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Published in final edited form as: Behav Brain Res. 2019 Dec 3;380:112413. doi: 10.1016/j.bbr.2019.112413

The Acute Toxic and Neurotoxic Effects of 3,4-methylenedioxymethamphetamine are More Pronounced in Adolescent than Adult Mice

Neha Milind Chitre 1, Monique Simone Bagwell 1, Kevin Sean Murnane 1
PMCID: PMC6984008  NIHMSID: NIHMS1546460  PMID: 31809766

Abstract

3,4-methylenedioxymethamphetamine (MDMA) recently achieved breakthrough status from the Food and Drug Administration (FDA) for post-traumatic stress disorder (PTSD). However, evidence indicates that exposure to toxic doses of 3,4-methylenedioxymethamphetamine (MDMA) can lead to long-lasting dysregulation of brain monoaminergic neurotransmitters, primarily from studies conducted in young adult rodents. To date, there is a paucity of data on whether toxic doses of MDMA can differentially affect neurotransmitter systems in adolescents and mature adults, which is an important question as adolescents and adults may be differentially vulnerable to MDMA abuse.

In the current study, adolescent (6–7 weeks of age) and adult (16–18 weeks of age) male, Swiss-Webster mice were exposed to MDMA (20 mg/kg) using a binge-like dosing regimen (4 administrations spaced every 2 hours). Acute lethality, acute hyperthermia, and acute decreases in body weight effects following MDMA administration were more pronounced in adolescent than adult mice. Likewise, acute loss of striatal dopamine neurochemistry was also exacerbated in adolescents, as determined by high-pressure liquid chromatography (HPLC) coupled to electrochemical detection. Exposure to MDMA induced greater turnover of dopamine into its major metabolite dihydroxyphenylacetic acid (DOPAC) in adolescents, but not in adults, suggesting a novel mechanism through which adolescents may show increased vulnerability to the acute toxic and neurotoxic effects of MDMA, or conversely that mature adults show greater protection. These data caution that MDMA exposure in adolescence may be particularly dangerous and that the therapeutic window for MDMA may differ between adolescents and mature adults.

Keywords: MDMA, adolescence, neurotoxicity, lethality, dopamine, dopamine turnover

1. Introduction

In recent years, research has examined the potential clinical uses of 3,4-methylenedioxymethamphetamine (MDMA), particularly in the treatment of post-traumatic stress disorder (PTSD). Using therapeutic regimens, no drug-related or neurocognitive adverse effects of MDMA have been reported [1]. This has led to use of MDMA in combination with psychotherapy recently receiving breakthrough therapy status by the FDA [2].

Despite the potential therapeutic role of MDMA for PTSD, the consequences of exposure to amphetamines have been a serious cause of concern. Amphetamine exposure has been associated with neural alterations such as dysregulation of monoamine neurotransmitters [3] as well as proteins involved in their regulation [4]. MDMA has been reported to elicit neurotoxic and neuroinflammatory effects, as well as behavioral changes in both experimental animals and humans [5]. While studies suggest correlations between MDMA exposure and psychopathology, more studies are needed to ascertain the nature of these relationships [6].

The effects of MDMA are known to be influenced by the species examined, as MDMA elicits distinct effects in different species [7–9]. Despite the differences observed in the effects of MDMA across models, murine models such as Swiss Webster mice, have been successfully used to study the behavioral, physiological, and neurochemical effects of MDMA [10–12]. It is important to note, however, in the mouse model, MDMA elicits pronounced dopaminergic depletions [13] that are known to occur within 72 hours of exposure and persist for up to 8 weeks without major recovery [14]. MDMA exposure in mice is associated with reduced levels of dopamine transporter positive fibers in the caudate-putamen and medial prefrontal cortex, along with reduced levels of tyrosine hydroxylase (TH)-positive nigral neurons [15]. We have previously reported that dosing regimens of MDMA engender loss of striatal dopamine neurochemical levels in adult Swiss-Webster mice [10]. Although mice do not exhibit face validity for other species that show more selective serotonin deficits, the mechanisms by which MDMA dysregulates monoamine neurotransmitters may generalize across species, and mice can be useful in the study of these mechanisms as well as subject factors (such as age) that affect the toxicity of MDMA.

