title: Examination of a role for metabotropic glutamate receptor 5 in the medial prefrontal cortex in cocaine sensitization in rats.
abstract: BACKGROUND
  Glutamatergic projection neurons in the medial prefrontal cortex (mPFC) are hyperexcitable in cocaine-sensitized animals, resulting in increased excitatory output to addiction-associated regions such as the ventral tegmental area (VTA) and nucleus accumbens. Evidence suggests that Group I metabotropic glutamate receptor 5 (mGluR5) is necessary for cocaine sensitization, and stimulation of this receptor in the mPFC potentially alters cell excitability directly through glutamate release or indirectly through downstream signaling cascades.
  
  
  OBJECTIVE
  Experiments in this report examined the role of mPFC mGluR5 in behavioral sensitization to cocaine. Group I mGluR agonist dihydroxyphenylglycine (DHPG) (15 nmol/side), mGluR5 antagonist 3((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) (15 nmol/side), mGluR1 antagonist YM298198 (15 nmol/side), AMPA receptor antagonist CNQX (1 nmol/side), and/or saline were administered through cannulae implanted 1 mm above the mPFC and/or VTA in male rats. Cocaine (15 mg/kg, i.p.) was systemically administered for four consecutive days to induce sensitization and/or once on test day immediately preceding locomotor monitoring.
  
  
  RESULTS
  Intra-mPFC DHPG induced an mGluR5-mediated cross-sensitization to cocaine preventable through the prior administration of an AMPA receptor antagonist in the VTA. Furthermore, mGluR5 blockade in the mPFC failed to prevent the initiation of sensitization. However, intra-mPFC injections of the mGluR5 antagonist MTEP prevented the expression of cocaine sensitization at 21, but not 7, days following daily cocaine injections suggesting a possible role for mPFC mGluR5 in the persistence of the cocaine-sensitized state.
  
  
  CONCLUSIONS
  These data suggest that stimulation of mGluR5s in the mPFC is sufficient to induce cocaine sensitization and is necessary for the expression of this sensitized response.
authors.affiliation: Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Ave., Rm. 115 Crowe, Memphis, TN 38163, USA. ktimmer@uthsc.edu
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Timmer
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Steketee
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D059333:Central Nervous System Sensitization / Q000187:drug effects / Q000502:physiology*; D003042:Cocaine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012118:Resorcinols / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C505455:6-amino-N-cyclohexyl-N,3-dimethylthiazolo(3,2-a)benzimidazole-2-carboxamide; D001562:Benzimidazoles; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D013844:Thiazoles; C079215:3,5-dihydroxyphenylglycine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D003042:Cocaine; D005998:Glycine