Elevated environmental temperature and methamphetamine neurotoxicity

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Abstract

Amphetamines have been of considerable research interest for the last several decades. More recent work has renewed interest in the role of ambient temperature in both the toxicity and neurotoxicity of these drugs. We have determined that the striatal dopaminergic neurotoxicity observed in the mouse is linked in some fashion to both body and environmental temperature. Most studies of d-methamphetamine (d-METH) neurotoxicity are conducted at standard laboratory ambient temperatures (e.g., ∼21–22°C) and utilizing a repeated dosage regimen (e.g., three to four injections spaced 2 h apart). A lowering of the ambient temperature provides neuroprotection, while an elevation increases neurotoxicity. d-METH causes long-term depletions of striatal dopamine (DA) that are accompanied by other changes that are indicative of nerve terminal degeneration. These include argyrophilia, as detected by silver degeneration stains, and an elevation in glial fibrillary acidic protein (GFAP), a marker of reactive gliosis in response to injury, as well as a long-term decrease in tyrosine hydroxylase (TH) protein levels. Here we show that increasing the ambient temperature during and for some time following dosing increases the neurotoxicity of d-METH. Mice (female C57BL6/J) given a single dosage of d-METH (20 mg/kg s.c.) and maintained at the usual laboratory ambient temperature show minimal striatal damage (an ∼15% depletion of DA and an ∼ 86% increase in GFAP). Substantial striatal damage (e.g., an ∼70% depletion of DA and an ∼200% elevation in GFAP) was induced by this regimen if mice were maintained at 27°C for 24 or 72 h following dosing. An increase in neurotoxicity was also apparent in mice kept at an elevated temperature for only 5 or 9 h, but keeping animals at 27°C for 24 or 72 h was the most effective in increasing the neurotoxicity of d-METH. Our data show how a relatively minor change in ambient temperature can have a major impact on the degree of neurotoxicity induced by d-METH. Single-dose regimens may aid in uncovering the as yet unknown mechanism(s) of substituted amphetamine neurotoxicity because they reduce the inherent complexity present in repeated dosage regimens.

Introduction

Many factors impact toxicity. The toxic agent, the exposure situation, and the organism itself are primary among these factors (Casarett and Doull, 1973). The exposure situation is by far the least studied, although it is known that variables related to exposure such as environmental temperature can have a significant impact on toxicity. In general, toxicologists evaluate agents for toxic qualities under ideal conditions that involve little or no stress to the organism. Most laboratories are maintained at temperature, humidity, and lighting conditions that are considered optimal for the health of the animal. Although it is acknowledged that exposure to toxic agents in the real world rarely occurs under ideal conditions, it is uncommon for less than ideal conditions to be utilized in a laboratory setting (see Gordon (2003) for a further discussion of these issues).

The substituted amphetamines, such as amphetamine (AMP), methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyamphetamine (MDA), are a good example of a series of related compounds which have toxic and neurotoxic properties which are affected by environmental temperature. Early work described the hyperthermia associated with exposure to these agents and the possible role that this increased body temperature might play in aggregate toxicity (Askew, 1962; Chance, 1946; Swinyard et al., 1961). However, the impact of environmental temperature on the toxic, and in particular neurotoxic, properties of these agents had been left unexamined until recently (Bowyer and Holson, 1995; Bowyer et al., 2001b; Miller and O’Callaghan, 1994). Recent interest in environmental temperature and substituted amphetamine toxicity has, in part, been generated by the reports of deaths due to 3,4-methylenedioxymethampetamine or “Ecstasy.” It is speculated that the hyperthermic actions of the compound experienced in conjunction with the high ambient temperatures found in dance clubs or at “raves” are responsible for the exacerbation of the toxicity (Chadwick et al., 1991; Randall, 1992).

Over the last several years we and others have been examining the impact of environmental temperature on the neurotoxicity of the substituted amphetamines (Bowyer and Holson, 1995; Bowyer et al. (2001a), Bowyer et al. (2001b); Johnson and Miller, 2001; Miller and O’Callaghan, 1994; O’Callaghan and Miller, 2001). When these agents are given to the mouse under certain dosing conditions (e.g., repeated dosing) they cause long-term depletions of striatal dopamine (DA) that are accompanied by other changes that are indicative of nerve terminal degeneration. These include argyrophilia, as detected by silver degeneration stains, and an elevation in glial fibrillary acidic protein (GFAP), a marker of reactive gliosis in response to injury, as well as a long-term decrease in tyrosine hydroxylase (TH) protein levels (O’Callaghan and Miller, 1994). Environmental temperature can modulate these neurotoxic effects (Miller and O’Callaghan, 1994). For example, slight modulations in room temperature can alter neurotoxicity such that a change in temperature from 20.5°C to 23.5°C significantly exacerbates neurotoxicity. Further, maintaining mice at 15°C during repeated dosing is totally neuroprotective (Johnson et al., 2000). Here we examined whether increasing the ambient temperature to 27°C following a single injection of a dosage of d-methamphetamine (d-METH) capable of causing only minimal striatal damage (i.e., limited gliosis and DA depletion) would produce a greater degree of neurotoxicity. In effect, our data show that increasing the environmental temperature following d-METH exposure is equivalent to increasing the dosage.

Section snippets

Materials

The following chemicals were kindly provided by or obtained from the sources indicated: d-METH and high-performance liquid chromatography (HPLC) standards (Sigma Chemical Co., St. Louis, MO, USA), and d-MDMA (Research Technology Branch of the National Institute on Drug Abuse, Rockville, MD, USA), BCA protein assay reagent and bovine serum albumin (Pierce Chemical Co., Rockford, IL, USA); reagents used for HPLC were of HPLC grade (ESA, Chelmsford, MA, USA). The materials used in the GFAP assay

Effects of elevated ambient temperature on animal status and the hyperthermia caused by d-METH

Although mice receiving a single dose of d-METH (20 mg/kg) were hyperactive and hyperthermic, there were no unusual behaviors (e.g., self-mutilation, etc.) or lethality associated with this dosing regimen. Informal observation revealed no overt differences between mice treated with saline or d-METH by 24 h after injection.

All mice given a single dosage of 20 mg/kg of d-METH showed a significant elevation in body temperature whether maintained at normal (∼21–22°C) or an elevated (27°C) ambient

Discussion

Several of the substituted amphetamines, including METH, AMP, MDMA, and MDA can serve as striatal dopaminergic neurotoxicants in the mouse, especially when repeated dose regimens are used (Logan et al., 1988; Miller and O’Callaghan, 1994). These agents cause long-term depletions in DA that are accompanied by other changes indicative of nerve terminal degeneration. These include argyrophilia, as detected by silver degeneration stains, and an elevation in GFAP, a marker of reactive gliosis, as

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