Adolescence is a period of particular vulnerability to stress and trauma, and substance abuse rates are high during this period, especially the initiation of illicit drug consumption and the consumption of potentially dangerous combinations of drugs [16]. Adolescence may also be a period of heightened vulnerability to the adverse effects of MDMA as previous studies have shown that combinations of MDMA and alcohol in adolescents produce potentially synergistic hippocampal toxicity and memory deficits [17]. Additionally, adolescent exposure to MDMA induces striatal dopamine dysregulation that may persist into adulthood [18]. Use of MDMA in dangerous settings, such as raves and night clubs, that may compound MDMA toxicity through increased ambient temperatures and crowded conditions may be more frequent in the young. Preclinical research indicates that crowding amplifies dopaminergic neurotoxicity in adolescent mice but not in adult mice [19]. Human studies report that adolescent users of MDMA are more susceptible to escalating their dose of MDMA, due to the development of tolerance [20]. Despite these findings, to date, there is a paucity of data on whether MDMA can differentially affect neurotransmitter systems in adolescents and adults, and many previous studies have focused on young adult mice that are intermediate in age to adolescents and mature adults. Therefore, in the current study, adolescent (6–7 weeks of age) and mature adult (16–18 weeks of age) male, Swiss-Webster mice were exposed to MDMA (20 mg/kg) using a binge-like dosing regimen. Swiss-Webster mice were chosen for these studies because these mice are a general purpose strain that has been used extensively to study behavior [21] physiology [22] and the acute and persistent toxic effects of amphetamines [10] and cathinones [23]. We measured the effects of MDMA in these two groups on acute lethality, acute hypothermia, and acute reduction in body weight. Additionally, we also used these two groups to study the effects of MDMA on cortical and striatal neurochemistry, to directly compare different aspects of the physiological toxicity and neurotoxic effects of MDMA in adolescents compared to adults.

2. Materials and Methods

2.1. Animals

The test subjects were male Swiss-Webster mice (Charles River Laboratories; Wilmington, MA). The mice were separated into an adolescent group with subjects that weighed 25–28 grams and ranged in age from 6–7 weeks and an adult group with subjects that weighed 38–46 grams and ranged in age from 16–18 weeks. The mice were housed 3 per cage in a temperature regulated room and were maintained at this housing density during MDMA treatment. All mice had ad libitum access to food and water. Mice were housed in rooms maintained in a 12-hour light/dark cycle. All experiments were conducted during the light phase (7:00 am–7:00 pm) and at typical ambient temperatures (22–23°C). All experiments were conducted using protocols approved by the Mercer University Institutional Animal Care and Use Committee.

2.2. Drugs and Chemicals

3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine hydrochloride were purchased from Sigma-Aldrich (St. Louis, MO). Perchloric acid (HClO4) was purchased from GFS Chemicals (Powell, OH). Hydrochloric acid (HCl) was purchased from Carolina Biological Supply Company (Burlington, NC). MDMA was purchased from Sigma Aldrich (St. Louis, MO).

2.3. Dosing Regimen

Mice were exposed to saline or MDMA (20 mg/kg) using a binge-like dosing regimen with the unit dose or vehicle administered 4 times with 2 hours separating each administration (QID, q2h) All injections were administered intraperitoneally at a volume of 0.01 ml physiological (0.9%) saline (vehicle) or drug solution (dissolved in vehicle) per gram body weight of each mouse. All doses are reported in the salt form. Amphetamine derivatives [10] and cathinone stimulants [23] induce persistent neurochemical depletions as well as disruption of learning and memory under this dosing regimen. All treatments are described as the unit dose per administration. Animals were sacrificed on the fifth day post treatment and brains were extracted for neurochemical analysis. This time period was selected as it has shown to produce neurotoxic effects using a binge-like dosing regimen of MDMA at a dose of 20 mg/kg [10, 24]. Due to the possible non-linear pharmacokinetics of MDMA, this dosage was selected to achieve metabolic saturation in both adolescent and adult mice as even lower dosages achieve metabolic saturation in adult Swiss-Webster mice [62.

2.4. Body Weight and Rectal Temperature

The body weight of the animals was recorded by placing each animal on a calibrated scale, prior to each injection and then at two hours after the last injection. Similarly, rectal temperature was recorded by placing a lubricated probe 1.5 cm into the rectum prior to each injection and two hours after the final injection. The readings for temperature were recorded on reaching a steady state from the readout from a connected TH-8 Thermalert temperature monitor (Physitemp Instruments; Clifton, NJ, USA).

