Carrier-mediated release of monoamines induced by the nicotinic acetylcholine receptor agonist DMPP.
We have previously shown that dimethylphenylpiperazinium (DMPP) increases the release of noradrenaline (NA) from rat hippocampal slices via two distinct mechanisms: a nicotinic acetylcholine receptor (nAChR)-mediated exocytosis and a carrier-mediated release induced by the reversal of NA transporters. Our aim was to investigate whether other monoaminergic systems are also affected by the multiple actions of DMPP. In our experiments DMPP dose-dependently increased the release of dopamine (DA) and serotonin (5-HT) from rat striatal and hippocampal slices, respectively. The dual effect was observed, however, only in case of DA at a lower DMPP concentration (30 microM), where the response was partly inhibited by mecamylamine, TTX and Ca2+-free medium (nAChR-mediated exocytosis) while the other part of the response was blocked only by the DA uptake inhibitor nomifensine (carrier-mediated release). In contrast, the DMPP-evoked 5-HT release and the DA release induced by high concentration DMPP was not inhibited by nicotinic antagonists, TTX and Ca2+-free medium but only by selective uptake inhibitors. In addition, DMPP dose-dependently inhibited the [3H]DA and [3H]5-HT uptake in striatal and hippocampal synaptosome preparation with an IC50 of 3.18 and 0.49 microM, respectively. Our data show that DMPP interacts with monoamine transporters and induces a substantial carrier-mediated release of DA and 5-HT, therefore caution is needed for the interpretation of data, when this drug is used as a nAChR agonist.
Szász
Bernadett K
BK
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, P.O.B. 67, H-1450 Budapest, Hungary.
Mayer
Aliz
A
Zsilla
Gabriella
G
Lendvai
Balázs
B
Vizi
E Sylvester
ES
Kiss
János P
JP
D000465:Algorithms; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000502:physiology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects*; D050486:Serotonin Plasma Membrane Transport Proteins; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D000779:Anesthetics, Local; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013779:Tetrodotoxin; D004246:Dimethylphenylpiperazinium Iodide; D008464:Mecamylamine; D002118:Calcium