• Amphetamine;
  • dopamine;
  • drugs of abuse;
  • glucocorticoids;
  • neurotoxicity


  1. Top of page
  9. Acknowledgements
  10. References

Aims  Methamphetamine is an amphetamine derivative that is abused increasingly world-wide at an alarming rate over the last decade. Pre-clinical and human studies have shown that methamphetamine is neurotoxic to brain dopamine and serotonin. Other lines of study indicate that stress enhances the vulnerability to drug abuse. The purpose of this review is to shed light on the biochemical similarities between methamphetamine and stress in an effort to highlight the possibility that prior exposure to stress may interact with methamphetamine to exacerbate neurotoxicity.

Methods  A review of the literature on methamphetamine and stress was conducted that focused on the common neurotoxic and biochemical consequences of methamphetamine administration and stress exposure.

Results  Experimental findings of a large number of studies suggest that there are parallels between stress and methamphetamine with regard to their ability to increase glutamate release, produce a metabolic compromise and cause oxidative damage.

Conclusion  A combination of methamphetamine administration and stress can act synergistically and/or additively to cause or augment toxicity in brain regions such as striatum and hippocampus.


  1. Top of page
  9. Acknowledgements
  10. References

Methamphetamine, a derivative of amphetamine, is a powerful sympathomimetic drug that affects the central nervous system (CNS). Some of the CNS actions include increased wakefulness and physical activity, hyperthermia, anorexia, euphoria and enhanced mental alertness, as well as irritability, insomnia and tremors. Methamphetamine abuse has increased dramatically world-wide, and epidemiological studies indicate that approximately 4.9% of the American population had tried methamphetamine at least once in their life-time [1]. The increasing use of methamphetamine emphasizes the need for a better understanding of its pharmacological actions and its long-lasting effects on the brain.

Pre-clinical research supports the view that methamphetamine administration is neurotoxic in both rodents and non-human primates. This is evidenced by long-term depletions in striatal dopamine (DA) and serotonin (5-HT) markers such as DA and 5-HT tissue content [2–4], decreases in tyrosine hydroxylase and tryptophan hydroxylase [5], loss of DA and 5-HT transporters [6] and structural degeneration of DA terminals [3]. Human studies in abstinent methamphetamine abusers using positron emission tomography have documented a significant loss of DA transporters [7], which appears to be associated with reduced motor function and memory impairments [8].

The experience of stress is common to all living organisms and both human and animal studies indicate that vulnerability to drug abuse is enhanced by stressful events. A stress response is elicited when sensations and observations do not match existing or anticipated perceptions and expectations [9]. A primary endocrine response to stress is the secretion of glucocorticoids (GCs) [corticosterone in rats; cortisol CORT in humans] through the activation of the hypothalamic–pituitary–adrenal axis [10]. Although their release serves to maintain homeostasis during acute episodes of stress [11], prolonged stress responses have been associated with structuralbrain damage both in humans [12,13] and animals [14,15]. In humans, stress enhances drug craving [16], and relapse to drug use is more likely to occur in individuals exposed to high levels of stress [17]. Similarly, animal studies have shown that both acute and chronic stress increase the self-administration of psychostimulants (for review see [18]). Moreover, both methamphetamine and stress alter neurotransmitter release and GC secretion. Methamphetamine increases the extracellular concentrations of both DA and glutamate (GLU) [19], as does stress [20–24]. Conversely, inhibition of increases in GCs by adrenalectomy or administration of the GC synthesis inhibitor metyrapone reduces extracellular concentrations of DA in the nucleus accumbens under basal conditions and in response to psychostimulants [25,26]. Interestingly, recent findings from our laboratory indicate that exposure to chronic unpredictable stress prior to methamphetamine administration enhances methamphetamine-associated toxicity in the rat striatum [27].

Despite the similarity in the neurochemical responses between stress and methamphetamine, it is surprising how little is known about how stress interacts with the neurotoxic effects of methamphetamine. This review will elucidate the major neurotoxic and biochemical consequences of methamphetamine and stress in an effort to shed light on how prior exposure to stress may interact with methamphetamine to further potentiate neurotoxicity.


