Several studies suggested that 5-HT_2A receptor (5-HT_2AR) blockade may provide a more favorable efficacy and side-effect profile to antipsychotic treatment. We hypothesized that a combined haloperidol (a D_2/3 receptor (D_2/3R) antagonist) and MDL-100,907 (a 5-HT_2AR antagonist) treatment would reverse the side effects and the neurochemical alterations induced by haloperidol alone and would potentialize its efficacy. We thus chronically treated male Mdr1a knock-out rats with several doses of haloperidol alone or in combination with a saturating dose of a MDL-100,907. Receptor occupancy at clinically relevant levels was validated with a dual-radiotracer in-vivo SPECT imaging of D_2/3R and 5-HT_2AR occupancy. Experimental tests of efficacy (dizocilpine-disrupted prepulse inhibition (PPI) of the startle reflex) and side effects (catalepsy, vacuous chewing movements) were performed. Finally, a second dual-radiotracer in-vivo SPECT scan assessed the neurochemical changes induced by the chronic treatments. Chronic haloperidol failed to reverse PPI disruption induced by dizocilpine, whilst administration of MDL-100,907 along with haloperidol was associated with a reversal of the effect of dizocilpine. Haloperidol at 0.5 mg/kg/day and at 1 mg/kg/day induced catalepsy that was significantly alleviated (by ~50%) by co-treatment with MDL-100,907 but only at 0.5 mg/kg/day dose of haloperidol. Chronic haloperidol treatment, event at doses as low as 0.1 mg/kg/day induced a significant upregulation of the D_2/3R in the striatum (by over 40% in the nucleus accumbens and over 20% in the caudate-putamen nuclei), that was not reversed by MDL-100,907. Finally, an upregulation of 5-HT_2AR after chronic haloperidol treatment at a moderate dose only (0.25 mg/kg/day) was demonstrated in frontal cortical regions and the ventral tegmental area. Overall, a partial contribution of a 5-HT_2AR antagonism to the efficacy and side-effect profile of antipsychotic agents is suggested.

几项研究表明，5-HT _2A受体（5-HT _2A R）阻断剂可能为抗精神病药物治疗提供更有利的疗效和副作用。我们假设氟哌啶醇（D _2/3受体（D _2/3 R）拮抗剂）和MDL-100,907（5-HT _2A R拮抗剂）联合治疗将逆转氟哌啶醇单独和单独使用所引起的副作用和神经化学改变。可以发挥其功效。因此，我们用数剂量的氟哌啶醇单独或与饱和剂量的MDL-100,907慢性治疗了雄性Mdr1a敲除大鼠。通过D _2/3的双放射性示踪剂体内SPECT成像验证了临床相关水平的受体占用率R和5-HT _2AR占用率。进行了功效（惊吓反射的地佐西平中断的脉冲抑制（PPI））和副作用（僵直，空腹咀嚼运动）的实验测试。最后，第二次双放射性示踪剂体内SPECT扫描评估了慢性治疗引起的神经化学变化。慢性氟哌啶醇不能逆转由地佐西平引起的PPI破坏，而与氟哌啶醇一起施用MDL-100,907与逆转地佐西平的作用有关。氟哌啶醇0.5 mg / kg / day和1 mg / kg / day引起的僵直症通过与MDL-100,907共同治疗可显着缓解（约50％），但氟哌啶醇的剂量仅为0.5 mg / kg / day。慢性氟哌啶醇治疗（剂量低至0.1 mg / kg /天）引起D _2/3明显上调纹状体中的R（伏隔核中超过40％，尾状-丘脑核中超过20％），MDL-100,907并未逆转。最后，在额叶皮层区和腹侧被盖区中，仅在中等剂量（0.25 mg / kg /天）的慢性氟哌啶醇治疗后，5-HT _2A R上调。总体上，建议了5-HT _2A R拮抗作用对抗精神病药的疗效和副作用的部分贡献。