Prenatal morphine exposure differentially alters learning and memoryinmaleandfemalerats Romana S Ï lamberova  a, *, Cheryl J. Schindler b , Marie Pometlova  c , Claudia Urkuti d , Jennifer A. Purow-Sokol b ,IlonaVathy a,b a Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ull. 111, Bronx, NY 10461, USA b Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA c Department of Normal, Clinical and Pathological Physiology, Third Medical Faculty of Charles University, Prague, Czech Republic d Karolinska Institute, Stockholm, Sweden Received8December2000;receivedinrevisedform22January2001;accepted3February2001 Abstract The present study tested the hypothesis that exposure to morphine on prenatal days 11±18 impairs performance on tasks requiring learningandmemoryinadultmaleandfemalerats.InExperiment1,asymmetricalmazewasusedtomeasurelearning.InExperiment2,an eight-armradialmazewasusedtoassessworkingspatialmemory.TheresultsofExperiment1demonstratedthatprenatalmorphineexposure reduces the time needed to complete the trials, but does not affect the accuracy of performance in male rats. In contrast, prenatal drug treatmenthadnoeffectsoneitherthetimeortheaccuracyofperformanceinfemalerats.InExperiment2,bothmaleandfemalemorphine- exposedratsneededmoretimetocompleteregulartrialsnodelay)thancontrols;however,morphineexposureinmaleratsdidnotaffect performanceontasksrequiringmemory,measuredwithdelaytrials,buthindereditinovariohysterectomizedOVX)femalerats.InOVX females, replacement injections of both estrogen and progesterone restored the impairment of performance on delay trials produced by prenatalmorphineexposure.Thus,thepresentstudydemonstratesthatprenatalmorphineexposuredifferentiallyaltersperformanceofadult maleandfemaleratsontasksrequiringlearningandspatialmemory. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Prenatal morphine; Learning; Spatial memory; Gonadal hormones 1. Introduction Some human studies describe adverse effects of pre- natal drug exposure on cognitive and neurobehavioral development [8,15]. For example, studies show hyper- active behavior during the neonatal period; high activity, impulsivity, poor self-control, and poor performance on cognitive tests during childhood; and school adjustment and delinquency behavioral problems during adolescence [8,15]. However, there are no studies available on how prenatal morphine exposure alters human behaviors and cognitive function in adulthood. Animal studies show that opiates modify learning and memory[3,4,13,29].Learningandmemorycanbeimpaired byacuteadministrationofopiates,suchasmorphine[3,29]. The opiate antagonist, naloxone, enhances working mem- ory-basedperformanceintheradial-armmaze[4].Pretreat- ment with naloxone antagonizes the disruptive effect of opiates on working memory [3], and opiate antagonists improvespatialmemoryinbothyoungandadultrats[13]. We and others [11,24,25,33,37,42] have shown that prena- tal morphine exposure alters the opiate system in adult offspring, which may result in an altered capacity for learning and memory in prenatally morphine-exposed rats. In addition, there is evidence demonstrating that learn- ing and memory in animals differ between the sexes and are affected by gonadal hormones [10,14,17,31,39,41]. In mazetasks,maleratsperformbetterthanfemalerats[1,6]. Doses of estrogen in diestrus levels enhance spatial mem- ory in the radial-arm maze [5,18] and in the water maze [22], while high levels of estrogen impede performance on mazetasks[12,40].Althoughmanystudieshaveexamined 0031-9384/01/$ ± see front matter D 2001 Elsevier Science Inc. All rights reserved. PII:S0031-938401)00469-3 * Corresponding author. Tel.: +1-718-430-3387; fax: +1-718-430- 8772. E-mail address: rslamber@aecom.yu.edu R. S Ï lamberova Â). Physiology&Behavior732001)93±103