A single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein

doi:10.1016/S0006-8993(98)00656-8

Brain Research

Volume 806, Issue 1, 21 September 1998, Pages 1-7

https://doi.org/10.1016/S0006-8993(98)00656-8 Get rights and content

Abstract

The neurotoxic effects of a single administration of methamphetamine (MA) were studied under conditions conducive to MA-induced hyperthermia. After a single dose of MA (10, 20, 30, or 40 mg/kg, s.c.) or saline (3 ml/kg) to Sprague–Dawley CD rats, rectal temperatures were monitored for 9 h in a room with an ambient temperature of 22.0±0.5°C. MA induced significant dose-dependent hyperthermia, however, no significant increase in mortality occurred. Neostriatal DA, 5-HT, TH, and GFAP were assayed 3 days following treatment. MA induced dose-dependent reductions of DA, 5-HT and TH, and increased GFAP. For DA, at doses of 20, 30, or 40 mg/kg the reductions were to 71%, 49%, and 29%, and for 5-HT were to 73%, 44%, and 19% of control values. No reductions were seen after the 10 mg/kg dose. Semiquantitative analysis Western blots of TH and GFAP demonstrated that TH was reduced to 52%, 75%, and 28%, and GFAP was increased to 125%, 134%, and 149% of control values at MA doses of 20, 30, or 40 mg/kg, respectively. No significant changes in TH or GFAP were seen at the 10 mg/kg MA dose. These results demonstrate that a single-dose of MA can be as effective as the widely used four-dose every 2 h regimen. Moreover, mortality can be minimized by monitoring core body temperature and preventing MA-induced hyperthermia from exceeding 41.5°C.

Introduction

One of the first reports of methamphetamine (MA)-induced neurotoxicity was in monkeys following chronic treatment [20]. Efforts to develop a rodent model of MA-induced neurotoxicity employed either very large doses (50 or 100 mg/kg) administered twice per day for four or more days 2, 18, 19, 26, 27or moderate doses (15 mg/kg) administered every 6 h for 24 h 12, 13. While such treatments were effective at reducing caudate–putamen dopamine (DA) by 30–40%, they also caused severe toxicity. For example, in studies using 50–100 mg/kg doses of MA, mortality rates were reported of 40–50% in rats 2, 18, 19, 26, 27.

In 1988, Sonsalla and Heikkila [21]introduced a more effective and less toxic MA dosing regimen in mice in which four doses of 10 mg/kg each of MA were administered every 2 h. This approach produced large reductions in caudate–putamen DA and the effects have proven reliable 15, 17, 22, 23. This regimen was later extended to rats, where it produced 60% reductions in caudate–putamen DA 3, 6; reductions greater than obtained with the earlier models.

Methamphetamine-induced neurotoxicity has been shown to be directly correlated to the degree of MA-induced hyperthermia 3, 6. Conditions which either enhance or inhibit MA-induced hyperthermia increase or decrease, respectively, the magnitude of DA and tyrosine hydroxylase (TH) reduction in the caudate-putamen 3, 6.

While the multiple-dose MA treatment regimen introduced by Sonsalla et al. 21, 22, 23has proven beneficial to investigations of MA-induced neurotoxicity, multiple dosing regimens present obstacles to mechanistic studies. For example, in a recent investigation of the neuroprotective effects of α-phenyl-N-tert-butyl nitrone (PBN) on MA-induced neurotoxicity, the optimal number and timing of PBN pretreatments could not readily be determined [7]. The extent to which a four-dose MA-treatment regimen necessitates a four-dose pretreatment with PBN to effectively inhibit neurotoxicity was unclear as was the interval between PBN pretreatment and each MA treatment. When a multiple dose treatment regimen is used, parametric studies to determine the optimal dose and timing of pretreatments generally become difficult. If MA-induced neurotoxicity could be effectively produced by a single dose, however, then a systematic exploration of pre- or post-treatment intervals and doses could be more effectively explored. With this in mind and the newer information on the enhancing effect of small increases in ambient temperature on MA-induced neurotoxicity, we sought to develop a single-dose MA model which would produce large reductions in caudate–putamen DA without increasing lethality.

Section snippets

Animals

Male Sprague–Dawley CD rats (251–275 g) were purchased from Charles River Laboratories (Raleigh, NC). The rats were housed individually in cages with controlled temperature (22±2°C) and lighting (14:10 h light–dark cycle). Food and water were given ad libitum. Animals were housed in a vivarium fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care.

Drug treatment and temperature monitoring

Animals were transferred to a room with a temperature of 22±0.5°C, 30 min prior to drug administration.

MA-induced mortality and hyperthermia

In the present study MA did not induce a significant increase in mortality at any of the doses employed (Table 1).

The rectal temperature vs. time curve is shown in Fig. 1 and the maximum temperature (T_max) increase in Fig. 2. MA administration significantly increased T_max at all doses (p<0.01 compared to saline controls). The maximum temperature increase induced by administration of MA was dose-dependent and T_max at 40 mg/kg was significantly higher than that at 10 or 20 mg/kg (p<0.01).

Neostriatal monoamine content

The

Discussion

The data demonstrate that a single dose of d-MA as low as 20 mg/kg effectively reduces neostriatal DA, 5-HT, and TH under appropriate conditions (although GFAP was increased significantly only at 30 and 40 mg/kg). Although these effects were evaluated at only one time point (three days post-treatment), the results are comparable to those induced by others using the typical four-dose treatment regimen 3, 6, 10, 11, 16, 24, 25. For example, at the highest dose tested (40 mg/kg), DA was reduced by

Acknowledgements

This work was supported by NIH grant DA06733 and Shiseido.

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¹: Currently at Shiseido Research Center, 1050 Nippacho, Kohokuku, Yokohama, 223, Japan.

²: Currently at WIL Research Laboratories, 1407 George Rd., Ashland, OH 44805-9281, USA.

³: Currently at the Department of Pathology, University of Tennessee College of Medicine, Memphis, TN 38163, USA.

⁴: Currently at Exxon Biomedical Sciences, Toxicology Division, Mettlers Rd., CN 2350, East Millstone, NJ 08875-2350, USA.

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Research reportA single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein

Abstract

Introduction

Section snippets

Animals

Drug treatment and temperature monitoring

MA-induced mortality and hyperthermia

Neostriatal monoamine content

Discussion

Acknowledgements

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Dev. Brain Res.

Neurotoxicol. Teratol.

Life Sci.

Brain Res.

Brain Res.

Drug Alcohol Depend.

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Brain Res. Bull.

Brain Res. Bull.

Brain Res.

Drug Alcohol Depend.

Research report
A single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein