title: Pre-treatment with the mGlu2/3 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression.
abstract: BACKGROUND
  Overactivation of serotonin (5-hydroxytryptamine, 5-HT)(2A) receptors causes impulsivity and attentional deficits. Since 5-HT(2A) receptors are known to entertain antagonistic interactions with metabotropic glutamate (mGlu)2/3 receptors, this interaction may provide an alternative target for a novel class of antipsychotics.
  
  
  OBJECTIVE
  The study characterizes interactions between 5-HT(2A) and mGlu2/3 receptors implicated in impulse control. Hooded Lister rats were trained in a 5-choice serial reaction time task (5-CSRTT) and treated with the 5-HT(2A/2C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride (DOI, 0.1 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg). In addition, associated drug-induced changes in neuronal activity were assessed via c-Fos immunoreactivity (Fos IR), and co-localization of c-Fos and GABAergic markers was detected using double immunofluorescence labeling.
  
  
  RESULTS
  Systemic DOI caused impulsive overresponding that was attenuated in animals pre-treated with LY379268. LY379268 itself had no significant effect on the rats' performance in the 5-CSRTT. DOI enhanced Fos IR within fronto-cortical and limbic brain structures, and this effect was blocked by LY379268 pre-treatment. Double immunofluorescence labeling showed a specific co-localization of DOI-elicited Fos IR with GABAergic (GAD(67)-positive) cells lacking the calcium-binding protein parvalbumin while LY379268 increased Fos IR in GABAergic and non-GABAergic cells.
  
  
  CONCLUSIONS
  Our results suggest that impulsivity is possibly due to a primary increase in Glu transmission mediated via 5-HT(2A) receptor activation. Thus, mGlu2/3 receptor agonists might have some potential for treating motor impulsivity-related impairments while their cognitive enhancing effects were not confirmed in this study.
authors.affiliation: Department of Neuropharmacology, Brain Research Institute, Center for Cognitive Sciences, University of Bremen, PO Box 330440, 28334 Bremen, Germany. lena_wischhof@yahoo.de
authors.forename: Lena
authors.initials: L
authors.lastname: Wischhof
authors.forename: Michael
authors.initials: M
authors.lastname: Koch
mesh_terms: D000596:Amino Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000662:Amphetamines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D021461:Animals, Outbred Strains; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos / Q000502:physiology; D007175:Impulsive Behavior / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D057054:Molecular Imaging / Q000379:methods / Q000523:psychology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012691:Serial Learning / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000502:physiology
chemical_list: D000596:Amino Acids; D000662:Amphetamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D017366:Serotonin Receptor Agonists; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine