Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants

Abstract

Background: The recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA.

Methods: The objectives of this study were to examine the dose-response characteristics of acute and chronic MDMA administration in rats and to determine whether MDMA elicits behavioral sensitization and whether it cross-sensitizes with amphetamine and methylphenidate. Adult male Sprague-Dawley rats were randomly divided into three MDMA dosage groups (2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) and a saline control group (N = 9/group). All three MDMA groups were treated for six consecutive days, followed by a 5-day washout, and subsequently re-challenged with their respective doses of MDMA (day 13). Rats were then given an additional 25-day washout period, and re-challenged (day 38) with similar MDMA doses as before followed by either 0.6 mg/kg amphetamine or 2.5 mg/kg methylphenidate on the next day (day 39). Open-field locomotor activity was recorded using a computerized automated activity monitoring system.

Results: Acute injection of 2.5 mg/kg MDMA showed no significant difference in locomotor activity from rats given saline (control group), while animals receiving acute 5.0 mg/kg or 10.0 mg/kg MDMA showed significant increases in locomotor activity. Rats treated chronically with 5.0 mg/kg and 10.0 mg/kg MDMA doses exhibited an augmented response, i.e., behavioral sensitization, on experimental day 13 in at least one locomotor index. On experimental day 38, all three MDMA groups demonstrated sensitization to MDMA in at least one locomotor index. Amphetamine and methylphenidate administration to MDMA-sensitized animals did not elicit any significant change in locomotor activity compared to control animals.

Conclusion: MDMA sensitized to its own locomotor activating effects but did not elicit any cross-sensitization with amphetamine or methylphenidate.

Figure 1

summarizes the experiments measuring acute dose-response to MDMA (2.5, 5.0, and 10.0 mg/kg, i.p.) for the HA, TD, VA, and NOS locomotor indices. The values are presented as the mean ± S.E.M. *, ‡, and ▲ are for significant differences compared to experimental day 2 saline, 2.5 mg/kg MDMA, and 5.0 mg/kg MDMA, respectively (p < 0.05).

Figure 2

summarizes the experiments measuring the chronic dose-response to MDMA (2.5, 5.0, and 10.0 mg/kg, i.p.) for the HA, TD, VA, and NOS locomotor indices. The values are presented as the mean ± S.E.M. Significance is determined by comparing activity counts to Day 2 (saline day). *p < 0.05.

Figure 3

summarizes the temporal pattern of experiments measuring chronic dose-response to MDMA (2.5, 5.0, and 10.0 mg/kg, i.p.) for HA. The values for each 10-minute bin are presented as the mean ± S.E.M. Significance for each bin is determined by comparing activity counts to the same temporal bin on Day 2 (saline day). *p < 0.05.

Figure 4

summarizes the temporal pattern of experiments measuring chronic dose-response to MDMA (2.5, 5.0, and 10.0 mg/kg, i.p.) for NOS. The values for each 10-minute bin are presented as the mean ± S.E.M. Significance for each bin is determined by comparing activity counts to the same temporal bin on Day 2 (saline day). *p < 0.05.

Figure 5

summarizes the effects of a single amphetamine (0.6 mg/kg, i.p.) injection in animals treated chronically with MDMA or saline (see Table 1) for the HA, TD, VA, and NOS locomotor indices on experimental days 14 and 39, comparing activity counts of each MDMA treatment group to the saline group on the same experimental day. The values are presented as the mean ± S.E.M. *p < 0.05.

Figure 6

summarizes the effects of a single methylphenidate (2.5 mg/kg, i.p.) injection in animals treated chronically with MDMA or saline (see Table 1) for the HA, TD, VA, and NOS locomotor indices on experimental day 39, comparing activity counts of each MDMA treatment group to the saline group. The values are presented as the mean ± S.E.M. *p < 0.05.