  1. Top of page
  9. Acknowledgements
  10. References

Methamphetamine administration

DA and GLU are elevated by methamphetamine and the resultant oxidative stress is known to contribute to their toxic effects. Oxidative stress is defined as the cytotoxic consequences of reactive oxygen species (ROS) (e.g. O2, OH). Exogenous administration of methamphetamine also causes production of free radicals, as evidenced by the formation of hydroxylated metabolites of salicylate (2, 3 dihydroxybenzoic acid) and d-phenylalanine (p-tyrosine) in the striatum [28–30].

Increases in ROS can adversely affect DNA, lipid and cellular proteins, resulting in nucleotide oxidation, lipid peroxidation or protein nitration, respectively. These consequences of oxidative stress produced by methamphetamine are reflected by increases in the lipid peroxidation product, malonyldialdehyde in the striatum and hippocampus [30–33]. Furthermore, repeated methamphetamine administration significantly increased the appearance of oxidized proteins as indicated by protein carbonyls, in both striatum and hippocampus [32]. Methamphetamine also selectively reduces the endogenous antioxidant glutathione (GSH) in the striatum [34] and increases the appearance of oxidized glutathione [35]. Conversely, methamphetamine-associated striatal toxicity is attenuated by antioxidants, lipid peroxidation inhibitors and spin trapping compounds which inactivate free radicals. Treatment of rats with antioxidants (e.g. ascorbic acid, mannitol and vitamin E) prior to methamphetamine administration attenuates striatal DA and 5-HT depletions, while inhibition of superoxide dismutase (SOD), an antioxidant enzyme, exacerbates depletions [36]. Similarly, pre-treatment with the spin trapping agents phenylbutylnitrone (PBN) or the free radical scavenger (Z)-α-[2-thiazol-2-yl)imidazol-4-yl]-N-tert butylnitrone (S34176) attenuates the long-term striatal DA depletions observed after methamphetamine [30,37,38]. Along these lines, over-expression of the antioxidant enzyme copper/zinc SOD (Cu/Zn SOD) can protect against striatal methamphetamine-induced neurotoxicity [39].

The mechanisms underlying the methamphetamine-induced oxidative stress and the resulting toxicity may be associated with DA oxidation related to changes in vesicular monoamine transporter 2 (VMAT-2). VMAT-2 is responsible for the sequestration of DA into vesicles and methamphetamine administration decreases tetrabenazine binding to VMAT-2 [40], causes a decrease in VMAT-2 immunoreactivity in the vesicle fraction [41] and decreases DA uptake into vesicles [42]. Thus, changes in VMAT-2 binding and function can increase DA in the cytoplasm to form ROS (e.g. H2O2, O2, OH) and DA quinones [28,43,44]. Dopamine quinones formed after methamphetamine could bind to cysteinyl residues to form protein-bound cysteinyl catechols, which are selectively toxic to DA terminals [44]. In contrast, both quinone formation and toxicity to DA are attenuated by antioxidants (ascorbic acid, glutathione) [45]. Taken together, these findings suggest that the formation of free radicals and quinones may be the result of decreases in VMAT-2 function and expression. The resultant increases in cytoplasmic DA concentrations could then promote the formation of ROS and quinones, thereby damaging the DA terminal.

Overall, studies have demonstrated that the administration of neurotoxic doses of methamphetamine, both in vivo and in vitro, causes DA oxidation leading to the formation of DA-derived ROS and quinones. The association between oxidative stress, pro-oxidant species, a compromised antioxidant pool and the toxicity to DA terminals is supported further by the attenuation of toxicity by antioxidant administration prior to the administration of methamphetamine.


In vitro and in vivo studies suggest that overexposure to GCs as a result of chronic stress or GC treatment leads to ROS accumulation and the production of oxidative stress. CORT or the synthetic GC, dexamethasone (DEX) increases the generation of ROS in both cortical and hippocampal cultures and augments the vulnerability of hippocampal neurons to an oxidative insult [46,47]. The oxidative role and damaging effects of GCs are supported further by the finding that the production of ROS in DEX-treated hippocampal progenitor cells is associated with apoptotic cell death and DNA fragmentation [47]. Furthermore, prenatal exposure to DEX increases the susceptibility of cerebellar cells to oxidative stress caused by the oxidants H2O2 and methylmercury, as noted by a significant increase in apoptotic cells [48].

