environmental cues and addicted patients often relapse when they come into contact with the drug-related context once again. Here, we used a conditioned place preference protocol to seek a more effective extinction methodology of methamphetamine (METH) memory and delineate its underlying mechanism. Conditioning METH for 3 days in mice markedly increased the time spent in the METH-paired compartment. Then the mice were conditioned with saline for 6 days, from day 6 to day 11, a procedure termed extinction training. However, METH memory returned after a priming injection of METH. We prolonged extinction duration from 6 to 10 days and found that this extensive extinction (EE) training prevented priming effect. At the molecular level, we discovered that prolonged extinction training reversed the METH-conditioned place preference-induced increase in surface expression of GluA2 and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/NMDA ratio in the basolateral amygdala. In addition, we found that extinction with metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE: reduced relapse after extinction, decreased synaptic AMPA receptors AMPARs and the AMPA/NMDA ratio. On the contrary, EE with mGluR5 inhibition suppressed the results of EE. These data indicate that EE training-elicited inhibition of METH-primed reinstatement is mediated by the mGluR5. Conditioning mice with methamphetamine place preference (METH CPP) increases surface expression of AMPA receptors (AMPARs) in the basolateral amygdala. We found prolongation of extinction duration from 6 to 10 days prevented priming effect. At the molecular level, we discovered that extensive extinction (EE) reversed the METH CPP-induced increase in surface expression of GluA2 and AMPA/NMDA ratio. In addition, we found that extinction with the metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE: reduced relapse after extinction, decreased synaptic AMPARs and the AMPA/NMDA ratio. On the contrary, EE with mGluR5 inhibition suppressed the results of EE. These data indicate that EE training-elicited inhibition of METH-primed reinstatement is mediated by mGluR5 (PAM: positive allosteric modulator).
authors.affiliation: Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Chien-Hsuan
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Yang-Jung
authors.initials: YJ
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Chih-Hua
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Po-Wu
authors.initials: PW
authors.lastname: Gean
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D019921:Biotinylation; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D001549:Benzamides; D000697:Central Nervous System Stimulants; D018683:Excitatory Amino Acid Agents; D058787:GABA-A Receptor Antagonists; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D008694:Methamphetamine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D001640:Bicuculline
keywords: Amygdala; addiction; conditioned place preference; extinction; mGluR5; methamphetamine