Developmental effects of ±3,4‐methylenedioxymethamphetamine on spatial versus path integration learning: Effects of dose distribution

Abstract

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 × 1 (40 mg/kg MDMA × 1 + saline × 3), 20 × 2 (20 mg/kg MDMA × 2 + saline × 2), 10 × 4 (10 mg/kg MDMA × 4), or Saline (saline × 4). Does were spaced 2 h apart. Group 40 × 1 received MDMA as the first daily dose followed by three saline doses; group 20 × 2 received MDMA as the first and last dose and saline for the middle two doses; group 10 × 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 × 1 and 20 × 2 MDMA groups showed impaired Cincinnati multiple Twater-maze learning and the 10 × 4 and 20 × 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.

Cincinnati water maze: A review of the development, methods, and evidence as a test of egocentric learning and memory

“…As shown in Fig. 8, even with minimal light, rats learned the maze fairly well in 5 days (Vorhees et al, 2007). Path-B errors were dramatically increased two weeks after an acute 1-day, 4-dose at 2 h interval treatment regimen with MA in adult animals when tested under infrared light (Herring et al, 2008; Herring et al, 2010) as illustrated in Fig.…”

“…One of the most consistent findings of learning effects was that P11-20, but not P1-10, treatment with the related substituted amphetamine (±)3,4-methylenedioxymethamphetamine (MDMA), caused increased CWM path-B errors in the offspring (Broening et al, 2001; Williams et al, 2003; Cohen et al, 2005; Skelton et al, 2006; Vorhees et al, 2007). In addition, P11-20 exposure to the related appetite suppressant, (+)-fenfluramine, also induced long-term, dose-dependent increases in CWM path-B errors in the light (Morford et al, 2002).…”

Effects of Pre- and Postnatal Exposure to Chromium Picolinate or Picolinic Acid on Neurological Development in CD-1 Mice

“…The straight-channel swim test is a method of evaluation commonly used to assess motor skills as well as a comparison of the motivation of the subjects prior to other tasks requiring these skills [42][43][44][45][46]. Briefly, a 76×30 cm tank was filled with tap water to a depth of 23 cm the day before testing.…”

Electroencephalographic and Convulsive Effects of Binge Doses of (+)- Methamphetamine, 5-methoxydiisopropyltryptamine, and (±)-3,4- Methylenedioxymethamphetamine in Rats

“…This experiment determined the EEG profile in rats of three popular drugs of abuse using the exact dosing regimen shown to induce learning and memory deficits [46, 47, 56, 62] and neurochemical changes consistent with those seen in chronic users upon post mortem examination [33, 35, 51, 53, 60, 61]. Both Foxy and MA resulted in altered EEG activity, with Foxy producing more severe effects.…”

“…Using interspecies scaling [48], a 10 mg/kg administration of MA in rats is equivalent to that used by an MA user taking approximately 1 mg/kg [49], which is within the range of what drug users are known to take [50]. This same dose of MDMA has been shown to be both well-tolerated in rodents as well as causing reductions and other alterations in the serotonergic system [51–54], elevated anxiety [54, 55], changes in locomotor activity [54, 56, 57], and deficits in learning [56, 58] and memory [56]. Few studies have investigated the effects of Foxy.…”