Chronic or acute stress significantly increases lipid peroxidation in whole brain or various brain structures, including hippocampus and cortex [49–52]. Moreover, stress-induced increases in protein carbonyls have been reported after immobilization stress in cortex and striatum, a treatment condition that also causes oxidative damage to nuclear DNA in cortex [49]. Collectively, these findings support a role for stress and stress-related hormones in brain oxidative damage.

A possible mechanism by which stress or stress-associated hormones may contribute to oxidative damage may be a compromised brain antioxidant defense system. Antioxidant enzymes [e.g. SOD, catalase, glutathione peroxidase (GSPx)] prevent oxidative damage to cells by catalyzing electron transfer. Chronic stress (restraint, social stress) has been associated with significant reductions in cortical GSH or in whole brain GSH content [50,52]. The association between chronic stress and antioxidants is supported further by findings that administration of CORT significantly decreased the activity of the Cu/Zn SOD and GSPx in the hippocampus, cortex and cerebellum [53], as well as levels of both reduced and oxidized forms of GSH in hippocampal cultures [54]. Similarly, decreases in the activity of another antioxidant, catalase, have been reported in cerebellar granule cells after prenatal exposure to DEX, a treatment that also increased the sensitivity of those cells to oxidative stress [48]. Therefore, a decrease in the antioxidant capacity of the brain may be responsible for the stress-related oxidative damage.

All the aforementioned parallels between methamphetamine and stress support the hypothesis that a combination of methamphetamine and environmental stress may have an additive or synergistic effect on oxidative stress. To date, our laboratory has shown enhanced methamphetamine-associated toxicity in both striatum and hippocampus after chronic unpredictable stress [27,55], but no studies have examined directly whether this effect is mediated by oxidative stress. However, it has been shown recently that chronic swim stress down-regulates VMAT-2 in the striatum [56]. Considering the important role of VMAT-2 in cytoplasmic DA sequestration, it could be hypothesized that stress-associated changes in this transporter may lead to enhanced methamphetamine-associated oxidative damage. In support of this hypothesis, recent findings from our laboratory suggest that stress prior to methamphetamine administration significantly depletes striatal VMAT-2 immunoreactivity with a parallel enhanced depletion of striatal DA (unpublished observations).


  1. Top of page
  9. Acknowledgements
  10. References

Methamphetamine administration

Glutamate is considered the major excitatory neurotransmitter in the mammalian CNS. The action of GLU is mediated via the activation of ionotropic [ligand-gated ion channels; N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)] and metabotropic (G protein-coupled) receptors. Although glutamate is essential for the modulation of excitatory synaptic transmission, prolonged elevations of extracellular concentrations of this neurotransmitter can have toxic effects and underlie the etiology of a number of neurodegenative diseases (for review see [57,58]). Glutamate-associated excitotoxicity is initiated by the overactivation of glutamate receptors which leads to elevations in intracellular Ca2+ and the activation of nitric oxide synthase (NOS) (for review see [59,60]). Activation of NOS generates nitric oxide (NO) and superoxide (O2) which interact to form peroxynitrite (ONOO-), a strong oxidant that can initiate neuronal damage [61,62].

It has been reported that methamphetamine administration increases extracellular glutamate in the striatum [19,63,64] and hippocampus [65]. Interestingly, the increase in striatal GLU is delayed and prolonged as indicated by significant elevations for at least 32 hours after the last injection of methamphetamine [66]. Our laboratory has shown that methamphetamine appears to increase striatal GLU via a polysynaptic pathway [67]. This process is characterized by enhanced activation of D1 receptors present on the presynaptic striatonigral terminals [68], which enhances GABA release within the substantia nigra pars reticulata [69,70], resulting in a decrease in GABAergic nigrothalamic activity and a subsequent disinhibition of corticostriatal GLU [67]. Recent data indicate that the methamphetamine-associated increases in GLU are paralleled by an up-regulation in the expression of vesicular glutamate monoamine transporter 1 (VGLUT1) in the striatum [66]. Because VGLUT1 determines the amount of GLU loaded into vesicles [71] and consequently the release of GLU (for review see [72]), methamphetamine-associated increases in the expression of VGLUT1 may contribute to the prolonged elevation and release of striatal GLU following methamphetamine administration.

