S Morisset, U G Sahm, E Traiffort, J Tardivel-Lacombe, J M Arrang, J C Schwartz
Unité de Neurobiologie et Pharmacologie Moléculaire (U.109) de Institut National de la Santé et de la Recherche Médicale, Paris, France.
The Journal of pharmacology and experimental therapeutics 1999 FebClozapine and olanzapine behave as weak H3-receptor antagonists in vitro with Ki values around 1 and 50 microM, respectively. Despite these modest apparent affinities, both compounds given orally to mice, nearly doubled steady-state tele-methylhistamine levels in brain, with ED50 values as low as 1 and 3 mg/kg, respectively, an effect comparable to those of potent H3-receptor antagonists. This effect corresponded to an enhancement of histamine turnover rate from 45 to 73 ng/g/h as measured in the case of olanzapine using the pargyline test. Other antipsychotics displaying, such as clozapine and olanzapine, high 5-hydroxytryptamine (5-HT)2A receptor antagonist potency, i.e., risperidone, thioridazine, seroquel, and iloperidone, also enhanced markedly tele-methylhistamine levels. This effect was 1) additive with that of a pure H3-receptor antagonist, ciproxifan, 2) mimicked by a 5-HT2A receptor antagonist, ketanserin, 3) reversed by a 5-HT2A receptor agonist, DOI, 4) not shared by antipsychotics with low affinity for the 5-HT2A receptor, i.e., haloperidol, sulpiride, raclopride, or remoxipride that, on the contrary, tended to reduce tele-methylhistamine levels. We conclude that in contrast to "typical" antipsychotics, "atypical" antipsychotics stimulate histamine neuron activity via blockade of the 5-HT2A receptor in vivo. This effect does not appear to account for their reduced extrapyramidal side-effects but may underlie their pro-cognitive properties.
S Morisset, U G Sahm, E Traiffort, J Tardivel-Lacombe, J M Arrang, J C Schwartz. Atypical neuroleptics enhance histamine turnover in brain via 5-Hydroxytryptamine2A receptor blockade. The Journal of pharmacology and experimental therapeutics. 1999 Feb;288(2):590-6
PMID: 9918563
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