Short-term effects of 3,4-methylen-dioxy-metamphetamine (MDMA) on 5-HT(1A) receptors in the rat hippocampus.

摘要

The first effects of 3,4-methylen-dioxy-metamphetamine (MDMA, "ecstasy"), on serotonin 1A (5-HT(1A)) receptors in rat hippocampus were determined by means of [(3)H]-8-hydroxy-dipropylamino-tetralin ([(3)H]-8-OH-DPAT) and 5'guanosine-(gamma-[(35)S]-thio)triphosphate ([(35)S]-GTPgammaS) binding as well as inhibition of forskolin (FK)-stimulated adenylyl cyclase (AC) activity. The study was completed by [(35)S]-GTPgammaS functional autoradiography experiments carried out in frontal sections of rat brain, including the hippocampal region. Results showed that MDMA was either able to displace [(3)H]-8-OH-DPAT binding (K(i) congruent with 500 nM) or to reduce the number of specific sites (B(max)) without affecting K(d). The drug also failed to change the [(35)S]-GTPgammaS binding or to inhibit AC velocity, underlying its behavior as a non-competitive 5-HT(1A) receptor antagonist. Further, MDMA (1 or 100 microM), partially antagonized either [(35)S]-GTPgammaS binding stimulation of the agonists 5CT and 8-OH-DPAT or the AC inhibition induced by 5CT and DP-5CT. However, in contrast to binding studies, in AC assays the amphetamine displayed an effect also on EC(50), always being less potent than the reference antagonist WAY100,635. In functional autoradiography, MDMA behaved either as a partial 5-HT(1A) antagonist in limbic areas or, added alone, as an agonist, increasing the coupling signal presumably through 5-HT release from synapses. Interestingly, the selective 5-HT re-uptake inhibitor (SSRI) fluoxetine had no effect on MDMA [(35)S]-GTPgammaS binding activation. This latter finding indicates that the amphetamine can release 5-HT via alternative mechanisms to 5-HT transporter binding, probably via membrane synaptic receptors or vesicular transporters. The release of other transmitters is not excluded. Therefore, our results encourage at extending the study of MDMA biochemical profiles, in the attempt to elucidate those amphetamine-induced pathways with a potential for neurotoxicity or psycho-stimulant activity.