Several studies suggest that GLU synergizes with DA to cause methamphetamine-induced depletions of DA tissue content [19,64]. Agents that prevent GLU overflow protect from subsequent methamphetamine-associated striatal toxicity despite increases in extracellular DA [19]. Along these lines, the local perfusion of methamphetamine directly into the striatum does not increase extracellular glutamate and does not cause striatal toxicity despite significant acute elevations in extracellular DA [73] (Fig. 1a,b). Furthermore, our laboratory has reported that although local perfusion of methamphetamine is not neurotoxic, co-perfusion of methamphetamine with GLU results in DA tissue depletions at warm ambient temperatures (28–38°C) [74]. In separate experiments conducted using rats maintained at normal ambient temperatures (21°C), we have shown a similar synergism between the local perfusion of methamphetamine and higher GLU concentrations (500 µm) on long-term DA depletions (Fig. 2). Thus, it appears that methamphetamine-induced damage to DA terminals requires increases in DA, GLU and hyperthermia.


Figure 1. Effects of systemic (10 mg/kg i.p.) or local (100 µm) perfusion of methamphetamine on extracellular concentrations of DA and GLU in the striatum. Systemic injections were administered every 2 hours (indicated by arrows), while local perfusion occurred over a period of 8 hours (shaded bar). (a) Both systemic and local adminstrations increased DA levels, although the pattern of release depended on the route of administration. Systemic administration increased DA concentrations 1 hour after each injection. Intrastriatal perfusion of methamphetamine caused a persistant elevation of extracellular DA. Data are expressed as mean ± SEM of picograms per 20 µl of dialysate. (b) Effects of systemic (10 mg/kg i.p.) or local (100 µm) methamphetamine administration on extracellular concentrations of GLU in the striatum. Only systemic administration caused a delayed rise in GLU levels. There was no significant increase in extracellular glutamate compared with baseline during the local perfusion of methamphetamine. Data were analyzed with a one-way repeated-measures ANOVA and are expressed as mean ± SEM of picograms per 20 µl of dialysate. *Significant difference between the two routes of administration beginning 2 hours after initiation of treatment, P < 0.05. Figure adapted from [73]

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Figure 2. Striatal DA tissue content of rats perfused locally with methamphetamine (100 µm) or in combination with GLU (500 µm). Local perfusion of methamphetamine or GLU alone did not deplete striatal DA concentrations. Co-perfusion of GLU and methamphetamine, but not GLU alone, significantly depleted DA tissue content in the striatum. Data are expressed as mean ± SEM of picogram per microgram of protein and were analyzed using an unpaired t-test. *Significant depletion in DA content compared to the condition of local perfusion of GLU alone, P < 0.05

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The consequences of the increases in extracellular GLU produced by methamphetamine appear to be related to a receptor-mediated increase in neuronal NOS expression [75]. Antagonism of ionotropic (NMDA/AMPA) or metabotropic (mGluR5) receptors blocks the methamphetamine-associated toxicity in the striatum [76–79] or hippocampus [80]. Administration of NOS inhibitors or ONOO- scavengers prior to methamphetamine treatment protects fully against striatal DA depletion [81–84], while nNOS-knock-out mice are resistant to methamphetamine toxicity [85]. These findings indicate that the formation of RNS as a result of GLU elevations is an important step leading to methamphetamine neurotoxicity.

In addition to the formation of RNS, GLU-induced increases in intracellular Ca2+ activate a number of calcium-dependent proteases, such as calpain I. Calpain causes proteolysis of the cytoskeletal membrane protein, spectrin, and has been demonstrated to be evidence of excitotoxicity [86] associated with cell death in various neurodegenerative conditions including ischemia [87] or traumatic brain injury [88]. Recent findings from our laboratory indicate methamphetamine-associated increase in striatal spectrin proteolysis that is mediated through AMPA receptor activation [89]. This study provided the first evidence of excitotoxic damage in the striatum after methamphetamine administration. Overall, methamphetamine-associated damage to the dopaminergic terminals may be the result of excitotoxic mechanisms triggered by the increases in extracellular GLU, stimulation of AMPA receptors and the resultant production of RNS and activation of calcium activated proteins, leading to spectrin proteolysis and neuronal damage.