2.5. Brain Dissection

Animals were sacrificed on the fifth day post injections and brains were extracted for neurochemical analysis. Mice were euthanized by cervical dislocation and decapitation and their brains were extracted on ice, and snap frozen for storage at −80°C for subsequent analysis. On the day of analysis, brains were thawed at 4°C and placed in an ice-cold mouse brain matrix. Brain coronal slices (1 mm thickness) were made using a razor blade and were placed on a cold metal plate over ice. A 1.5 mm diameter tissue biopsy-punch was used to obtain specific regions of interest (prefrontal cortex and striatum) from the individual slices for further neurochemical analysis as we have described previously [10, 23].

2.6. Neurochemical Measurements

The individual frozen tissue punches were weighed, and sonically disrupted in 100 μl of 0.3 N HClO4 to produce a homogenate. The tissue homogenate was centrifuged for 10 minutes at 4°C at 17,000 g to remove cellular debris. A 100 μl aliquot of the supernatant was placed in an WPS-3000TBSL autosampler maintained at 10°C, and 10 μl was injected onto a Thermo Scientific (Waltham, MA) Hypersil BDS C18 column (35°C) with Thermo Scientific Dionex Test Phase running at a flow rate of 0.5 mL/min. Coulometric detection was accomplished with a Thermo Scientific Dionex 6011RS electrode cell, and the signal analyzed on a Thermo Scientific Dionex Chromeleon CDS processing platform. DOPAC and dopamine absolute tissue concentrations (ng/mg) were determined by comparison with external standard curves and corrected for tissue weight, as we have described previously [10, 23].

2.7. Data Analysis

All graphical data presentations were created using GraphPad Prism (GraphPad Software Inc.; La Jolla, CA) and results are presented as the mean ± the standard error of the mean (SEM). The data were analyzed by two-way analysis of variance (ANOVA) using age and treatment as independent variables, with post-hoc comparisons by Bonferroni’s test to confirm the interaction of age with treatment. Statistical significance is represented as a single symbol for p < 0.05, a double symbol for p < 0.01, and a triple symbol for p < 0.001, as noted in the figure legends.

3. Results

3.1. Acute Toxicity

There was a significant main effect (F1,8 = 11.17; p = 0.0102) of age affecting the lethality of MDMA. Bonferroni’s post-hoc test confirmed that MDMA elicited significantly (p < 0.001) more lethality in adolescent mice compared to adult mice, indicating an age interaction on treatment effect, as shown in Figure 1. There was a significant main effect (F1,124 = 7.63; p = 0.0066) of age affecting the hyperthermic response to MDMA. Bonferroni’s post-hoc test confirmed that MDMA elicited significant (p < 0.001) hyperthermia in adolescent mice compared to adult mice, indicating an age interaction on treatment effect, as shown in Figure 2. Moreover, there was a significant main effect (F1,27 = 4.79; p = 0.0374) in change in body weight in adolescent mice compared to adult mice upon MDMA exposure. Bonferroni’s post-hoc test confirmed that MDMA elicited a significantly (p < 0.01) greater loss of body weight in adolescent mice compared to adult mice, indicating an age interaction on treatment effect, as shown in Figure 3.

Figure 1:

Figure 1:

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The effects of MDMA in comparison to saline on 24-hour lethality. All values are the mean ± SEM. (N= 9–12). *** = p < 0.001 as assessed by two-way analysis of variance followed by Bonferroni’s post-hoc test.

Figure 2:

Figure 2:

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The effects of MDMA in comparison to saline on rectal temperature over the course of the dosing regimen in adolescent and adult mice. The time courses for absolute change in rectal temperature (top) and the average change in rectal temperature (bottom) are presented in the top row. All values are the mean ± SEM. N = 8–12 mice per group. *** = p < 0.001 as assessed by two-way analysis of variance followed by Bonferroni’s post-hoc test.

Figure 3:

Figure 3:

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The effects of MDMA in comparison to saline on body weight over the course of the dosing regimen in adolescent and adult mice. The time courses for absolute change in body weight (top) and the peak change in body weight (bottom)are presented in the top row. All values are the mean ± SEM. N = 8–12 mice per group. ** = p < 0.01 as assessed by two-way analysis of variance followed by Bonferroni’s post-hoc test.

