Elevated environmental temperature and methamphetamine neurotoxicity
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
References (23)
- et al.
Phenobarbital and dizocilpine can block methamphetamine-induced neurotoxicity in mice by mechanisms that are independent of thermoregulation
Brain Research
(2001) Role of environmental stress on the physiological response to chemical toxicants
Environ. Res.
(2003)- et al.
Restraint as a stressor in miceagainst the dopaminergic neurotoxicity of D-MDMA, low body weight mitigates restraint-induced hypothermia and consequent neuroprotection
Brain Res.
(2000) - et al.
Differences between rats and mice in MDMA (methylenedioxymethamphetamine) neurotoxicity
Eur. J. Pharmacol.
(1988) Quantification of glial fibrillary acidic proteincomparison of slot-immunobinding assays with a novel sandwich Elisa
Neurotoxicol. Teratol.
(1991)- et al.
Characterizaton of the origins of astrocyte response to injury using the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Brain Res.
(1990) - et al.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage of striatal dopaminergic fibers attenuates subsequent astrocyte response to MPTP
Neurosci. Lett.
(1990) - et al.
Measurement of protein using bicinchoninic acid
Anal Biochem.
(1985) - et al.
Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in micepharmacological profile of protective and nonprotective agents
J. Pharmacol. Exp. Ther.
(1995) Hyperpyrexia as a contributory factor in the toxicity of amphetamine to aggregated mice
Br. J. Pharmacol.
(1962)