Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079
Received March 22, 1999; accepted December 22, 1999
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ABSTRACT |
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Key Words: neurotoxicity; microdialysis; ephedrine; striatum; dopamine; serotonin.
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INTRODUCTION |
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The mechanism(s) behind the lethality of preparations containing ephedrine appear similar to those involved in the toxicity/lethality of amphetamine and methamphetamine (Kalant and Kalant 1975; Keplinger et al., 1959
; Parmley 1963; Sellers et al. 1979
). In addition to their lethal effects, amphetamine and methamphetamine can produce neurotoxic effects in laboratory animals. Multiple doses of amphetamine and methamphetamine produce long-term neurotoxicity involving damage to dopaminergic terminals and long-term tissue-dopamine depletions in the CPu after administration of only twice the dose (3 to 5 mg/kg) necessary to induce stereotypy (Bowyer and Holson, 1995
; Seiden and Sabol, 1995
). Somatic degeneration of parietal cortex neurons can also occur at the same doses of amphetamine and methamphetamine (Commins and Seiden, 1986
; Eisch and Marshall, 1998
). At higher doses (10 to 15 mg/kg) of amphetamine and methamphetamine, specific thalamic nuclei and areas of the limbic system (Bowyer et al., 1998
; Schmued and Bowyer, 1997
) become targets for amphetamine-induced neurodegeneration. The brain levels of methamphetamine and amphetamine necessary to produce neurotoxicity in laboratory animals (Clausing et al., 1995
; Melega et al., 1995
) are less than or equal to that seen in postmortem brain from chronic methamphetamine abusers (Wilson et al., 1996
). However, the degree of neurotoxicity seen in human methamphetamine abusers has yet to be resolved (McCann et al., 1998
; Wilson et al., 1996
). In the rat, and to a lesser extent the mouse, the neurotoxicity produced by amphetamine and methamphetamine is dependent on the generation of hyperthermia during drug exposure (Bowyer et al., 1992
, 1993
, 1994
, 1998
; Bowyer and Holson, 1995
; Eisch and Marshall, 1998
; Miller and O'Callaghan, 1994
; Schmued and Bowyer, 1997
). However, little is known about whether ephedrine produces neurotoxicity similar to that produced by amphetamine and methamphetamine.
The current study was designed to determine the systemic doses of l-ephedrine necessary to produce hyperthermia in the rat, and the extracellular concentrations of ephedrine in the CPu after systemic doses of l-ephedrine which produce hyperthermia. In addition, increases in CPu extracellular levels of dopamine, 5-HT, and metabolites, as well as glutamate, after either l-ephedrine or d-amphetamine doses that cause hyperthermia, were determined. Finally, the potential for neurotoxicity to dopaminergic terminals was determined by measuring striatal tissue dopamine content 7 days after multiple doses of either l-ephedrine or d-amphetamine were administered. In vivo brain microdialysis was used to monitor changes in CPu extracellular levels of ephedrine and norephedrine, as well as changes in dopamine, serotonin, and glutamate levels. The effects of multiple doses of l-ephedrine that produced acute hyperthermia, and increases in CPu extracellular dopamine levels on striatal tissue dopamine levels 7 days after dosing were compared to the effects of neurotoxic doses of 4 x 5 mg/kg d-amphetamine. In addition, the effects of doses 4 x 25 mg/kg of l-ephedrine on CPu microdialysate levels of dopamine, serotonin (5-HT), and glutamate were compared to 4 x 5 mg/kg d-amphetamine. Comparing the effects of ephedrine with amphetamine should aid in evaluating the neurotoxic potential of ephedrine in humans. The more active (l) isomer of ephedrine was selected, rather than the (d) isomer (Chen and Schmidt, 1930), and was compared with the more active (d) isomer of amphetamine.
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MATERIALS AND METHODS |
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The Institutional Animal Care and Use Committee of the NCTR approved all the procedures involving animals. Studies were carried out in accordance with the declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health.
Drugs.
For these experiments, l-ephedrine HCl, l-norephedrine HCl, and d-amphetamine sulfate were purchased from Sigma Chemical Co. (St. Louis, MO). Amphetamines were dissolved in normal saline and injected ip. Concentrations of dosing solutions of l-ephedrine were verified using HPLC techniques described later.
