Wadenberg M G, Browning J L, Young K A, Hicks P B
Department of Psychiatry, Scott & White Clinic and Scott & White Memorial Hospital, Temple, TX 76508, USA.
Pharmacol Biochem Behav. 2001 Mar;68(3):363-70. doi: 10.1016/s0091-3057(00)00483-4.
High affinity for serotonin-2A (5-HT(2A)) over dopamine (DA) D(2) receptors is a leading hypothesis for clozapine's favorable therapeutic profile. Recent preclinical studies also indicate that a sufficient antipsychotic effect might be obtained by a combined high 5-HT(2A)/low D(2) receptor blockade. Thus, addition of a 5-HT(2A) receptor antagonist to an ineffective dose of a D(2) receptor antagonist produces a robust antipsychotic-like effect in the conditioned avoidance response (CAR) test. Electrophysiological and biochemical studies also show that 5-HT(2A) receptor antagonists can confer an atypical (clozapine-like) profile on a D(2) receptor antagonist. Improved therapeutic efficacy by adjunctive 5-HT(2A) receptor antagonist treatment to a traditional D(2) receptor blocking regimen has been suggested. However, the ability of 5-HT(2A) receptor blockade to protect against, or ameliorate, parkinsonian symptoms still remains unclear. Using the CAR and the catalepsy (CAT) tests as indices for antipsychotic activity and extrapyramidal side effect (EPS) liability, respectively, the effects of the selective 5-HT(2A) receptor antagonist MDL 100,907 in combination with the DA D(2) receptor antagonists haloperidol or raclopride were studied in rats. Haloperidol (0.025 or 0.1 mg/kg sc, -30 min) produced a dose-dependent suppression of CAR. Pretreatment with MDL 100,907 (0.5, 1.0, or 1.5 mg/kg sc; -60 min) enhanced and prolonged the haloperidol-induced suppression of CAR without escape failures. MDL 100,907 (1 mg/kg sc, -60 min) had no effect on CAT when coadministered with ineffective doses of raclopride. Raclopride (1 mg/kg sc, -30 min) alone produced a submaximal cataleptic response that was significantly enhanced by pretreatment with MDL 100,907. The present results confirm and extend previous results by showing that 5-HT(2A) receptor blockade can enhance the antipsychotic-like effects of a very low dose of a commonly used traditional antipsychotic. 5-HT(2A) receptor blockade does not, however, prevent EPS (CAT). The therapeutic advantage of this combination might, therefore, operate within a fairly narrow window.
与多巴胺（DA）D₂受体相比，对5-羟色胺-2A（5-HT₂A）具有高亲和力是氯氮平良好治疗效果的主要假说。最近的临床前研究还表明，通过联合高5-HT₂A/低D₂受体阻断作用可能获得足够的抗精神病效果。因此，在条件性回避反应（CAR）试验中，向无效剂量的D₂受体拮抗剂中添加5-HT₂A受体拮抗剂可产生强大的抗精神病样效应。电生理和生化研究也表明，5-HT₂A受体拮抗剂可赋予D₂受体拮抗剂非典型（氯氮平样）特征。有人提出，通过向传统的D₂受体阻断治疗方案中添加5-HT₂A受体拮抗剂来提高治疗效果。然而，5-HT₂A受体阻断对预防或改善帕金森症状的能力仍不清楚。分别以CAR试验和僵住症（CAT）试验作为抗精神病活性和锥体外系副作用（EPS）倾向的指标，研究了选择性5-HT₂A受体拮抗剂MDL 100,907与DA D₂受体拮抗剂氟哌啶醇或雷氯必利联合应用对大鼠的影响。氟哌啶醇（0.025或0.1mg/kg皮下注射，-30分钟）对CAR产生剂量依赖性抑制。用MDL 100,907（0.5、1.0或1.5mg/kg皮下注射；-60分钟）预处理可增强并延长氟哌啶醇诱导的CAR抑制，且无逃脱失败情况。当与无效剂量的雷氯必利联合给药时，MDL 100,907（1mg/kg皮下注射，-60分钟）对CAT无影响。单独使用雷氯必利（1mg/kg皮下注射，-30分钟）产生次最大僵住反应，而用MDL 100,907预处理可显著增强该反应。本研究结果证实并扩展了先前的结果，表明5-HT₂A受体阻断可增强极低剂量常用传统抗精神病药物的抗精神病样效应。然而，5-HT₂A受体阻断并不能预防EPS（CAT）。因此，这种联合用药的治疗优势可能在相当窄的范围内起作用。
