Behavioral sensitization to 3,4-methylenedioxymethamphetamine is long-lasting and modulated by the context of drug administration

Abstract

To begin to characterize the temporal profile of behavioral sensitization to the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA), rats were treated with either saline or MDMA (5.0 mg/kg) twice daily for 5 days, followed by a challenge injection of MDMA (2.5 mg/kg) either 15 or 100 days later. Because we found previously that contextual drug associations are important for the expression of behavioral sensitization to MDMA following relatively short withdrawal periods, rats received the repeated injections either in their home cages (unpaired group) or in the activity monitors that were used for testing sensitization on challenge day (paired group). Locomotor sensitization was evident at 15 days of withdrawal but only in the paired MDMA-treated group. Interestingly, however, sensitization was apparent at 100 days of withdrawal in both paired and unpaired rats but the form of sensitization differed between groups. Thus, sensitization in paired rats was expressed as an increase in stereotypy, whereas sensitization in unpaired rats was expressed as an increase in locomotion, paralleling locomotion levels in paired animals at 15 days of withdrawal. These results suggest that the neural changes that underlie behavioral sensitization to MDMA are quite enduring but involve an interaction between withdrawal time and the context of drug administration.

Fig. 1

(A, B) Time-course of locomotor activity in 20-min blocks across 60-min session following MDMA challenge (2.5 mg/kg), in rats treated 15 or 100 days earlier with saline vehicle or MDMA injections (5.0 mg/kg twice daily for 5 days) in either their home cages (unpaired group) or the activity monitors that were used for subsequent tests of sensitization (paired group). *p < .05 compared with all other treatment groups. (C) Overall locomotor activity in response to MDMA challenge. *p < .05 and **p < .01 compared with all other treatment groups. (D, E) Time-course of stereotypy in 20-min blocks across 60-min session following MDMA challenge. *p < .05 compared with all other treatment groups; #p < .05 compared with saline/unpaired group; †p < .05 compared with both saline groups. (F) Overall stereotypy time in response to MDMA challenge. ^##p < .01 compared with MDMA/unpaired; ***p < .001 compared with saline groups. All points represent mean (±SEM).