Single doses of l-ephedrine.
The dose of l-ephedrine necessary to produce hyperthermia (core body temperatures of greater than 39.5°C) and pronounced hyperactivity in a 2223°C environment was determined. Rats were treated with 0, 20, or 40 mg/kg ip l-ephedrine, and rectal temperatures were recorded hourly. Activity levels were monitored after 20 and 40 mg/kg doses using 6 drug-naïve animals at each dose. The apparatus used to determine activity was a Plexiglas cube (46.5 x 46.5 x 46.5 cm) bisected with photo beams and interfaced with a computer (Ferguson et al., 1996). Each rat was weighed and placed into the cube for 60 min to determine the pre-drug (baseline activity), then injected with either 20 or 40 mg/kg l-ephedrine and observed for 2 h to determine post-drug activity. The activity was recorded as the number of beam breaks per h. Subsequently, a 40 mg/kg single dose of l-ephedrine was selected to be administered to rats implanted for the first microdialysis experiment (see below for details of microdialysis procedures), and levels of ephedrine and its metabolite norephedrine (phenylpropanolamine) were measured, as well as of dopamine, 5-HT, and their metabolites.
Multiple doses of either l-ephedrine or d-amphetamine.
As determined above, in the first set of neurotoxicity experiments a dose of 40 mg/kg l-ephedrine was chosen for repeated administration with dosing intervals of 3 h, because it produced a hyperthermia above 39.5°C or greater in all the animals tested. The controls were given 3 doses of 1 ml/kg saline. Although dosing intervals of 2 h were used for previous methamphetamine and amphetamine studies, an interval of 3 h was selected, since the half-life of ephedrine in the microdialysate appeared to be about 50% longer than that previously observed with amphetamine (Clausing et al., 1995). Initially, 3 instead of 4 doses of 40 mg/kg (3 x 40) l-ephedrine were given to rats not implanted for microdialysis, so that the total time of ephedrine exposure would be as long as with amphetamine. Body temperature was measured hourly for 9 h from the start of the l-ephedrine dosing. Rats were monitored for behavioral activity every 30 min, and for signs of behaviors commonly elicited by 5-HT receptor stimulation (e.g., head weaving, forepaw treading, retrograde propulsion; Jacobs et al., 1976) as well as other stereotypic behavior. Seven days later, rats were sacrificed for measurement of striatal aromatic monoamine levels (described below). Later, 3 groups of non-implanted animals were administered 4 doses, each dose given 2 h apart, of either 1 ml/kg saline, 25 mg/kg (4 x 25) l-ephedrine, or 5 mg/kg (4 x 5) d-amphetamine. These animals were also sacrificed 7 days post-dosing for striatal aromatic monoamine levels.
Early extreme hyperthermia and extensive cooling intervention was necessary with the 3 x 40 mg/kg l-ephedrine dosing paradigm. Because the cooling procedures used to prevent lethal hyperthermia can drastically interfere with in vivo microdialysis, a second dosing regimen of 4 x 25 mg/kg l-ephedrine was selected for the second microdialysis experiment to determine ephedrine, norephedrine and dopamine, 5-HT, and metabolite levels in CPu microdialysate. Also, this dosing paradigm produced temperature changes more commonly seen with 4 x 5 mg/kg d-amphetamine in a 2223°C environment. The third microdialysis experiment directly compared the effects of either 4 x 25 mg/kg l-ephedrine or 4 x 5 mg/kg d-amphetamine on CPu microdialysate levels of dopamine, 5-HT, and glutamate. Seven pairs of rats were run, with one of the pair receiving 4 x 25 mg/kg l-ephedrine, while the other was given 4 x 5 mg/kg d-amphetamine.
Brain microdialysis.
CPu microdialysis was carried out in the manner as previously described (Clausing et al., 1995). CMA microdialysis equipment (Carnegie Medicine, Stockholm, Sweden) was used and CMA/12 guide cannulae were implanted into the CPu using the coordinates AP 0.2 mm, LAT 3.0 mm, DV 5.5 mm relative to bregma (Paxinos and Watson, 1995
). The artificial cerebrospinal fluid (ACSF) was composed of: 145 mM NaCl, 1.5 mM KCl, 1.5 mM MgCl2*6H2O, 1.25 mM CaCl2*2H2O, 1 mM glucose, 1.5 mM K2HPO4, adjusted to pH 7.0 with HCl. After surgery, each rat was allowed a recovery period of 7 days.
