Abstract
Clozapine and olanzapine behave as weak H3-receptor antagonists in vitro with Ki values around 1 and 50 μM, respectively. Despite these modest apparent affinities, both compounds given orally to mice, nearly doubled steady-statetele-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 markedlytele-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-HT2Areceptor, i.e., haloperidol, sulpiride, raclopride, or remoxipride that, on the contrary, tended to reducetele-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.
Footnotes
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Send reprint requests to: Séverine Morisset, Unité de Neurobiologie et Pharmacologie Moléculaire (U.109), Centre Paul Broca de l’INSERM, 2ter rue d’Alésia, 75014 Paris, France.
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↵1 This work was supported by grants from the Biomedical and Health Research Program EEC BMH4 CT96 to 0204, the Direction des Recherches Etudes et Techniques (DRET 92/045), and the Wellcome Trust.
- Abbreviations:
- HA
- histamine
- t-MeHA
- tele-methylhistamine
- (R)α-MeHA
- (R)α-methylhistamine
- HALO
- haloperidol
- CLZ
- clozapine
- OLZ
- olanzapine
- KET
- ketanserin
- CPX
- ciproxifan
- 5-HT
- 5-hydroxytryptamine
- Received April 30, 1998.
- Accepted August 14, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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