Elevations in extracellular GLU have also been associated with stress. Exposure to acute or chronic stressors increases GLU levels in various brain regions such as hippocampus, prefrontal cortex, striatum and nucleus accumbens [20,24,90–92] as well as basal GLU release from hippocampal synaptosomes [93]. Interestingly, this enhanced glutamatergic response to stress is attenuated by adrenalectomy [94,95]. In addition, the increases in GLU observed after CORT administration parallel elevations in plasma CORT [90]. Based on these data, it has been postulated that stress-associated increases in brain extracellular GLU may be GC-dependent.

Although GLU release and activation of GLU receptors is very important for neurotransmission, its accumulation in the synaptic cleft and the resulting overstimulation of GLU receptors may lead to excitotoxic neuronal damage and an increase in vulnerability of neurons to various insults. Existing evidence indicates that anatomical alterations in the hippocampus after CORT administration or stress are mediated by enhanced excitatory tone. Agents that block GLU release (e.g. phenytoin) or antagonize NMDA receptors (e.g. MK-801) protect against stress and CORT-associated dendritic atrophy in the hippocampus [96,97]. Chronic stress augments neurotoxin-associated damage and this damage is NMDA-dependent [98]. Similarly, CORT administration or stressexacerbated kainic acid (KA)-induced increases in hippocampal extracellular GLU [99], as well as neuronal injury evidenced by augmented neuron loss, spectrin proteolysis and tau immunoreactivity [100]. Along the same lines, the synergism of the cytotoxic effects of CORT and NMDA exposure in vitro was prevented by the NMDA antagonist MK-801 [101]. Taken together, these findings support the hypothesis that GLU is the primary cause of GC-associated morphological changes and suggest a synergy between GC and GLU in stress-induced structural damage.

The regulation of extracellular GLU is regulated tightly by its uptake via transporter proteins (for review see [102]). It serves to reason that possible stress-related changes in the expression of these transporters may be associated with elevations in GLU and the resulting excitoxicity. In fact, recent data suggest that chronic stress up-regulates the expression of the glial glutamate transporter (GLT-1) in the hippocampus as a compensatory mechanism in response to the elevations in extracellular GLU [55,103,104]. The association between GLU uptake and extracellular GLU is further supported by the prevention of GLT-1 up-regulation in the hippocampus by agents (i.e. lithium, tianeptine) which prevent hippocampal damage (i.e. dendritic atrophy) associated with stress-induced elevations of GLU [103,104]. In addition, CORT exposure in vitro significantly inhibited GLU uptake, thus increasing the vulnerability of neurons by exacerbating extracellular GLU concentrations [105].

Stress-related increases in extracellular GLU may contribute to excitotoxicity via increases in NO production due to the interaction of NO with O2 to form ONOO- anions (for review see [60]). Chronic stress increases NO production in whole brain homogenates [51,52], or more specifically in cortex and hippocampus under conditions that also cause lipid peroxidation [50,106]. Interestingly, chronic stress up-regulates the NO system, whereas the iNOS inhibitor, aminoguanidine [50,107,108] blocks both the increase in NO as well as the production of oxidative stress [50].

There is a paucity of studies that have examined the interaction between glutamate mediated excitoxicity produced by methamphetamine and its relationship to chronic stress. Data from our laboratory indicate that prior exposure to chronic unpredictable stress enhances the increases in extracellular concentrations of glutamate in the hippocampus and striatum in response to methamphetamine [109,110]. The augmented glutamatergic response in the hippocampus is coincident with a stress-related increase in VGLUT-1 expression [109], and may mediate the depletions of hippocampal 5-HT or the augmentation of methamphetamine-induced depletions of striatal DA content after the combination of chronic unpredictable stress and methamphetamine [27,55,110].


