Testing the Efficacy of Ibudilast to Attenuate Meth-Seeking and Associated Synaptic Inflammation at the Synapse
Led by Dr. Gurudutt Pendyala University of Nebraska Medical Center
Prior to the start of this project, Dr. Pendyala graduated from RDAR COBRE funding. A description of the proposed project is provided below.
Study Overview:
While there is no approved medication to treat methamphetamine use disorder, the anti-inflammatory drug ibudilast (AV-411 or MN-166)—a phosphodiesterase inhibitor that modulates the activity of glial cells by suppressing the production of pro-inflammatory cytokines—shows promise as such a drug. Ibudilast has been fast-tracked by the U.S. Food and Drug Administration to treat progressive multiple sclerosis and is used as an anti-inflammatory in Japan. We demonstrated its efficacy in attenuating drug-seeking behavior (i.e., active lever presses) in male rats when meth was no longer available (i.e., extinction) (1), and research shows that the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) is down regulated in the synaptosomes of rats that self-administer methamphetamine. This effect was reversed by ibudilast treatment, which suggests a potential role of PEBP1 in the inflammation induced by chronic methamphetamine intake. While these findings are promising, there is a critical need for additional research to investigate the value of ibudilast as a possible treatment drug for methamphetamine use.
Study Specific Aims:
(Aim 1): Index a role for synaptic PEBP1 as a potential pathogenic marker for meth seeking between the sexes.
(Aim 2): Identify changes in neurochemical correlates by ibudilast as biological variables between the sexes.
Unique Study Procedures:
Animal-based preclinical research
Long-Term Goals:
The long-term goal of this research was to test the efficacy of ibudilast as a repurposed drug to treat synaptic targets of methamphetamine use disorder.
Dr. Gurudutt PendyalaProject Director
The overarching goal of my research is understanding how chronic drug addiction (opioids, psychostimulants such as methamphetamine, nicotine) leads to synaptic alterations and subsequent behavioral changes. My lab uses various model systems including human biospecimens, rodent models and in vitro based approaches. Current ongoing research funded by the NIH in my laboratory focuses on understanding the role of extracellular vesicles (EVs) in the damaging effects of methamphetamine and nicotine between the sexes using drug-triggered reinstatement (relapse) of extinguished intravenous meth self-administration in rats including testing the application of anti-inflammatory drugs (cf. Ibudilast) to attenuate behavioral, synaptic and subsequent drug seeking. Another arm of research ongoing in my lab is understanding how prescription drug abuse during and after pregnancy impacts neurodevelopment in the exposed offspring. We are studying synaptic and behavioral changes in the exposed offspring during the course of neurodevelopment i.e. during neonatal, juvenile and young adulthood including the role of sex differences. A common chord connecting these two arms of my research program is the application of high throughput ‘omics’ approaches (genomics, transcriptomics, proteomics, metabolomics etc) to identify novel pathogenic markers including delineating their downstream mechanisms.