On the morning of the experiment, each rat was hand-held as the CMA/12 dialysis probe (2-mm probe tip) was carefully inserted through the guide cannula into the right CPu. Microdialysate flow rate was held at 1.0 µl/min throughout, and fractions were collected every 20 min. In order that the aromatic monoamine levels in the microdialysate reached a relatively stable baseline, dosing did not begin until 2 h or more after probe insertion. Tubes that collected the fractions each contained 2 µl of 0.25 M phosphoric acid to acidify and stabilize the aromatic monoamines in the microdialysate as the fraction was collected. Each 20-min aliquot was immediately halved into 11-µl aliquots and frozen on dry ice. The frozen aliquots were then transferred to a 150°C freezer until analysis.
After microdialysis, each rat was sacrificed and the brain removed and fixed in 4% formalin for later verification of microdialysis probe location. In vitro probe recovery was performed to assess the functionality of the individual probes and to exclude non-functional probes from the experiment after each probe, was used in vivo. Percent in vitro probe recovery for ephedrine and norephedrine was determined as [concentration in collected sample x 100/concentration in standard solution] at 23°C and 1 ml/min flow rate. The estimated average in vitro probe recoveries for ephedrine and norephedrine for the probes used in these experiments ranged from 15 to 22%.
HPLC-quantitation of ephedrine and norephedrine.
Analyses of ephedrine and norephedrine were performed using modified high performance liquid chromatography (HPLC) methods previously developed to detect fenfluramine and norfenfluramine levels in plasma, brain, and microdialysate. Details of this HPLC method have been by described (Clausing et al., 1997). The only alteration necessary was a change in the HPLC elution gradient, which is shown in Table 1
.
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HPLC-quantitation of aromatic monoamine levels in microdialysate and striatum.
Striatal tissue levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), and 5-hydroxy-indole acetic acid (5-HIAA) were analyzed by electrochemical detection. For tissue striatal levels, each striatum was weighed and diluted with a measured volume (20% w/v) of 0.2-M perchloric acid containing 100 ng/ml 3,4-dihydroxybenzylamine (Sigma) as internal standard. After sonication and centrifugation, the supernatant was removed and injected directly onto the HPLC/EC system.
Samples were analyzed under the conditions previously described (Bowyer et al., 1995a) using reverse-phase HPLC. The isocratic mobile phase consisted of 92% KH2PO4-buffer (0.07 M, pH 3.0) and 8% methanol, containing 1 mM Na-1-heptanesulfonic acid and 0.2 mM Na2-EDTA per liter, and its flow rate was 1.0 ml/min. A Supelcosil LC18 3 µm analytical column (7.5 cm x 4.6 mm, Supelco, Bellefonte, PA) was used for separation, and a BAS-LC4B amperometric detector with a BAS-LC-17 oxidative flow cell was used for detection. For tissue samples, the detector was set at a sensitivity range of 5 nanoamperes while a 0.5- or 1-nanoampere range was used for microdialysate.
Microdialysate levels of dopamine, DOPAC, HVA, 3-methoxytryamine, 5-HT, and 5-HIAA were determined using reverse-phase HPLC by methods similar to Stephans et al. (1998). Dopamine, DOPAC, and 5-HIAA could be quantitated at 0.5 pg/10 µl microdialysate while 5-HT and HVA were measurable at the 1 pg/10 µl levels and 3-methoxytyramine at the 2 pg/10 µl level. For the 10-µl microdialysate plus 1 µl of 0.25 M phosphoric acid aliquots, 15 µl of HPLC mobile phase was added to adjust the pH, and the sample immediately injected onto the HPLC for analysis.
Statistics.
Data are presented as arithmetic mean ± standard error of the mean (SEM) unless otherwise indicated. Multiple groups were analyzed by either a one- or two-way analysis of variance (ANOVA) or a repeated measures two-way ANOVA. A post hoc Tukey's least-significant-difference test was applied if significant main effects were observed.