  1. Top of page
  9. Acknowledgements
  10. References

Methamphetamine administration

Mitochondria are unique among other organelles for their role in the generation of cellular ATP via the electron transport chain, formation of ROS and buffering of calcium. Recent emerging studies demonstrated that neurotoxic doses of methamphetamine compromise mitochondria function through inhibition of the electron transport chain and a resultant reduction in ATP levels that precede the long-term depletions in DA tissue content [111]. Specifically, systemic administration of methamphetamine acutely disrupts complex IV of the mitochondrial chain, as indicated by decreases in cytochrome oxidase staining in areas densely innervated by DA terminals (i.e. striatum, nucleus accumbens, substantia nigra) [112]. Recent evidence demonstrates that methamphetamine also decreased striatal complex II activity (i.e. succinate dehydrogenate) within hours after drug administration [113]. It should be noted, however, that the alteration in energy metabolism has been only associated, but not linked directly, with methamphetamine-induced damage to DA terminals. Regardless, a reduction in energy production by methamphetamine in combination with increases in energy utilization, as implied by high levels of lactate in both striatum and medial prefrontal cortex [4], may be due in part to the methamphetamine-induced hyperthermia and hyperactivity (for review see [114]). In contrast, administration of compounds (i.e. ubiquinone, nicotinamide) that enhance ATP production protects against DA depletions in striatum and prefrontal cortex [4]. Because the conversion of glutamate to glutamine is dependent on Na+/K+ ATPase (for review see [102]), this striatal energy impairment raises the possibility of a further potentiation of methamphetamine-associated toxicity by enhanced glutamatergic tone. Therefore, the methamphetamine-associated decreases in both production and levels of ATP may contribute to the toxicity to DA terminals after methamphetamine administration.

Several lines of evidence indicate that elevations in extracellular GLU after methamphetamine may contribute to mitochondrial dysfunction. It is well established that GLU-associated excitotoxicity is mediated by mitochondrial damage through stimulation of the NMDA receptor, massive calcium influx, the attenuation of mitochondrial membrane potential, and an increase in the permeability of the transition pore resulting in cell death [115]. An additional link between GLU and mitochondrial impairment in methamphetamine-associated toxicity is highlighted by findings that the administration of the NMDA receptor antagonist, MK-801 or the peroxynitrite scavenger 5,10,15,20-tetrakis (2,4,6-trimethamphetamineyl-3,5-sulphonatophenyl) porphinato iron III (Fe-TPPS), which inhibits increases in peroxynitrite, prevents the decrease in complex II activity produced by methamphetamine [113]. The methamphetamine-associated decrease in complex IV activity (cytochrome c oxidase) [112] appears to be mediated by the production of NO which, in turn, can inhibit complex IV [116]. Furthermore, the increases in striatal GLU and the subsequent damage to DA terminals after the simultaneous intrastriatal perfusion of the complex II inhibitor malonate and methamphetamine [73,117], and the blockade of the malonate-dependent increases in GLU by the NMDA receptor antagonist MK-801 [117] support further the role of glutamate in mitochondrial dysregulation as a mediator of methamphetamine-associated toxicity. Thus, inhibition of energy metabolism due to enhanced GLU overflow is an additional and important component of the methamphetamine-associated neurotoxicity.


Stress could affect mitochondria, as evidenced by changes in cellular respiration and ATP production through the stress-associated overproduction of NO [50]. More specifically, chronic stress significantly inhibits the activities of mitochondrial respiratory chain complexes I/III, II/III and IV that, in turn, are prevented by administration of the iNOS inhibitor aminoguanadine during the stress period [50]. In addition, the deleterious effects of stress on mitochondria can also be mediated partially by GCs and their receptors on brain mitochondria [118]. Pre-natal DEX treatment impairs mitochondrial function, as revealed by a lower rate of calcium uptake and a decrease in oxygen consumption [48]. Exposure to DEX in vitro inhibits complex I and V activities [119] and CORT exacerbates ATP loss after hypoxia [120]. Similar effects of stress or CORT treatment on mitochondrial function are also observed in peripheral tissues [121,122]. Moreover, changes in mitochondria are not limited to biochemical parameters but are also reflected in changes in brain mitochondrial volume. For example, a chronic treatment of CORT (56 days) significantly reduced the mitochondrial volume fraction in the hippocampal apical dendritic neuropil of CA3 [123], although other researchers reported no changes in the hippocampal mitochondrial surface density after 3 days of CORT administration [124].


