Sergios Charntikov1, Steven T Pittenger1, Ishwor Thapa2, Dhundy R Bastola2, Rick A Bevins1, Gurudutt Pendyala3. 1. Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, USA. 2. Department of Computer Science, University of Nebraska-Omaha, Omaha, NE, USA. 3. 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.
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. CONCLUSION: 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.
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. CONCLUSION: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: Steven T Pittenger; Shinnyi Chou; Scott T Barrett; Isabella Catalano; Maxwell Lydiatt; Rick A Bevins Journal: Pharmacol Biochem Behav Date: 2017-07-13 Impact factor: 3.533
Authors: Kyle T Brown; Sophia C Levis; Casey E O'Neill; Alexis L Northcutt; Timothy J Fabisiak; Linda R Watkins; Ryan K Bachtell Journal: Brain Behav Immun Date: 2017-08-13 Impact factor: 7.217
Authors: Subhash Chand; Austin Gowen; Mason Savine; Dalia Moore; Alexander Clark; Wendy Huynh; Niming Wu; Katherine Odegaard; Lucas Weyrich; Rick A Bevins; Howard S Fox; Gurudutt Pendyala; Sowmya V Yelamanchili Journal: J Extracell Vesicles Date: 2021-12
Authors: Steven T Pittenger; Shinnyi Chou; Nathen J Murawski; Scott T Barrett; Olivia Loh; Juan F Duque; Ming Li; Rick A Bevins Journal: Pharmacol Biochem Behav Date: 2021-01-08 Impact factor: 3.697
Authors: Rahul S Guda; Katherine E Odegaard; Chengxi Tan; Victoria L Schaal; Sowmya V Yelamanchili; Gurudutt Pendyala Journal: Int J Mol Sci Date: 2021-06-15 Impact factor: 5.923