3.2. Effects on Neurochemistry

The effects of MDMA exposure on cortical and striatal levels of dopamine and its major metabolite DOPAC, as well as turnover of dopamine into DOPAC, were evaluated in adolescent and adult mice. In the prefrontal cortex, there was no significant main effect of MDMA exposure on dopamine (F1,21 = 0.04; p = 0.8530) or DOPAC levels (F1,21 = 2.81; p = 0.1087). There was no significant main effect (F1,20 = 3.18; p = 0.0895) of MDMA exposure on dopamine turnover in the prefrontal cortex. (Figure 4, TOP). In contrast, in the striatum, there is a significant main effect (F1,21 = 10.05; p = 0.0046) of MDMA exposure on dopamine levels. Bonferroni’s post-hoc test confirmed that MDMA elicited a significantly (p < 0.001) greater loss of dopamine in adolescent mice compared to adult mice, indicating an age interaction on treatment effect, as shown in Figure 4 (BOTTOM). Likewise, there was a significant main effect (F1,22 = 8.33; p = 0.0086) of MDMA exposure on dopamine turnover. Bonferroni’s post-hoc test confirmed that MDMA elicited a significant (p<0.01) increase in dopamine turnover in adolescent mice compared to adult mice, indicating an age interaction on treatment effect, as shown in Figure 4 (BOTTOM). There was no significant main effect (F1,18 = 0.07; p = 0.7982) of MDMA exposure of DOPAC levels.

Figure 4:

Figure 4:

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The effects of MDMA in comparison to saline on dopamine neurochemistry 5 days after dosing in adolescent and adult mice. The levels of dopamine are presented in the prefrontal cortex (top) and the striatum (middle) and the DOPAC/DA turnover in the prefrontal cortex and striatum (bottom). All values are the mean ± SEM. N=4–8 mice per group. ** = p < 0.01, ***= p < 0.001 as assessed by two-way analysis of variance followed by Bonferroni’s post-hoc test.

4. Discussion

Amphetamines such as MDMA are popularly used as recreational psychostimulants. Investigating the effects of MDMA in adolescents is important because MDMA abuse is high in adolescents [25] and studies show that adolescents may be more prone to MDMA toxicity [26, 27]. Thus, it is imperative to conduct studies that directly compare the potential toxic effects of MDMA in adolescents and adults, as was done in the present study. Our major finding is the interaction of age with treatment is significant in the adolescent group, suggesting the adolescent group was more susceptible to the effects of MDMA, as compared to adult mice. Thus, adolescents may exhibit greater vulnerability to MDMA exposure related acute lethality, hyperthermia and decreased body weight effects. Likewise, adolescents appeared to exhibit greater vulnerability to striatal dopamine depletions following MDMA exposure. Interestingly, MDMA exposure led to greater metabolism of dopamine into its major metabolite DOPAC in the adolescent group, which suggests a novel mechanism through which adolescents might show increased vulnerability to the neurotoxic effects of MDMA.

Hyperthermia is associated with the acute dangers of MDMA [28]. Furthermore, hyperthermia is a key component of the neurotoxic effects of amphetamine derivatives [27] as the prevention of the hyperthermic response to MDMA has been shown to block MDMA associated neurotoxicity [29]. It is well known that the hyperthermic response induced by MDMA is greatly increased by warm ambient temperatures, suggesting that warm ambient temperatures may pose enhanced danger for exposure to MDMA. Likewise, crowded conditions are known to amplify dopaminergic neurotoxicity in adolescent mice [19, 30]. Our study employed housing 3 mice per cage, which is not representative of the typical crowding conditions employed in previous studies [19, 31]. However, it should be noted that this could contribute to the enhanced toxicity of MDMA. It is also worth noting that we did not record food or water intake during the present dosing regimen, and if MDMA has different effects on these measures between adolescent and mature adult mice, this may have impacted our findings. Nevertheless, enhanced adolescent vulnerability to the hyperthermic effects of MDMA as well as crowding induced facilitation of the adverse effects of MDMA is particularly concerning when adolescents consume MDMA at “rave” parties or dance clubs, which are often crowded and have warm ambient environments [32]. This is an area of concern that should be examined more in future research and bolsters the case for the importance of understanding the mechanisms associated with vulnerability to MDMA neurotoxicity in adolescents.

