title: Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats.
abstract: BACKGROUND
  Chronic methamphetamine intake has been shown to induce a neuroinflammatory state leading to significant changes in brain functioning including behavioral changes. These changes can persist for years after drug use is discontinued and likely contribute to the risk of relapse. A better understanding of inflammation responses associated with methamphetamine intake may help in designing novel and more efficacious treatment strategies.
  
  
  METHODS
  Rats were trained to self-administer methamphetamine or saline on a variable ratio 3 schedule of reinforcement (25 days). This training was followed by 12 days of extinction (i.e., methamphetamine unavailable) during which rats received daily post-session administration of ibudilast (AV411; 2.5 or 7.5mg/kg) or saline. Following extinction, synaptosomes were isolated from the prefrontal cortex (PFC) and the differential pattern of synaptic proteins was assessed using mass spectrometry based proteomics.
  
  
  RESULTS
  Treatment with ibudilast allowed for deeper extinction of active lever pressing. Quantitative mass spectrometry based proteomics on the PFC identified one potential hit; the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1). While methamphetamine intake was associated with reduced PEBP1 protein levels, treatment with ibudilast reversed this effect. Furthermore, decreased PEBP1 expression was correlated with subsequent activation of Raf-1, MEK, and ERK signaling components of the mitogen-activated protein kinase cascade (MAPK). Raf-1, MEK, and ERK expression levels were also attenuated by ibudilast treatment.
  
  
  CONCLUSIONS
  PEBP1, given its synaptic localization and its role as a signaling molecule acting via the ERK/MAPK pathway, could be a potential therapeutic target mediating drug-seeking behaviors associated with neuroinflammation.
authors.affiliation: Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, USA.
authors.forename: Sergios
authors.initials: S
authors.lastname: Charntikov
authors.affiliation: Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pittenger
authors.affiliation: Department of Computer Science, University of Nebraska-Omaha, Omaha, NE, USA.
authors.forename: Ishwor
authors.initials: I
authors.lastname: Thapa
authors.affiliation: Department of Computer Science, University of Nebraska-Omaha, Omaha, NE, USA.
authors.forename: Dhundy R
authors.initials: DR
authors.lastname: Bastola
authors.affiliation: Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, USA.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Bevins
authors.affiliation: Developmental Neuroscience Department, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA; Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: gpendyala@unmc.edu.
authors.forename: Gurudutt
authors.initials: G
authors.lastname: Pendyala
mesh_terms: D000818:Animals; D058999:Drug-Seeking Behavior / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000494:pharmacology*; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects; D040901:Proteomics; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D012055:Reinforcement Schedule; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism*; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D008694:Methamphetamine; D049488:Phosphatidylethanolamine Binding Protein; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles
keywords: Ibudilast; Methamphetamine; Neuroinflammation; PEBP1; Proteomics; Synapse