Differences in the temperature dependence of drug interaction with the noradrenaline and serotonin transporters.
High affinity, sodium-dependent binding of [3H]mazindol is associated with the noradrenergic transporter while the binding of [3H]imipramine and [3H]paroxetine are associated with the serotonin transporter, e.g. in human platelets. In general radioligand binding studies to the monoamine transporters are performed at a temperature different from the physiological temperature (37 degrees C) at which uptake occurs. Previously reported data show a temperature dependence for tricyclic but not for nontricyclic inhibitors of the uptake of serotonin in their interaction with radioligand binding to the serotonin transporter. In the present study, both tricyclic and nontricyclic inhibitors of the uptake of noradrenaline were shown to have equal affinity for the binding of [3H]mazindol to the noradrenergic transporter at 0 degrees and 25 degrees C. Moreover, whereas serotonin transporter substrates inhibit the binding of [3H]imipramine/paroxetine in human platelets in an essentially temperature-independent manner (0-37 degrees C), noradrenaline transporter substrates are of higher affinity in inhibiting the binding of [3H]mazindol at 0 degrees C than at 25 degrees C. At 0 degrees C, substrate affinity for inhibition of the binding of [3H]mazindol to the noradrenaline transporter in the salivary gland of the rat approximates to the substrate affinity for transport by the noradrenaline carrier. The present data point to significant differences in the interaction of both substrates and inhibitors with the noradrenergic and serotonergic transporters, as studied using the radioligand binding. Thus, the pharmacological profile of the serotonin transporter, in terms of substrate and inhibitor affinity, is best studied using radioligand binding at 37 degrees C, whereas radioligand binding to the noradrenaline transporter is most representative at 0 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
De Oliveira
A M
AM
Department of Biology, Laboratoires d'Etudes et de Recherches Synthélabo, Paris, France.
Schoemaker
H
H
Segonzac
A
A
Langer
S Z
SZ
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008454:Mazindol / Q000378:metabolism / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D017374:Paroxetine; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013696:Temperature
D015306:Biogenic Monoamines; D010880:Piperidines; D012702:Serotonin Antagonists; D012701:Serotonin; D017374:Paroxetine; D008454:Mazindol; D007099:Imipramine; D009638:Norepinephrine