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  The Role of the P2X7 Receptor in Chronic Methamphetamine Abuse

  Anisha Kadubandi, Katherine E. Odegaard, and Sowmya V. Yelamanchili

  Methamphetamine, also known as crystal meth, is a powerful psychoactive stimulant affecting the central nervous system. Long-term misuse of the substance can lead to addiction, compulsive drug-seeking behaviors, functional and molecular changes within the brain, increased inflammatory response, changes in intracellular ATP leading to neurotoxicity within the brain, and alterations of the dopaminergic system in the limbic loop. Methamphetamine addiction is a rising concern in the United States and accounts for 15% of all drug overdose deaths. The purinergic P2X7 receptor is found in cells of the hematopoietic lineage as well as cells of other lineages, such as nervous tissue. It plays a role in synaptic transmission, and due to its inflammatory effects, it has been linked to chronic pain in neurocognitive disorders. A major symptom attributed to the neurological problems in meth addicts is chronic inflammation, which is caused by impaired energy metabolism in the brain. The ionotropic ATP receptor, P2X7, is involved in the regulation of neuroinflammation through maintaining energy homeostasis. However, how P2X7R is related to meth-induced neuronal damage is not entirely clear. Our preliminary work from in vitro studies revealed synaptodendritic damage in primary neuronal cultures, which were isolated from P2X7R knockout (K/O) mice, leading us to in vivo studies. The experimental methodology began with establishing a chronic meth mice regimen, which was administered three times a day via intraperitoneal injection. The treatment period was ten days in length and increased in dosage. After extracting the neuronal tissue from the prefrontal cortex, the synaptosomes were isolated and prepared into samples. Finally, the synaptic protein expression was measured using Western Blot. Our findings revealed that the P2X7R does, in fact, mediate meth-induced neurotoxicity by altering the critical synaptic proteins GluR5, GAD65, and ATP1a3. The upregulation in GluR5, GAD65, and ATP1a3 provides a potential explanation for the methamphetamine reinforcement and drug-seeking behavior, the development of amphetamine-type stimulant disorders, and the compensatory effect of high levels of meth-induced ATP being released into the cell system.