PharmacologyBiochemistry& Behavior, Vol. 33, pp. 641-648. © PergamonPress plc, 1989. Printed in the U.S.A. 0091-3057/89 $3.00 + .00 Long-Term Central 5-HT Depletions Resulting From Repeated Administration of MDMA Enhances the Effects of Single Administration of MDMA on Schedule-Controlled Behavior of Rats 1 ABBY A. LI, GERARD J. MAREK, z GEORGETTA VOSMER AND LEWIS S. SEIDEN 3'4 The University of Chicago, Department of Pharmacological and Physiological Sciences 947 East 58th Street, Chicago, IL 60637 Received 27 May 1988 LI, A. A., G. J. MAREK, G. VOSMER AND L. S. SEIDEN. Long-term central 5-HT depletions resulting from repeated administration of MDMA enhances the effects of single administration of MDMA on schedule-controlled behavior of rats. PHARMACOL BIOCHEM BEHAV 33(3) 641-648, 1989.--The behavioral effect of single administration of +--3,4-methylene- dioxymethamphetamine (MDMA) on rats performing on the differential-reinforcement-of-low-rate 72-second schedule (DRL 72-sec) was compared before and after a period of repeated administration of MDMA known to deplete 5-hydroxytryptamine (5-HT) levels in the brain. Single administration of MDMA decreased reinforcement rate (1, 2, 4, 6 mg/kg) and increased response rate (4,6 mg/kg) of rats performing on the DRL 72-sec schedule. This effect is typical of amphetamines and other psychomotor stimulants. Four weeks after repeated administration of MDMA (6 mg/kg twice daily for 4 days) there was an increase in sensitivity to the effect of single administration of MDMA. Doses of 2, 4 and 6 mg/kg of MDMA resulted in increases in response rate that were significantly greater after repeated MDMA administration than before. Doses of 0.5, 2, and 6 mg/kg of MDMA resulted in decreases of reinforcement rate that were significantly greater after repeated MDMA administration than before. Repeated administration of MDMA resulted in long-term depletion of serotonin levels by 30-50% in the amygdala, neostriatum, hippocampus and the frontal cortex. Norepinephrine and dopamine (DA) levels were not significantly different from control in any of the brain regions analyzed. The behavioral and neurochemical results suggest that serotonergic neurons normally exert an inhibitory action upon the psychomotor stimulant effects of MDMA. Since the psychomotor stimulant effects of amphetamines appear to be mediated primarily by the dopamine system, these results provide evidence that 5-HT and DA may represent opposing systems in the DRL schedule-controlled behavior. ---3,4-Methylenedioxymethamphetamine DRL 72-sec schedule of reinforcement MDMA-induced serotonin depletion Psychomotor stimulants AMPHETAMINE (AMPH) and its derivatives, methamphetamine (MA) and 3,4-methylenedioxyamphetamine (MDA), have been found to induce neurotoxicity in the CNS of a number of species including rats, cats and monkeys. Repeated administration of AMPH or MA produce long-term depletions of striatal DA levels (29, 38, 45, 48, 49), a reduction in tyrosine hydroxylase activity (10,20), and a loss of DA high-affinity uptake sites (29, 45, 48). In addition to the toxic effects on the DA neurons, repeated administration of MA also produces long-term depletions of 5-HT, decreases tryptophan hydroxylase activity and reduces the number of 5-HT high-affinity uptake sites in rats and other species. (20, 29, 47). MDA is selectively toxic to 5-HT neurons. MDA produces long-term decreases in hippocampal and neostriahal serotonin levels, hippocampal 5-hydroxyindole acetic acid (5- HIAA) levels, hippocampal 5-HT uptake sites along with degen- erating axons and terminals in the hippocampus and neostriatum as ~This research is supported by PHS MH 11191. 2Gerard J. Marek is an MSTP Trainee supported by PHS Training Grant No. 5 T32 GM07281. 3Lewis S. Selden is the recipient of a Research Scientist Award No. MH-10562. '*Requests for reprints should be addressed to Lewis S. Seiden. 641