Disparity in the temporal appearance of methamphetamine-induced apoptosis and depletion of dopamine terminal markers in the striatum of mice

Abstract

Methamphetamine (METH) causes damage in the striatum at pre-and post-synaptic sites. Exposure to METH induces long-term depletions of dopamine (DA) terminal markers such as tyrosine hydroxylase (TH) and DA transporters (DAT). METH also induces neuronal apoptosis in some striatal neurons. The purpose of this study is to demonstrate which occurs first, apoptosis of some striatal neurons or DA terminal toxicity in mice. This is important because the death of striatal neurons leaves the terminals in a state of deafferentation. A bolus injection (i.p.) of METH (30 mg/kg) induces apoptosis (TUNEL staining) in approximately 25% of neurons in the striatum at 24 h after METH. However, in contrast to apoptosis, depletion of TH (Western blotting) begins to appear at 24 h after METH in dorsal striatum while the ventral striatum is unaffected. The peak of TH depletion (approximately 80% decrease relative to control) occurs at 48 h after METH. Autoradiographic analysis of DAT sites showed that depletion begins to appear 24 h after METH and peaks at 2 days (approximately 60% depletion relative to control). Histological analysis of the induction of glial fibrillary acidic protein (GFAP) by METH in striatal astrocytes revealed an increase at 48 h after METH that peaked at 3 days. These data demonstrate that striatal apoptosis precedes the depletion (toxicity) of DA terminal markers in the striatum of mice, suggesting that the ensuing state of deafferentation of the DA terminals may contribute to their degeneration.

Ammonia Mediates Methamphetamine-Induced Increases in Glutamate and Excitotoxicity

“…The increases in GFAP expression are indicative of astrocyte activation presumably in response to damage and is consistent with previous studies that have demonstrated increases in GFAP expression days to weeks after exposure to a neurotoxic dose of METH (O'Callaghan and Miller 1994;Zhu et al, 2005). Astrocyte activation after METH exposure is a likely consequence of damage to monoamine terminals in the striatum (Bowyer et al, 1994;O'Callaghan and Miller 1994) and cell body damage in the somatosensory cortex (Pu et al, 1996).…”

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

“…Greater loss of TH-IR in the lateral versus the medial striatum of wild-type mice after METH treatment confirms previous reports (Joyce et al, 2004;O'Callaghan and Miller, 1994;Koike et al, 2005) and extends this observation to the striatum of mice 9.5 months after METH treatment. The reason for less TH-IR loss in the medial versus lateral striatum of WT mice is unknown, but may be attributable to a greater density of DAT normally in the lateral striatum of rodents (Ciliax et al, 1995;Watanabe et al, 2004;Zhu et al, 2005). In contrast, TH-IR loss in the medial striatum was greater in GDNF ϩ/Ϫ mice than in WT mice, consistent with an overall increase in striatal DAT activity in the GDNF ϩ/Ϫ mice.…”

Single or multiple injections of methamphetamine increased dopamine turnover but did not decrease tyrosine hydroxylase levels or cleave caspase‐3 in caudate‐putamen

“…In fact, Fukumara et al (1998) found that a single dose of 20 mg/kg METH reduced TH immunoreactivity 3 days posttreatment. Also, Zhu et al (2005) demonstrated that using a single bolus of METH (30 mg/kg) does not cause depletion of TH at 16 or 24 h, but induced TH depletion at 2 days, reaching the lowest point 3 days after exposure. These might suggest that down-regulation of TH and other events at the DA terminals (e.g., inhibition of vesicular DA uptake (Brown et al, 2000)) must precede the depletion of TH.…”