Electrophysiologic Changes in Ventral Midbrain Dopaminergic Neurons Resulting from (+/-) -3,4-Methylenedioxymethamphetamine (MDMA-"Ecstasy")

Background: Although dopamine (DA) has been implicated in the psychostimulant properties of 3,4-methylenedioxymethamphetamine (MDMA), there is no detailed information on its modalities of action on single ventral midbrain dopaminergic neurons. Methods: We examined the actions of MDMA on intracellularly recorded dopaminergic neurons maintained in slices. Results: At 1 μmol/L, MDMA depolarized and excited the cells; at 3 μmol/L, either excited or inhibited the neurons. Interestingly, higher concentrations (10-30 μmol/L) inhibited firing through membrane hyperpolarization or caused an outward current. Whereas MDMA's excitatory effects were antagonized by pindolol, indicating involvement of 5-HT 1B receptors, the inhibitory effects were counteracted by sulpiride indicating involvement D2 receptors. Treatment of the cells with carbidopa eliminated MDMA-induced firing inhibition and membrane hyperpolarization. MDMA enhanced DA-induced cellular responses but reduced those of amphetamine. Cocaine-induced outward currents were not affected by MDMA. These actions are consistent with inhibition of the DA transporter. Moreover, MDMA depressed the GABA_B IPSP by activating 5-HT 1B receptors. Conclusions: Our data demonstrate that 3-30 μmol/L MDMA preferentially inhibits the dopaminergic cells via indirect activation of D2 autoreceptors due to increased extracellular concentration of DA. In contrast, reduction of the GABA_B IPSP could partially account for excitation caused by 1-3 μmol/L drug.