The Modulatory Role of TAAR1 in Neurotoxicity of Substituted Amphetamines Public Deposited
Methamphetamine (MA) use is a global epidemic, causing mental, physical, and societal damage. Although dopamine (DA) dysregulation is the hallmark of MA-induced neurotoxicity,
many underlying mechanisms remain unknown. The trace amine-associated receptor 1 (TAAR1) is activated by numerous agonists, including MA and 3,4 methylenedioxymethamphetamine (MDMA). Activation of TAAR1 inhibits DA neuronal firing and decreases rewarding effects of amphetamines, suggesting TAAR1 mitigates their harmful effects. This dissertation investigated the regulatory role of TAAR1 on transitory and sustained neurotoxic effects of amphetamines in a mouse model. Neurotoxicity was assessed through quantification of striatal biomarkers indicative of DA terminal degeneration and astrocyte activation. Thermal response to amphetamines was also recorded as hyperthermia exacerbates neurotoxicity and hypothermia can provide neuroprotection.