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RESULTS |
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The results of this experiment showed that the increases in CPu microdialysate levels of dopamine in the 4 x 25 mg/kg l-ephedrine group were less than one-half of the 4 x 5 mg/kg d-amphetamine group over the first 3 doses (Fig. 6, top). This difference was significant for the first 3 doses because there was a significant drug x time interaction (the F test yielded a value of F[19, 209] = 10.5). The post-hoc tests showed there was a significant difference in the dopamine levels at 20, 40, and 60 min after both the first and second doses, as well as at 40 min after the third dose. The increases in CPu microdialysate levels of 5-HT and glutamate were not significantly less in the 4 x 25 mg/kg l-ephedrine group compared to the 4 x 5 mg/kg d-amphetamine group (Fig. 6
, bottom; Fig. 7
, top). However, there were indications that, regardless of treatment, the animals with the greatest responses to hyperthermia and dopamine increases showed the greatest increases in 5-HT and glutamate (comparing individual levels with group levels). Changes in CPU microdialysate levels of DOPAC, HVA and 5-HIAA did not differ between the 2 groups (data not shown).
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DISCUSSION |
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Since l-ephedrine produced significantly less long-term reduction in striatal tissue dopamine when compared to either d-amphetamine (Table 4) or that previously seen with d-methamphetamine (Bowyer et al., 1992
, 1994
), differences between ephedrine and amphetamine with respect to the factors contributing to long-term depletions should also exist. The hyperthermia produced by either 3 x 40 mg/kg or 4 x 25 mg/kg l-ephedrine was equal to or greater than that produced by neurotoxic doses of either amphetamine or methamphetamine. Thus, the extent of hyperthermia is not a factor in the degree of long-term dopamine depletion differences seen with l-ephedrine and to d-amphetamine.
From the initial phases of the studies, the minimal serotonergic behavior (such as head weaving, forepaw treading, and retrograde propulsion; Jacobs, 1976) produced by l-ephedrine indicated that less 5-HT release might occur during l-ephedrine, compared to d-amphetamine, treatment. Although dopamine release has been implicated in the long-term depletions in 5-HT produced by methylenedioxyamphetamine (Schmidt et al., 1992), the role of 5-HT release or receptor stimulation on long-term dopamine depletions produced by methamphetamine and amphetamine is unclear. It has been postulated that fluoxetine enhances methamphetamine neurotoxicity by elevating brain levels of methamphetamine (Ricaurte et al., 1983
) but the effects of fluoxetine on extracellular 5-HT levels also might be a factor.
However, the increases in 5-HT levels seen in CPu microdialysate after 4 x 25 mg/kg l-ephedrine treatment were not significantly less than those produced by 4 x 5 mg/kg d-amphetamine despite the fact that serotonergic behaviors were rarely observed in the ephedrine group. Thus, we could find no direct evidence that a decrease in the extracellular CPu 5-HT levels during l-ephedrine exposure was a factor in the reduced long-term dopamine depletions produced by l-ephedrine compared to d-amphetamine. Nonetheless, increases in extracellular 5-HT levels may play a role in the long-term dopamine depletions, since they were significantly greater in animals that had the greatest increases in microdialysate dopamine and body temperature during exposure to either amphetamine or ephedrine. In contrast, 4 x 5 mg/kg d-amphetamine produced more than 2-fold greater increases in dopamine levels in the CPu microdialysate than 4 x 25 mg/kg l-ephedrine in the side-by-side comparison. Also, the rate of increase in CPu microdialysate dopamine was faster after amphetamine than after ephedrine, due to the more rapid rate of rise of amphetamine compared to ephedrine in the brain.
