Acutely applied MDMA enhances long-term potentiation in rat hippocampus involving D1/D5 and 5-HT2 receptors through a polysynaptic mechanism.
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a drug of abuse that induces learning and memory deficit. However, there are no experimental data that correlate the behavioral evidence with models of synaptic plasticity such as long-term potentiation (LTP) or long-term depression (LTD). Using field potential recordings in rat hippocampal slices of young rats, we found that acute application of MDMA enhances LTP in CA3-CA1 synapses without affecting LTD. Using specific antagonists and paired-pulse facilitation protocols we observed that the MDMA-dependent increase of LTP involves presynaptic 5-HT₂ serotonin receptors and postsynaptic D1/D5 dopamine receptors. In addition, the inhibition of PKA suppresses the MDMA-dependent increase in LTP, suggesting that dopamine receptor agonism activates cAMP-dependent intracellular pathways. We propose that MDMA exerts its LTP-altering effect involving a polysynaptic interaction between serotonergic and dopaminergic systems in hippocampal synapses. Our results are compatible with the view that the alterations in hippocampal LTP could be responsible for MDMA-dependent cognitive deficits observed in humans and animals.
Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Santiago, Chile.
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Loyola
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Ugarte
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Zeise
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Reyes-Parada
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Pancetti
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Morales
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D018492:Dopamine Antagonists / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005071:Evoked Potentials / Q000187:drug effects; D006213:Hallucinogens / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D050641:Receptors, Dopamine D5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects
D018492:Dopamine Antagonists; C493607:Drd5 protein, rat; D006213:Hallucinogens; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D044348:Receptors, Serotonin, 5-HT2; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents; D050641:Receptors, Dopamine D5; D017868:Cyclic AMP-Dependent Protein Kinases; D018817:N-Methyl-3,4-methylenedioxyamphetamine