Bollweg G, Wei Y X, Sparber S B
Department of Pharmacology, University of Minnesota, Minneapolis 55455, USA.
Pharmacol Biochem Behav. 1998 May;60(1):175-81. doi: 10.1016/s0091-3057(97)00577-7.
The 5-HT2 antagonist ritanserin (RIT) is undergoing Phase III clinical trials for the treatment of substance abuse disorders. RIT has also shown preclinical therapeutic potential for attenuating or blocking lethal and/or toxic effects of exposure to cocaine or the selective 5-HT2 agonist dimethoxyiodophenyl-aminopropane (DOI) in the developing chicken. To assess the potential toxicity ("side effects") of RIT itself during development, we exposed chicken embryos to 0, 0.1, 0.3, 0.9, or 2.7 mg RIT/kg egg by injecting the drug into eggs with 14-day-old embryos (E14). Voltage generated by spontaneous embryonic activity (motility) was measured on E15 to assess short-term effects of RIT; none were observed. There was no overall effect of these RIT doses on hatchability, though sample sizes were small (n = 13-15 per group). One to 2 weeks after hatching, chicks' acquisition of a detour learning response was tested. There were no observable effects of any RIT dose on detour learning. To assess potential effects of RIT on responsiveness to stress, some chicks were exposed to isolation stress approximately 3 weeks after hatching and killed 15 min later. Blood was assayed for serum corticosterone. There was no effect of any embryonic RIT dose on corticosterone concentrations in nonstressed subjects. Although corticosterone was elevated in all stressed groups, the group exposed to the highest embryonic RIT dose (2.7 mg/kg egg) showed a stress-induced elevation greater than other groups. Thus, except for the highest RIT dose (six to seven times greater than a therapeutically effective dose used in earlier work), embryonic RIT exposure on E14 had no effect on embryonic behavior, hatchability, posthatch learned behavior, and basal serum corticosterone concentrations. At a supraefficacious dose it appears to have modified the responsiveness of the neuroendocrine axis to mild stress.
5-羟色胺2（5-HT2）拮抗剂利坦色林（RIT）正在进行治疗物质使用障碍的III期临床试验。RIT在临床前研究中还显示出具有减轻或阻断可卡因或选择性5-HT2激动剂二甲氧基碘苯基-氨基丙烷（DOI）对发育中的鸡产生的致死和/或毒性作用的治疗潜力。为了评估RIT在发育过程中自身的潜在毒性（“副作用”），我们通过向含有14日龄胚胎（E14）的鸡蛋中注射药物，使鸡胚胎暴露于0、0.1、0.3、0.9或2.7mg RIT/kg鸡蛋。在E15测量自发胚胎活动（运动性）产生的电压，以评估RIT的短期影响；未观察到任何影响。尽管样本量较小（每组n = 13 - 15），但这些RIT剂量对孵化率没有总体影响。孵化后1至2周，测试雏鸡获得迂回学习反应的情况。任何RIT剂量对迂回学习均未观察到明显影响。为了评估RIT对应激反应性的潜在影响，一些雏鸡在孵化后约3周暴露于隔离应激，并在15分钟后处死。检测血液中的血清皮质酮。任何胚胎期RIT剂量对非应激受试者的皮质酮浓度均无影响。尽管所有应激组的皮质酮均升高，但暴露于最高胚胎期RIT剂量（2.7mg/kg鸡蛋）的组显示出比其他组更大的应激诱导升高。因此，除了最高RIT剂量（比早期研究中使用的治疗有效剂量高六至七倍）外，E14期胚胎暴露于RIT对胚胎行为、孵化率、孵化后学习行为和基础血清皮质酮浓度均无影响。在超有效剂量下，它似乎改变了神经内分泌轴对轻度应激的反应性。
