Developmental effects of +/-3,4-methylenedioxymethamphetamine on spatial versus path integration learning: effects of dose distribution.

We previously demonstrated that postnatal day 11-20 +/-3,4-methylenedioxymethamphetamine (MDMA) exposure reduces locomotor activity and impairs path integration and spatial learning independent of the effects on activity. The effects were seen when the drug was administered twice per day, but the optimal dosing regimen is unknown. We tested whether the same total daily dose of MDMA administered in different patterns would equally affect later behavior. A split-litter design (15 litters) was used with one male/female pair per litter receiving one of four treatment regimens. All offspring received four injections per day on P11-20 as follows: 40 x 1 (40 mg/kg MDMA x 1 + saline x 3), 20 x 2 (20 mg/kg MDMA x 2 + saline x 2), 10 x 4 (10 mg/kg MDMA x 4), or Saline (saline x 4). Doses were spaced 2 h apart. Group 40 x 1 received MDMA as the first daily dose followed by three saline doses; group 20 x 2 received MDMA as the first and last dose and saline for the middle two doses; group 10 x 4 received MDMA for all four doses; and the saline group received saline for all four doses. Regardless of dose schedule, all groups treated with MDMA exhibited reduced locomotor activity. No MDMA effects were found on swimming ability in a straight channel. Modest MDMA effects were found on Barnes maze performance. The major findings were that the 40 x 1 and 20 x 2 MDMA groups showed impaired Cincinnati multiple T-water-maze learning and the 10 x 4 and 20 x 2 MDMA groups showed impaired Morris water maze learning. The results suggest that MDMA dose distribution has a long-term differential effect on different types of learning. Dose distribution warrants greater attention in the design of developmental drug studies along with the standard considerations of dose and age.