METHYLENEDIOXYMETHAMPHETAMINE-INDUCED INHIBITION OF NEURONAL FIRING IN THE NUCLEUS-ACCUMBENS IS MEDIATED BY BOTH SEROTONIN AND DOPAMINE

Methylenedioxymethamphetamine (MDMA) is a mood-altering, legally restr icted drug that has been reported to inhibit glutamate-evoked firing o f cells in the nucleus accumbens. This study used extracellular record ing combined with microiontophoresis to examine whether the inhibitory effect of MDMA on neuronal firing in the nucleus accumbens is mediate d by serotonin and/or dopamine. Serotonin and serotonin agonists with relative selectivity for the receptor subtypes 5-HT1A, 5-HT1B, 5-HT2A/ 2C and 5-HT3 all significantly (P < 0.01) inhibited glutamate-evoked f iring of cells in the nucleus accumbens compared to the effects of an acidic saline control solution (30-60 nA, 60 s ejection currents for a ll). The current (dose)-dependent inhibition produced by the serotonin agonists did not differ significantly from the inhibition produced by MDMA except for the 5-HT1A agonist 8-hydroxy-(2-di-n-propylamino)tetr alin, which inhibited glutamate-evoked firing significantly more than MDMA or any of the other serotonin agonists. At the highest ejection c urrent tested (60 nA, 60 s), glutamate-evoked firing was inhibited by MDMA in 94% of tested cells, by serotonin in 80% of tested cells and b y the serotonin receptor subtype agonists in 95-100% of the tested cel ls. In addition to being mimicked by serotonin and serotonin agonists, MDMA-induced inhibition of glutamate-evoked firing in the nucleus acc umbens was partially blocked by the serotonin antagonists ketanserin ( 100% of tested cells), methysergide (80% of tested cells), methiothepi n (100% of tested cells) and WAY100135 (100% of tested cells). Further more, application of the serotonin uptake blocker fluoxetine, which pr events MDMA-induced serotonin release, also significantly attenuated M DMA-induced inhibition of glutamate-evoked firing in all of the cells that were tested. These observations suggest that MDMA-induced inhibit ion of nucleus accumbens cell firing is al least partially mediated by serotonin. Depletion of dopamine by pretreatment with the neurotoxin 6-hydroxydopamine and the synthesis inhibitor alpha-methyl-p-tyrosine blocked the inhibition of glutamate-evoked firing produced by MDMA app lied with low ejection currents (30-40 nA, 60 s). However, this dopami ne depletion had no effect on inhibition of glutamate-evoked firing pr oduced by serotonin ejected with low or high currents (20-60 nA, 60 s) . These results suggest that both dopamine release and an intermediate step of MDMA-induced serotonin release are necessary for the inhibito ry effects of MDMA on neuronal excitability in the nucleus accumbens. The dopamine- and serotonin-mediated inhibitory effects of MDMA on glu tamate-evoked firing of nucleus accumbens cells may play a role in the mood-altering properties of this increasingly popular drug. Copyright (C) 1996 IBRO. Published by Elsevier Science Ltd.