title: Cocaine-induced behavioral sensitization is associated with changes in the expression of endocannabinoid and glutamatergic signaling systems in the mouse prefrontal cortex.
abstract: BACKGROUND
  Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction.
  
  
  METHODS
  We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamate-signaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors.
  
  
  RESULTS
  Although acute cocaine (10 mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20 mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10 mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios. Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine-sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression. These endocannabinoid changes were associated with modifications in glutamatergic transmission-related genes. An overall decrease was observed in the mRNA expression of the glutamate-synthesizing gene kidney-type glutaminase (KGA), the metabotropic glutamate receptors (mGluR3 and GluR), and subunits of NMDA ionotropic receptors (NR1, NR2A, NR2B and NR2C) after acute cocaine administration, while mice repeatedly exposed to cocaine only displayed an increase in NR2C. However, in cocaine-sensitized mice primed with cocaine, this inhibition was reversed and a strong increase was detected in the mGluR5, NR2 subunits, and both GluR1 and GluR3.
  
  
  CONCLUSIONS
  These findings indicate that cocaine sensitization is associated with an endocannabinoid downregulation and a hyperglutamatergic state in the PFC that, overall, contribute to an enhanced glutamatergic input into PFC-projecting areas.
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Eduardo
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Ana
authors.initials: A
authors.lastname: Palomino
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Luque-Rojas
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Patricia
authors.initials: P
authors.lastname: Rivera
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Francisco
authors.initials: F
authors.lastname: Alen
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Margarita
authors.initials: M
authors.lastname: Vida
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao).
authors.forename: Juan
authors.initials: J
authors.lastname: Suárez
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA-Hospital Regional Universitario de Málaga, Málaga, Spain (Drs Blanco, Pavón, Palomino, Luque-Rojas, Serrano, Rivera, Alen, Vida, Suárez, and de Fonseca); Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, Málaga, Spain (Dr Blanco); Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany (Dr Bilbao). fernando.rodriguez@fundacionimabis.org.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D063388:Endocannabinoids; D018698:Glutamic Acid; D005972:Glutaminase; D008071:Lipoprotein Lipase; D008994:Monoacylglycerol Lipases; D010739:Phospholipase D; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D017470:Receptors, Glutamate; D000099252:Fatty Acid Amide Hydrolases
keywords: cannabinoid; cocaine; glutamate; prefrontal cortex.; sensitization