Characterization of binge-dosed methamphetamine-induced neurotoxicity and neuroinflammation

Abstract

Methamphetamine (MA) is a potent, highly addictive psychostimulant abused by millions of people worldwide. MA induces neurotoxicity, damaging striatal dopaminergic terminals, and neuroinflammation, with striatal glial activation leading to pro-inflammatory cytokine and reactive oxygen species production. It is unclear whether MA-induced neuroinflammation contributes to MA-induced neurotoxicity. In the current study, we examined the linkage between the time course and dose response of MA-induced neurotoxicity and neuroinflammation. Adult male mice underwent a binge dosing regimen of four injections given every two hours with doses of 2, 4, 6, or 8 mg/kg MA per injection, and were sacrificed after 1, 3, 7, or 14 days. Binge MA treatment dose-dependently caused hyperthermia and induced hypoactivity after one day, though activity returned to control levels within one week. Striatal dopamine (DA) was diminished one day after treatment with at least 4 mg/kg MA, while DA turnover rates peaked after seven days. Although striatal tyrosine hydroxylase and DA transporter levels were also decreased one day after treatment with at least 4 mg/kg MA, they trended toward recovery by day 14. All doses of MA activated striatal glia within one day. While astrocyte activation persisted, microglial activation was attenuated over the two weeks of the study. These findings help clarify the relationship between MA-induced neuroinflammation and neurotoxicity, particularly regarding their temporal and dose-specific dynamics.

Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity

“…At peak astrocyte activation (2 days post-administration), increases in GFAP expression were even larger with MA 2.5 and 5 mg/kg increasing GFAP expression greater than two-fold in Taar1 -WT mice and three-fold in Taar1 -KO mice. This magnitude of change is commensurate with previous research using MA doses less than 10 mg/kg (Thomas et al , 2004;McConnell et al , 2015) and indicates that TAAR1 may play an even more significant role in astroglial activation than DA terminal degeneration.…”

“…An increase in GFAP expression peaks 2–3 days after MA administration and correlates with increased neurotoxicity, inflammatory response, and ROS (O’Callaghan & Miller, 1994;Lau et al , 2000;McConnell et al , 2015), though it can also increase independently of decreases in markers such as TH and DA (Pu & Vorhees, 1993;Miner et al , 2017). We report the novel finding that astrocyte activation in response to MA is increased when TAAR1 is not activated.…”

“…A second time point of 7 days was chosen as a reflection of sustained neurotoxicity. Under similar treatments and doses, DA, TH and GFAP remain significantly altered at 7, 14 and 21 days post-treatment (O’Callaghan & Miller, 1994;Ladenheim et al , 2000;McConnell et al , 2015). Although TH levels are still significantly decreased 30 days later, some recovery from peak depletion is observed (Ares-Santos et al , 2014).…”

“…MA also increases striatal glutamate (GLU) levels leading to excitotoxicity and increased levels of ROS, contributing to terminal degeneration (Yamamoto & Raudensky, 2008). MA dose-dependently increases striatal DA terminal degeneration (Sonsalla et al , 1989;Ares-Santos et al , 2014;McConnell et al , 2015), although the mesolimbic pathway is spared (Granado et al , 2010;Kuhn et al , 2011) and is characterized by a decrease in striatal DA markers: tyrosine hydroxylase (TH), the rate limiting enzyme for DA synthesis, DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and DAT and VMAT2 levels (O’Callaghan & Miller, 1994;Guilarte et al , 2003;Eyerman & Yamamoto, 2007). Striatal astrocyte activation, another robust marker of neurotoxicity, is characterized by expression of glial fibrillary acidic protein (GFAP) (O’Callaghan & Sriram, 2005).…”

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone

“…In mouse studies, this toxicity primarily impacts dopaminergic axons in the forebrain (Moratalla et al, 2015). METH elicits a pronounced depletion in both tissue DA content and in protein markers of dopaminergic terminals, including the dopamine transporter (DAT) and the synthetic enzyme tyrosine hydroxylase (TH) (McConnell et al, 2015). This toxicity is widely thought to be mediated by oxidative stress, as evidenced by increases in reactive oxygen and nitrogen species, resulting in damage to cellular components (Yamamoto and Raudensky, 2008).…”