Ž . European Journal of Pharmacology 346 1998 181–188 ž / MDMA ‘Ecstasy’ enhances 5-HT receptor density and 1A 8-OH-DPAT-induced hypothermia: blockade by drugs preventing 5-hydroxytryptamine depletion Norberto Aguirre, Santiago Ballaz, Berta Lasheras, Joaquın Del Rıo ) ´ ´ Department of Pharmacology, UniÕersity of NaÕarra Medical School, c r Irunlarrea 1, 31008 Pamplona, Spain Received 22 September 1997; revised 12 January 1998; accepted 16 January 1998 Abstract Ž . One week after a single administration of 3,4-methylenedioxymethamphetamine MDMA P HCl, 30 mgrkg i.p. , 5-HT receptor 1A density was significantly increased by approximately 25–30% in the frontal cortex and hypothalamus of rats. The increased density Ž . correlated with the potentiation of the hypothermic response to the 5-HT receptor agonist 8-hydroxy-2- di-n-propylamino tetralin 1A Ž . 8-OH-DPAT, 1 mgrkg s.c. . Hypothalamic 5-HT receptors, which also bind 8-OH-DPAT, were not changed, however, by MDMA. 7 Ž . Ž . Ž . Fluoxetine 5 mgrkg s.c. , ketanserin 5 mgrkg s.c. or haloperidol 2 mgrkg i.p. , given 15 min prior to MDMA, prevented the Ž . depletion of 5-hydroxytryptamine 5-HT induced by MDMA and also blocked the effects of this neurotoxin on 5-HT receptor density 1A and on 8-OH-DPAT-induced hypothermia. The protection afforded by drugs against 5-HT loss did not correlate, however, with the antagonism of the acute hyperthermic effect of MDMA. The present results indicate that drugs able to prevent or to attenuate MDMA-induced 5-HT loss also prevent the changes in 5-HT receptor density as well as the enhanced hypothermic response to the 1A 5-HT receptor agonist 8-OH-DPAT in MDMA-treated rats. q 1998 Elsevier Science B.V. 1A Ž . Ž . Ž Ž Keywords: MDMA 3,4-methylenedioxymethamphetamine ; 5-HT serotonin, 5-hydroxytryptamine ; 5-HT receptor; 8-OH-DPAT 8-hydroxy-2- di-n- 1A . . propylamino tetralin ; Temperature 1. Introduction It has been widely reported that single or repeated administration of high doses of the ring-substituted am- Ž phetamine 3,4-methylenedioxymethamphetamine MDMA, . ‘Ecstasy’ produces long-lasting changes in various 5-HT parameters in the brain of rodents and nonhuman primates Ž . McKenna and Peroutka, 1990 . Different findings support Ž . this contention: a reduction of 5-hydroxytryptamine 5-HT Ž and its major metabolite 5-hydroxyindoleacetic acid 5- . Ž HIAA in several brain regions Stone et al., 1986; Schmidt, . 1987 , a decline in the activity of tryptophan hydroxylase Ž . Stone et al., 1986 , a decrease in the number of w 3 x Ž H paroxetine-labeled 5-HT uptake sites Battaglia et al., . Ž 1987 and degeneration of serotonergic terminals O’Hearn . et al., 1988; Slikker et al., 1988 . ) Corresponding author. Tel.: q34-48-425600; fax: q34-48-425649; e-mail: jdelrio@unav.es Although the mechanism by which MDMA damages 5-HT terminals remains elusive, different drugs interfering with central serotonergic or dopaminergic systems, such as blockers of 5-HT or dopamine uptake, 5-HT and dopamine 2 receptor antagonists, the dopamine synthesis inhibitor a- methyl-p-tyrosine or previous lesioning of brain dopamine pathways with the neurotoxin 6-hydroxydopamine, prevent the depletion of brain 5-HT following MDMA administra- Ž tion to rats Schmidt, 1987; Stone et al., 1988; Schmidt et . al., 1990b,c; Hewitt and Green, 1994 . Other drugs, like dextromethorphan, chlormethiazole or dizocilpine, with no direct action on the serotonergic or dopaminergic system Ž also prevent the neurotoxic effects of MDMA Finnegan et . al., 1990; Colado et al., 1993; Colado and Green, 1994 . In a previous study, we reported a significant increase in 5-HT receptor number in the rat frontal cortex 7 days 1A Ž after single or repeated MDMA administration Aguirre et . al., 1995 . It appeared of interest to determine whether different drugs that presumably prevent 5-HT depletion, a landmark in MDMA-induced neurotoxicity, would be also able to prevent the change in 5-HT receptor density 1A 0014-2999r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.