Atypical neuroleptics enhance histamine turnover in brain via 5-hydroxytryptamine(2A) receptor blockade

Clozapine and olanzapine behave as weak H-3-receptor antagonists in vitro w ith K-i values around 1 and 50 mu M, respectively. Despite these modest app arent affinities, both compounds given orally to mice, nearly doubled stead y-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 H-3-rece ptor antagonists. This effect corresponded to an enhancement of histamine t urnover rate from 45 to 73 ng/g/h as measured in the case of olanzapine usi ng the pargyline test. Other antipsychotics displaying, such as clozapine a nd olanzapine, high 5-hydroxytryptamine (5-HT)(2A) receptor antagonist pote ncy, i.e., risperidone, thioridazine, seroquel, and iloperidone, also enhan ced markedly tele-methylhistamine levels. This effect was 1) additive with that of a pure H-3-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 rece ptor, i.e., haloperidol, sulpiride, raclopride, or remoxipride that, on the contrary, tended to reduce tele-methylhistamine levels. We conclude that i n contrast to "typical" antipsychotics, "atypical" antipsychotics stimulate histamine neuron activity via blockade of the 5-HT2A receptor in vivo. Thi s effect does not appear to account for their reduced extrapyramidal side-e ffects but may underlie their pro-cognitive properties.