Functional consequences of perinatal exposure to 3,4-methylenedioxymethamphetamine in rat brain

Abstract

1. In this study we have examined methylenedioxymethamphetamine (MDMA)-induced toxicity in perinatal rat brain, related this to normal development of serotonin transporter sites (SERT), and determined whether early exposure to MDMA subsequently alters cerebral function in adults. 2. Perinatal development of SERT was visualized and quantified using [(3)H]-paroxetine binding autoradiography in embryonic and neonatal rat brain from embryonic day 15 (E15) to postnatal day p30 (p30). Cerebral glucose utilization (lCMR(glu)) was measured by 2-deoxyglucose autoradiography in adult rats. 3. [(3)H]-Paroxetine binding was observed in forebrain from E18. From birth (p0), binding was organized into neocortical columns (75% higher at p10 than in adult) which declined toward adult levels between p20 and p25. 4. MDMA treatment (20 mg x kg(-1) s.c. twice daily for four days) commencing at developmental stages from E15 (treatment given to dams) to p20, had no effect upon [(3)H]-paroxetine binding measured at p40. Treatments started on p25 or later resulted in significant decreases in [(3)H]-paroxetine binding (>or=46%). This was coincident with the development of adult patterns of binding in forebrain. 5. Despite the lack of MDMA-induced neurotoxicity, rats treated in utero (E15) showed increased lCMR(glu) in locus coeruleus (+37%), and in areas receiving ascending noradrenergic innervation, such as anterior thalamus (+44%) and septal nucleus (+24%). 6 These studies confirm that the susceptibility of serotonergic terminals to the neurotoxic properties of MDMA is absent in the immediate perinatal period, but also suggests that in utero MDMA exposure produces significant long-term effects on cerebral function by a mechanism as yet unknown.

Figure 1

[³H]-paroxetine radioligand binding autoradiography in coronal sections of the rat brain at the level of the caudate nucleus. Sections were taken from animals at (a) E18, (b) P0, (c) P5, (d) P10, (e) P25, and (f) adult (dams of E18 foetuses) and show total binding from which non-specific binding was subtracted for quantification. Scale bar on Figure 1a indicates 5 mm. The same scale was maintained for all other images.

Figure 2

Saturation isotherms (a,c) with Scatchard plots (b,d) of [³H]-paroxetine binding to neocortical cell membranes prepared from 40 day old rats pretreated with saline or MDMA twice daily for four consecutive days commencing on postnatal day 20 (a,b), and postnatal day 25 (c,d). The data illustrated were derived from single representative animals from each treatment group at both time points.