BEHAVIORAL AND NEUROENDOCRINE ASSESSMENT OF RITANSERIN EXPOSURE IN THE DEVELOPING CHICKEN - LACK OF TOXICITY AT EFFECTIVE DOSES

The 5-HT2 antagonist ritanserin (RIT) is undergoing Phase III clinical trials for the treatment of substance abuse disorders. RIT has also s hown preclinical therapeutic potential for attenuating or blocking let hal and/or toxic effects of exposure to cocaine or the selective 5-HT2 agonist dimethoxyiodophenyl-aminopropane (DOI) in the developing chic ken. To assess the potential toxicity (''side effects'') of RIT itself during development, we exposed chicken embryos to 0, 0.1, 0.3, 0.9, o r 2.7 mg RIT/kg egg by injecting the drug into eggs with 14-day-old em bryos (E14). Voltage generated by spontaneous embryonic activity (moti lity) was measured on E15 to assess short-term effects of RIT; none we re observed. There was no overall effect of these RIT doses on hatchab ility, though sample sizes were small (n = 13-15 per group). One to 2 weeks after hatching, chicks' acquisition of a detour learning respons e was tested. There were no observable effects of any RIT dose on deto ur learning. To assess potential effects of RIT on responsiveness to s tress, some chicks were exposed to isolation stress approximately 3 we eks after hatching and killed 15 min later. Blood was assayed for seru m corticosterone. There was no effect of any embryonic RIT dose on cor ticosterone concentrations in nonstressed subjects. Although corticost erone was elevated in all stressed groups, the group exposed to the hi ghest embryonic RIT dose (2.7 mg/kg egg) showed a stress-induced eleva tion 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 embr yonic behavior, hatchability, posthatch learned behavior, and basal se rum corticosterone concentrations. At a supraefficacious dose it appea rs to have modified the responsiveness of the neuroendocrine axis to m ild stress. (C) 1998 Elsevier Science Inc.