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 micromol/L, MDMA depolarized and excited the cells; at 3 micromol/L, either excited or inhibited the neurons. Interestingly, higher concentrations (10-30 micromol/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 micromol/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 micromol/L drug.
Federici
Mauro
M
Laboratory of Experimental Neurology, Fondazione Santa Lucia-IRCCS and Neurological Clinic, University of Rome Tor Vergata, Rome, Italy.
Sebastianelli
Luca
L
Natoli
Silvia
S
Bernardi
Giorgio
G
Mercuri
Nicola B
NB
D000200:Action Potentials / Q000187:drug effects; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000187:drug effects; D002230:Carbidopa / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008636:Mesencephalon / Q000187:drug effects* / Q000502:physiology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010869:Pindolol / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
D017660:Autoreceptors; D050483:Dopamine Plasma Membrane Transport Proteins; D006213:Hallucinogens; D017448:Receptors, Dopamine D2; D010869:Pindolol; D000661:Amphetamine; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D002230:Carbidopa; D004298:Dopamine