Heat increases MDMA-enhanced NAcc 5-HT and body temperature, but not MDMA self-administration

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Abstract

There is a concern that hot environments enhance adverse effects of 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”). In this study, long-term (4-weeks) daily MDMA self-administration sessions and an MDMA Challenge test were conducted with rats under normal and high thermal conditions (23° or 32 °C). During MDMA self-administration sessions, activity and body temperature were increased by heat or MDMA experience, while MDMA self-administration rates increased with experience, but were comparable between thermal conditions. At the MDMA Challenge test (3.0 mg/kg, i.v.), in vivo microdialysis showed that nucleus accumbens serotonin (NAcc 5-HT) and dopamine (DA) responses were significantly increased in both thermal conditions. In the heated environment, MDMA-stimulated 5-HT responses and core temperature (but not DA) were significantly greater than at room temperature. Though the heated environment did not acutely boost MDMA intake, exaggerated NAcc 5-HT responses to MDMA may result in 5-HT depletion; a condition associated with Ecstasy use escalation and neural dysfunctions altering mood and cognition.

Introduction

The amphetamine derivative, 3,4-methylenedioxymethamphetamine (MDMA), is a major component of Ecstasy, a commonly abused drug that is particularly popular among electronic dance music enthusiasts and club goers. Nightclubs and raves feature loud techno music, laser lights, crowded and hot social environments that attract Ecstasy users. Indeed, human subjects report a higher euphoric state when taking the drug in sensory rich environments, as compared to people who take the drug in less stimulating contexts (McElrath and McEvoy, 2002, Parrott, 2004, Bedi and Redman, 2006). Though MDMA-induced lethality is rare, the use of MDMA is associated with several negative consequences such as cardiac arrhythmias, renal failure, rhabdomyolysis, cognitive deficits, negative affect and aggressive bias (Kalant, 2001, Curran et al., 2004, Hall and Henry, 2006, Indlekofer et al., 2009). It has been proposed that elevated ambient temperatures, such as those encountered in rave venues, can exacerbate MDMA-induced temperature-increasing effects and the likelihood of adverse drug effects (Parrott, 2002, Parrott, 2004).

MDMA increases extracellular levels of both serotonin (5-HT) and dopamine (DA) (Gudelsky and Nash, 1996, Kankaanpaa et al., 1998). Several studies show that the increase in magnitude is greater for 5-HT (e.g., Verrico et al., 2007, Baumann et al., 2008), though others report greater DA effects (Gough et al., 1991). As the specific receptor subtypes, D1 and 5-HT2A have been shown to influence thermoregulatory responses (Benamar et al., 2008, Shioda et al., 2008), and the combined enhancement of 5-HT and DA may contribute to MDMA's unique effects on thermoregulation. In animal studies, MDMA has been reported to induce both hypothermia and hyperthermia, depending on several factors including MDMA dosage, amount of MDMA experience, and environmental ambient temperature (Malberg and Seiden, 1998). High MDMA doses (20 mg/kg, i.p.) reliably produce hyperthermia in rats (Benamar et al., 2008), but a heated environment (e.g., 30 °C) can elicit hyperthermia from a lower MDMA dose (10 mg/kg, i.p.) (Hargreaves et al., 2007). In rodents, the magnitude of the hyperthermic response has been tightly correlated with MDMA-induced 5-HT depletion in various brain regions (Broening et al., 1995, Malberg and Seiden, 1998, Sanchez et al., 2004).

MDMA is thought to be of lower reinforcement value than other abused drugs, such as cocaine (Lile et al., 2005), but is reliably self-administered by rodents (e.g., Daniela et al., 2004). We previously reported that initial response rates for MDMA are low, but that MDMA-reinforced responding increases with experience (Reveron et al., 2006, Reveron et al., 2010). These findings are in line with other MDMA effects that are also experience-dependent. For example, with increasing levels of MDMA exposure, MDMA-stimulated activity levels, behavioral sensitization and temperature dysregulation effects are enhanced (Ratzenboeck et al., 2001, Schenk et al., 2003, Daniela et al., 2004, Kalivas et al., 1998, Reveron et al., 2006, Schenk et al., 2007).

In the present study, operant chambers were maintained at either 23 °C (e.g., Room Temperature) or 32 °C (e.g., High Temperature). During 20 daily 2-hour sessions, operant-trained rats had the opportunity to press a lever that delivered either MDMA or saline. Following completion of the self-administration sessions, a 1-hour MDMA Challenge test was conducted using in vivo microdialysis techniques. For this test, animals were placed in the operant chamber under the same thermal conditions as during self-administration sessions and were allowed to elicit a single lever response that resulted in either MDMA (3.0 mg/kg) or saline (0.1 ml). Dialysate samples collected in 10-minute intervals enabled the determination of NAcc 5-HT and DA levels under differing thermal conditions.

Section snippets

Animals

Male Sprague–Dawley rats (5 weeks old, Charles River Laboratories, Inc., Wilmington, MA) were housed in an animal colony (ambient temperature 22 +/− 1 °C) in clear cages with a 12:12 reverse light dark cycle. Laboratory food pellets and water were available ad libitum. Rats underwent 2 weeks of handling before the start of the experiment. All protocols and procedures were in accordance with the Guide for the Care and Use of Laboratory Animals (U.S. Public Health Service, National Institute of

Acquisition (Session Days 1–10)

A three-way repeated measures ANOVA performed on daily lever responses during Acquisition showed significant Day [F(9,252) = 12.86; p < 0.001], Drug [F(1,28) = 13.068; p < 0.001] and Drug × Day interaction effects [F(9, 252) = 14.188; p < 0.001], but no significant Temperature or additional interaction effects were detected. Post hoc tests revealed that Control groups had significantly greater lever responses than MDMA groups on several occasions (see Fig. 2A).

Maintenance (Session Days 11–20)

Significant Drug [F(1,28) = 15.388; p < 0.001] and

Discussion

Findings from the present experiment indicate that the heated environment did not influence voluntary MDMA intake or MDMA-stimulated locomotor activity, but did increase MDMA-stimulated NAcc 5-HT and core temperature. On the other hand, MDMA experiences significantly enhanced MDMA intake, locomotor activity and core temperature. For instance, MDMA intake and locomotor activity were significantly enhanced in the last 10 self-administration sessions (e.g., during Maintenance), but not in the

Role of the funding source

This project was supported by University of Texas, The Waggoner Center for Alcohol and Addiction Research Bruce-Jones Graduate Fellowship and a NIH grant; the NIH and the Waggoner Center had no role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Allison Feduccia and Christine Duvauchelle designed the study, managed the literature search and performed statistical analyses. Allison Feduccia and Nundhun Kongovi conducted the experiments and the histological analyses. Allison Feduccia wrote the first drafts of the manuscript. Christine Duvauchelle was the project supervisor and edited the manuscript. All authors approved the final manuscript.

Conflict of interest

Authors do not have any conflict of interest to report.

Acknowledgements

This project was supported by a University of Texas Faculty Research grant (C.L.D), The Waggoner Center for Alcohol and Addiction Research Jones Fellowship and NIH/NIAA Training Grant AA07471 (A.A.F). (+/−) MDMA was generously supplied by The National Institute on Drug Abuse Drug Supply Program.

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