  1. Top of page
  9. Acknowledgements
  10. References

Pre-exposure of rats to chronic stress enhances the hyperthermic response to methamphetamine [27]. Based on this finding, it could be hypothesized that the exacerbation of methamphetamine-induced toxicity may be mediated by enhanced hyperthermia in animals pre-exposed to chronic stress. It is well documented that methamphetamine-associated hyperthermia mediates, in part, the neurotoxic effects of the drug, possibly through compromised mitochondrial function in the DA terminal [112,113] or alterations in the DA transporter, resulting in increased uptake of methamphetamine [125]. Furthermore, prevention of hyperthermia or exposure to cold ambient temperatures during methamphetamine administration attenuates the long-term decreases in DA and 5-HT content [41,44,126,127], decreases in tryptophan hydroxylase activity and increases in ROS (e.g. 3,4-DHBA formation) [29]. However, it should be noted that although hyperthermia per se may contribute to methamphetamine-induced damage, agents such as reserpine can attenuate methamphetamine-associated hyperthermia but do not protect against methamphetamine toxicity [128]. Nevertheless, stress could enhance the hyperthermic response to methamphetamine and exacerbate methamphetamine toxicity in that manner. In fact, recent reports have shown that chronic unpredictable stress augments 5-HT (2 A/C) receptor-mediated hyperthermia even weeks after exposure to stress [129], and that pre-exposure to chronic stress enhanced methamphetamine-associated hyperthermia and striatal DA toxicity [27]. It remains to be determined if the interaction between stress, methamphetamine and hyperthermia is brain region-dependent, as blockade of the augmented hyperthermia attenuates only striatal DA depletions [110], whereas it blocks completely the methamphetamine-induced 5-HT depletions in the hippocampus observed in rats pre-exposed to stress and treated subsequently with methamphetamine (unpublished observations).


  1. Top of page
  9. Acknowledgements
  10. References

There are close parallels between stress and methamphetamine related to their propensities to increase GLU and DA and the associated oxidative and metabolic damage (Fig. 3). Both methamphetamine and stress increase the production of ROS to compromise cellular integrity by targeting DNA, lipid and cellular proteins. Oxidative damage can be potentiated further by depletions of endogenous antioxidant systems caused by either methamphetamine administration or stress exposure. Moreover, and similar to methamphetamine, stress increases extracellular concentrations of GLU, activates RNS and triggers excitotoxic mechanisms. Finally, both treatments compromise mitochondrial function by disrupting the electron transport chain and causing ATP depletion. These collective findings support the conclusion that a combination of methamphetamine administration and stress can act synergistically and/or additively to cause or augment toxicity to DA and 5HT terminals [27,55]. Despite the recent evidence of a potentially dangerous interaction between the excitotoxic effects of stress and methamphetamine administration, it remains to be determined how stress enhances the glutamatergic response to methamphetamine [109,110]. Regardless, the elucidation of the biochemical underpinnings related to the stress-induced enhancement of methamphetamine neurotoxicity may provide insight into the etiology of the high comorbidity associated with substance abuse and post-traumatic stress disorder [16,130].


Figure 3. Stress can contribute to the toxic effects of methamphetamine through three interdependent but different pathways, including dopamine-mediated oxidative damage, glutamate-initiated excitotoxicity and mitochondrial dysfunction. DA: dopamine, VMAT-2: vesicular monoamine transporter 2, ROS: reactive oxygen species, RNS: reactive nitrogen species, ETC: electron transport chain, NO: nitric oxide

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  9. Acknowledgements
  10. References

This work was supported by grants DA07606, DA16866, DAMD17-99-1-9479, and a gift from Hitachi America, Inc. We would like to thank Dr Kristan Burrows for the results illustrated in Figs 1 and 2.


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