Typical and Atypical Antipsychotic Drugs Increase Extracellular Histamine Levels in the Rat Medial Prefrontal Cortex: Contribution of Histamine H(1) Receptor Blockade

Atypical antipsychotics such as clozapine and olanzapine have been shown to enhance histamine turnover and this effect has been hypothesized to contribute to their improved therapeutic profile compared to typical antipsychotics. In the present study, we examined the effects of antipsychotic drugs on histamine (HA) efflux in the mPFC of the rat by means of in vivo microdialysis and sought to differentiate the receptor mechanisms which underlie such effects. Olanzapine and clozapine increased mPFC HA efflux in a dose related manner. Increased HA efflux was also observed after quetiapine, chlorpromazine, and perphenazine treatment. We found no effect of the selective 5-HT(2A) antagonist MDL100907, 5-HT(2c) antagonist SB242084, or the 5-HT(6) antagonist Ro 04-6790 on mPFC HA efflux. HA efflux was increased following treatment with selective H(1) receptor antagonists pyrilamine, diphenhydramine, and triprolidine, the H(3) receptor antagonist ciproxifan and the mixed 5-HT(2A)/H(1) receptor antagonist ketanserin. The potential novel antipsychotic drug FMPD, which has a lower affinity at H(1) receptors than olanzapine, did not affect HA efflux. Similarly, other antipsychotics with lower H(1) receptor affinity (risperidone, aripiprazole, and haloperidol) were also without effect on HA efflux. Finally, HA efflux after antipsychotic treatment was significantly correlated with affinity at H(1) receptors whereas nine other receptors, including 5-HT(2A), were not. These results demonstrate that both typical and atypical antipsychotics increase mPFC histamine efflux and this effect may be mediated via antagonism of histamine H(1) receptors.