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Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine
Author(s) -
Peeters Magali,
Romieu Pascal,
Maurice Tangui,
Su TsungPing,
Maloteaux JeanMarie,
Hermans Emmanuel
Publication year - 2004
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.0953-816x.2004.03297.x
Subject(s) - amantadine , pharmacology , sigma receptor , dopaminergic , dopamine , sigma 1 receptor , chemistry , nmda receptor , memantine , receptor , agonist , biology , endocrinology , biochemistry
Pharmacological effects of amantadine on dopaminergic transmission are proposed to result from an uncompetitive antagonism at glutamate N ‐methyl‐ d ‐aspartate (NMDA) receptors. However, our previous studies examining amantadine‐mediated dopamine receptor regulation in the rat striatum revealed a discrepancy from a direct interference with glutamate transmission. Preliminary in vitro binding data from the literature suggested the interaction of amantadine with the sigma 1 receptor. Therefore, we have now further characterized the pharmacological properties of amantadine and memantine at this receptor and investigated its involvement in the modulation of striatal dopaminergic transmission. Our binding studies using [ 3 H]‐(+)SKF‐10,047 indicated that amantadine and memantine behave as ligands of the sigma 1 receptor in rat forebrain homogenates ( K i values of 7.44 ± 0.82 and 2.60 ± 0.62 µ m , respectively). In NG108‐15 neuroblastoma cells, both drugs (amantadine (100 µ m ) and memantine (10 µ m )) potentiated the bradykinin‐induced mobilization of intracellular Ca 2+ , mimicking the effect of the sigma 1 receptor agonist PRE‐084 (1 µ m ). Finally, we previously showed that in striatal membranes from amantadine‐treated rats, the functional coupling of dopamine receptors with G‐proteins was enhanced. Similarly, PRE‐084 dose‐dependently increased the [ 35 S]GTPγS binding induced by dopamine ( E max 28 and 26% of basal, 0.3 and 1 mg/kg PRE‐084, respectively). By contrast, BD1047, which is without effect on its own, antagonized the effects of amantadine and PRE‐084. Together, these data demonstrate that aminoadamantanes behave as sigma 1 receptor agonists, and confirm an involvement of this receptor in modulating dopamine receptors exerted by therapeutically relevant concentrations of amantadine.