Typical and atypical antipsychotic drugs increase extracellular histamine levels in the rat medial prefrontal cortex: contribution of histamine h(1) receptor blockade

Abstract

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.

Keywords: FMPD; antipsychotic; clozapine; histamine; in vivo microdialysis; olanzapine.

Figure 1

Effect of the atypical antipsychotic drug (A,B) clozapine (1–10 mg/kg, s.c.) or (C,D) olanzapine (1–10 mg/kg, s.c.) on histamine efflux in the mPFC. Data are mean ± SEM of the dialyzate HA levels, expressed as a percentage of the baseline. Time course data shown in (A) and (C) were analyzed by two-way analysis of variance (ANOVA) followed by post hoc Bonferroni corrected t-test. Summary data (B) and (D) represent average percent of baseline HA (±SEM) for the 3.5 h post-drug or vehicle and were subjected to one-way analysis of variance (ANOVA) followed by post hoc Dunnett’s corrected t-test (n = 5–6 per group). **P < 0.01 compared to the vehicle treated animals.

Figure 2

Effects of the selective 5-HT_2A receptor antagonist MDL100907 (0.125 and 0.25 mg/kg, s.c.) or vehicle on histamine efflux in the mPFC. Data are mean ± SEM of the dialyzate HA levels, expressed as a percentage of the baseline. Time course data shown in (A) were analyzed by two-way analysis of variance (ANOVA) followed by post hoc Bonferroni corrected t-test. Summary data (B) represent average percent of baseline HA (±SEM) for the 3.5 h post-drug or vehicle and were subjected to one-way analysis of variance (ANOVA) followed by post hoc Dunnett’s corrected t-test (n = 5–6 per group).

Figure 3

Effects of the selective H₁ receptor antagonist pyrilamine (1–20 mg/kg, s.c.) or vehicle on histamine efflux in the mPFC. Data are mean ± SEM of the dialyzate HA levels, expressed as a percentage of the baseline. Time course data shown in (A) were analyzed by two-way analysis of variance (ANOVA) followed by post hoc Bonferroni corrected t-test. Summary data (B) represent average percent of baseline HA (±SEM) for the 3.5 h post-drug or vehicle and were subjected to one-way analysis of variance (ANOVA) followed by post hoc Dunnett’s corrected t-test (n = 4–6 per group). **P < 0.01 compared to the vehicle treated animals.

Figure 4

The effects of the potential novel antipsychotic drug FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] (1–10 mg/kg) on histamine efflux in the mPFC. Data are mean ± SEM of the dialyzate HA levels, expressed as a percentage of the baseline. Time course data shown in (A) FMPD were analyzed by two-way analysis of variance (ANOVA) followed by post hoc Bonferroni corrected t-test. Summary data (B) represent average percent of baseline HA (±SEM) for the 3.5 h post-drug or vehicle and were subjected to one-way analysis of variance (ANOVA) followed by post hoc Dunnett’s corrected t-test (n = 6 per group).

Figure 5

The effect of pyrilamine or clozapine on HA efflux after local perfusion into mPFC. Data are mean ± SEM of the dialyzate HA levels, expressed as a percentage of the baseline. n = 5–6 rats per group.

Figure 6

Effects of typical and atypical antipsychotic drugs or vehicle on histamine efflux in the mPFC. Summary data in (A) represents the mean average percent of baseline HA (±SEM) for the 3.5 h post-drug or vehicle. Data in (B) shows the correlation between propensity of nine antipsychotic drugs to induce histamine efflux (log %HA) in the mPFC and affinity (log K_i) at histamine H₁ receptors. Log 3.5 h average %HA values were plotted against the affinity (log K_i) at human receptors and where data existed against affinity (log K_i) at rat receptors. All K_i values used are shown in Tables S1 and S2 in Supplementary Material.