Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H₃ receptors

Abstract

It was the aim of the present study to determine the affinities of four neuroleptics and five antidepressants for histamine H₃ receptors. In rat brain cortex membranes, the specifically bound [³H]-M ^α-methylhistamine was monophasically displaced by clozapine (pK_i 6.15). The other drugs did not completely displace the radioligand even at 100 µM; the pK_i values were: haloperidol (4.91); sulpiride (4.73); amitriptyline (4.56); desipramine (4.15); levomepromazine (4.14); fluovoxamine (4.13); maprotiline (4.09); moclobemide (<4.0). The effect of clozapine was further examined in a functional H₃ receptor model, i.e., in superfused mouse brain cortex slices preincubated with [³H]-noradrenaline. The electrically evoked tritium overflow was not affected by clozapine 0.5–32 µM. However, clozapine shifted the concentration-response curve of histamine for its inhibitory effect on the evoked overflow to the right, but did not affect the maximum effect of histamine. The Schild plot yielded a pA₂ value of 6.33. In conclusion, clozapine shows an intermediate affinity and potency (as a competitive antagonist) at H₃ receptors. The K_i value of clozapine at H₃ receptors resembles its K_i value at D₂ receptors (the target of the classical neuroleptics), but is higher than its K_i values at D₄, 5-HT₂ or muscarinic acetylcholine receptors, which according to current hypotheses, might be involved in the atypical profile of clozapine.