Although the 3 x 40 mg/kg dose of l-ephedrine should produce CPu extracellular dopamine levels more comparable to the 4 x 5 mg/kg d-amphetamine dose, the excessive cooling necessary to prevent lethality would obtund dopamine and 5-HT levels. The reduction in dopamine and 5-HT levels is not the only mechanism by which cooling would reduce long-term dopamine depletions. We have previously observed that animals dosed with 4 x 10 mg/kg d-amphetamine in a cold environment have higher CPu microdialysate dopamine levels than animals dosed with 4 x 5 mg/kg d-amphetamine at 23°C temperature but no significant long-term dopamine depletions (Bowyer et al., 1993). The cooling should also reduce oxidative stress, since indices of oxidative stress produced by quinones of dopamine are decreased when hyperthermia does not occur during methamphetamine exposure (LaVoie and Hastings, 1999
). Increased oxidative stress and reactive oxidative species of dopamine, such as 6-hydroxy-dopamine and quinones of dopamine, have been postulated to be mediators of dopamine neurotoxicity in the CPu (Graham, 1978
; O'Dell et al., 1991
; Seiden and Sabol, 1995
; Stokes et al., 1999
; Yamamoto and Zhu, 1998
). Thus, from these previous studies, it seems likely that the greater the dopamine release and hyperthermia the greater the generation of reactive dopamine-like species. However, it is possible that the increase of dopamine within the dopaminergic terminals of the CPu is primarily mediating long-term neurotoxicity (LaVoie and Hastings, 1999
).
CPu microdialysate levels of glutamate in the 4 x 5 mg/kg d-amphetamine group compared to the 4 x 25 mg/kg l-ephedrine group were not statistically different. Thus, differences in glutamate release and extracellular levels may not explain why ephedrine produces less dopamine depletion than amphetamine. Nonetheless, the data indicates that increased extracellular glutamate levels could play an important role in the long-term dopamine depletions since, like 5-HT levels, they were significantly greater in animals with the greatest increases in microdialysate dopamine and body temperature during exposure to either amphetamine or ephedrine.
The more than 4-fold increase in peak ephedrine levels in the microdialysate that occurred between the first and fourth doses of 25 mg/kg l-ephedrine cannot be explained by the t1/2 of 1.1 h obtained from a single dose of 40 mg/kg l-ephedrine. A 4-fold increase would be expected if the t1/2 was more than 3 h. It is possible that the prolonged hyperthermia produced by multiple doses has more of an effect on the pharmacokinetics than the shorter hyperthermia produced by a single dose. Hyperthermia has been shown to increase bioavailability and plasma levels of ephedrine in humans (Vanakoski et al., 1993). Also, amphetamine treatment increases lactic acid levels in the brain (Nahorski, 1980
; Zalis et al., 1967
) and microdialysate (Stephans et al., 1998
). It is possible that lactic acid accumulation in brain during amphetamine exposure leads to an increased t1/2 of amphetamine in microdialysate, particularly after the third and fourth doses (Fig. 7
, bottom; Clausing and Bowyer, unpublished data). A similar phenomenon may produce the elevation of l-ephedrine after multiple doses. Further studies examining the time course of plasma and brain tissue, as well as microdialysate levels of ephedrine and norephedrine, will be necessary to determine the potential alteration in ephedrine t1/2 that occurs during multiple dosing.
In summary, the doses of l-ephedrine tested produced parent-compound levels in the CPu microdialysate of 2 to 10 µM with the metabolite levels of norephedrine being less than 10% ephedrine. The peak levels of CPu microdialysate ephedrine were reached 40 to 80 min after dosing, which was 20 to 40 min after peak levels of amphetamine levels were attained; however, the pharmacokinetic mechanisms behind this difference were not determined. The increases in CPu microdialysate 5-HT levels as well as the hyperthermia induced after multiple doses of l-ephedrine did not significantly differ from that seen during amphetamine exposure. Also, microdialysate glutamate levels were not statistically different. However, the increase in microdialysate dopamine levels was significantly less in the 4 x 25 mg/kg l-ephedrine-treated rats compared to the 4 x 5 mg/kg d-amphetamine-treated rats. From the research of other investigators, it is possible that a reduced increase of dopamine within nerve terminals, which would also result in reduced extracellular levels, could be the prime factor in the lesser long-term striatal dopamine depletions produced by l-ephedrine. The enhancement of CPu dopamine levels produced by higher doses of l-ephedrine (3 x 40 mg/kg) may not increase dopamine depletions because of the early and extensive cooling necessary to prevent lethal hyperthermia.
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NOTES |
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