Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats.
Lamotrigine is a novel anticonvulsant drug which also stabilises mood in bipolar illness via an unknown mechanism. We report the concentration-dependent inhibition of 5-hydroxytryptamine (5-HT) uptake in both human platelets and rat brain synaptosomes (IC50s were 240 and 474 microM, respectively) by lamotrigine. Synaptosomal uptake of noradrenaline (IC50 239 microM) and dopamine (IC50 322 microM) was also inhibited. Tetrodotoxin failed to modulate 5-HT uptake suggesting that sodium channel blockade does not mediate the lamotrigine effect. Lithium, sodium valproate, zonisamide, and carbamazepine all possess anti-manic activity but only the latter inhibited 5-HT uptake. The inhibition of the p-chloroamphetamine-induced 5-HT syndrome in rats suggests that lamotrigine also inhibits 5-HT uptake in vivo. These effects probably reflect an affinity for biogenic amine transporters. However, at present, it remains uncertain whether, at clinically effective doses, these effects contribute significantly to the efficacy of lamotrigine in bipolar illness.
Southam
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Neuroscience Unit, Glaxo Wellcome Medicines Research Centre, Stevenage, Herts, UK. es36365@ggr.co.uk
Kirkby
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Higgins
G A
GA
Hagan
R M
RM
D000085:Acetates / Q000494:pharmacology; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001679:Biogenic Amines / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D004298:Dopamine / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D000077206:Gabapentin; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D000077213:Lamotrigine; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000493:pharmacokinetics*; D018490:Serotonin Agents / Q000494:pharmacology; D020230:Serotonin Syndrome / Q000517:prevention & control; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology; D000078305:Zonisamide; D005680:gamma-Aminobutyric Acid; D010133:p-Chloroamphetamine / Q000494:pharmacology
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D001679:Biogenic Amines; D002220:Carbamazepine; D003509:Cyclohexanecarboxylic Acids; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D000077206:Gabapentin; D007555:Isoxazoles; D000077213:Lamotrigine; D008094:Lithium; D009638:Norepinephrine; D010672:Phenytoin; D012701:Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D013779:Tetrodotoxin; D014227:Triazines; D014635:Valproic Acid; D000078305:Zonisamide; D005680:gamma-Aminobutyric Acid; D010133:p-Chloroamphetamine