3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine analog that possesses both stimulant and hallucinogenic properties. In recently completed preliminary experiments we have identified neurobehavioral effects following developmental MDMA exposure. Specifically, neonatal MDMA administration (analogous to late in utero stages of human development) results in long-lasting deficits in spatial and sequential water maze learning and memory. The largest effects occurred after MDMA treatment on postnatal days 11-20, with smaller effects after treatment on days 1-10. In a follow up experiment completed since the last submission, we replicated these effects in a between-litter design and showed that the effects were not the result of undernutrition or saline-injection stress occurring during critical stages of development. The primary focus of this proposal is to characterize those aspects of learning and memory that are disrupted following developmental MDMA exposure and to identify the endocrine changes that are associated with these effects. To accomplish this the following specific aims will be investigated: (la) Test the hypothesis that deficits in the Morris water maze following developmental MDMA exposure result from disruptions in working memory using both appetitive (Olton maze) and aversively motivated (working memory version of the Morris maze) approaches and (lb) conduct pharmacokinetic studies on neonatal rats exposed to MDMA at the two exposure stages of interest to determine if there are developmental differences in brain or plasma concentrations of drug that might explain the stage-specific cognitive deficits we have found. (2) Determine the time-dependent onset and long-term effects of the induced cognitive deficits by examining animals at different developmental stages after treatment with MDMA. (3) Determine if the adult cognitive effects could be associated with HPA axis changes as reflected by alterations in plasma corticosterone and ACTH, or hypothalamic CRF; or by alterations in fearfulness as measured in the elevated plus maze (uncontaminated by changes in locomotor activity levels). Further, we will determine whether, in a test of distracter cues on Morris maze, alterations in attention may contribute to the learning and memory changes. Changes in this revised application include the addition o multiple dose groups to all of the behavioral experiments and to the pharmacokinetic and endocrine experiments, elimination of monoamine determinations, and reducing, the scope of work on NMDA and NE receptor binding to pilot studies. The expanded dose-response experiments (including counter-balancing for cross-task effects) will be the first of their kind to demonstrate that developmental MDMA exposure induces long-term learning and memory impairments. Such data will help identify risks associated with the prenatal use of MDMA on brain and cognitive development.
