THE ROLE OF P2X7R IN METHAMPHETAMINE-INDUCED BEHAVIORAL CHANGES AND MICROGLIAL EFFECTOR FUNCTIONS [article]

(:Unkn) Unknown, Raghava Potula, University, My
2020
Methamphetamine (METH) is a powerful psychostimulant with a high abuse liability. Due to its potent and long lasting effects in the central nervous system (CNS), METH addiction is a major and growing public health concern. Dextro-METH or the racemic mixture of the two isomers can be consumed through oral, nasal, and anal administrations, or injected intravenously or subcutaneously, and there is no FDA approved therapeutic for the treatment of METH addiction. METH abuse causes many deleterious
more » ... many deleterious physiological effects, such as anxiety, mood disturbances, and visual and auditory hallucinations. In addition, neuroimaging studies have demonstrated altered structural and functional changes in the brain associated with emotion and memory, as well as reduced motor speed and impaired verbal learning. Current literature implicates microglia, the resident macrophages of the CNS, as major mediators of the neurological side effects. Upon activation, microglia undergo a morphological change to an amoeboid shape with increased capacity for migration, phagocytosis and cytokine production. Although the initial microglial activation is poorly understood, METH-induced microgliosis precedes dopaminergic neurotoxicity, and drugs that prevent glial activation are candidate therapies for METH addiction. Microglia express purinergic receptors, ligand-gated ion channels, which have been implicated in a variety of chronic inflammatory and neurodegenerative processes. In particular, P2X7R is activated by pathological concentrations of ATP. I show the concurrent increases in P2X7R expression with Iba-1, a marker of microglial activation after chronic METH treatment in vivo. I confirmed the METH-induced increases in P2X7R protein and mRNA expression in the Embryonic Stem cell derived microglia (ESdM) cell line. siRNA knockdown of P2X7R in ESdM significantly reduced the METH-induced TNF-α secretion, compared to scrambled siRNA. Furthermore, I demonstrated METH-induced microglial migration and phagocytosis is blocked by pretreatment with a P2X7R [...]
doi:10.34944/dspace/1189 fatcat:b63zt66zpzcmxh6rebwz46cpru