Like other amphetamines [33], MDMA elicits a major release of dopamine from nerve endings in all species investigated [34, 35]. This release of dopamine is believed to be involved in both the acute and potentially life-threatening hyperthermia associated with MDMA, as well as the persistent changes in behavior and neurochemistry seen after MDMA exposure [14]. MDMA exposure is associated with the loss of dopaminergic fibers and cell bodies [36]. Studies in mice have shown these depletions are related to the number of MDMA administrations and are associated with reduced dopaminergic markers such as reduced DAT–positive fibers and reduced TH fibers [15]. Additional studies have reported that the acute administration of MDMA leads to severe depletions of striatal dopamine, TH, dopamine transporter–reactivity and persistent loss of dopaminergic cell bodies in the substantia nigra in mice [13, 37]. We report that adolescent mice showed greater loss of dopamine neurochemistry following MDMA exposure than adult mice. A point worth mentioning is that although the adult mice showed significantly less neurotoxicity than the adolescents, the adult mice still displayed significant neurotoxicity compared to the saline control group. Interestingly, MDMA exposure led to greater metabolism of dopamine to its major metabolite DOPAC in the adolescent group, but not in the adult group. Increased dopamine turnover may be a novel mechanism through which adolescents show increased vulnerability to the persistent toxic effects of MDMA. Whether an increased dopamine turnover is associated with neurotoxicity or compensatory mechanisms associated with dopaminergic neuronal loss is still not clearly understood [38]. Some studies link an increased dopamine turnover with increased oxidative stress. This arises due to the increased production of hydrogen peroxide, formed during the oxidative deamination of dopamine by monoamine oxidase.

On the other hand, it is also established that excessive dopamine can be detrimental, and an increase of extracellular dopamine is implicated in the psychostimulant effects of MDMA [39]. Some studies implicate increased dopamine turnover with neuroprotective, compensatory mechanisms, that are in place to maintain clinical function in situations such as increased dopamine synthesis, increased dopamine release and reduced reuptake of dopamine into the synaptic vesicles. Other important compensatory mechanisms related to the dopamine system include formation of new branches of TH fibers in response to partial dopaminergic depletion. [40]. Thus, an increased dopamine turnover following MDMA exposure may be a compensatory mechanism to compensate for increased dopamine levels, and could be in place to prevent even more deleterious consequence of auto-oxidation of excess dopamine and increased oxidative stress [41]. Although we have found that this varies across the dimension of age, as only males were evaluated in this study and sex-differences in the effects of MDMA have been reported [29, 42], interactions between age and sex should be considered.

In some cases, previous research has tied changes in neurochemistry following MDMA exposure to changes in behavior, affect, and cognition. Studies using functional magnetic resonance imaging in adolescent MDMA users indicate impairments and malfunctions of the inhibitory circuits within the hippocampus. [43] Likewise, research in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task [44]. The interplay between increased dopamine turnover and behavioral, affective, and cognitive deficits that emerge following MDMA exposure across the lifespan, is an area that also warrants further consideration.

In conclusion, it appears that adolescent mice are more susceptible to acute toxic effects of MDMA such as lethality and hyperthermia as compared to mature adults. In turn, and likely related, adolescents exhibit greater vulnerability to the neurotoxic effects of MDMA. Considering that MDMA is more likely to be abused by adolescents or young adults, it is important to better understand the mechanisms underlying any increased vulnerability to the adverse effects of MDMA in adolescents. We have begun to highlight the novel putative mechanism of greater metabolism of dopamine to its metabolite DOPAC, which appears to occur only in the adolescents. However, future preclinical animal studies will be instrumental in establishing these mechanisms [45], especially considering the complex polypharmacology of MDMA and similar compounds [46, 47]. Our data also suggest the converse interpretation that mature adults are protected from the adverse effects of MDMA, and the mechanisms mediating this protection should also be examined in future studies. The data presented in this study caution that MDMA exposure in adolescence may be particularly dangerous and that the therapeutic window for MDMA may differ between adolescents and mature adults. As such, the present data provide novel insights into a drug that continues to exhibit significant abuse and is progressing through clinical trials for an important unmet medical need.

Acknowledgments

These studies were supported by the National Institutes of Health [DA040907 (KSM) and NS100512 (KSM)] and by funding from the Mercer University College of Pharmacy. These studies represent partial fulfillment of NC’s PhD dissertation research project at Mercer University.

Footnotes

COI: The authors have no conflicts of interest to disclose.

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