Developmental neurotoxicity of CI-943: a novel antipsychotic.
Offspring from Sprague-Dawley rats administered 0, 10, 25, or 75 mg/kg/day CI-943 in the diet prior to mating and throughout gestation and lactation (fertility study) or during the last week of gestation and throughout lactation (perinatal/postnatal study) were evaluated for developmental neurotoxicity using a screen of behavioral tests designed to evaluate rotorod performance, motor activity, acoustic startle responding, and learning and memory via a two-way shuttle avoidance paradigm. Treatment-related effects were evident for each behavioral parameter; they occurred at parentally toxic and nontoxic doses and in the absence of detrimental effects on offspring growth and development. Behavioral effects were in general more robust and occurred at lower doses in the perinatal-postnatal study than in the fertility study. Vertical movement was the most sensitive motor activity parameter in each study; decreases of the greatest magnitude occurred during the first minute of testing, and in males more often than in females. Acoustic startle responding and learning and memory were diminished in each study; these effects were in general concomitant with diminished motor activity, although the pattern of response differed for each study. These results indicate that behavior of offspring from parents administered CI-943 was altered regardless of the developmental stage of exposure, although the pattern of response was dependent on exposure regimen.
Henck
J W
JW
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105.
Petrere
J A
JA
Anderson
J A
JA
D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D001362:Avoidance Learning / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D007093:Imidazoles / Q000633:toxicity*; D007743:Labor, Obstetric / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009420:Nervous System / Q000254:growth & development*; D009422:Nervous System Diseases / Q000139:chemically induced*; D004856:Postural Balance / Q000187:drug effects; D011247:Pregnancy; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D012098:Reproduction / Q000187:drug effects
D014150:Antipsychotic Agents; D007093:Imidazoles; D011743:Pyrimidines; C061283:CI 943