Pharmacology Biochemistry and Behavior, Vol. 42, pp. 509-515, 1992 0091-3057/92 $5.00 + .00 Printed in the U.S.A. All rights reserved. Copyright © 1992 Pergamon Press Ltd. Cocaine In Utero Enhances the Behavioral Response to Cocaine in Adult Rats JOANNA PERIS, l MIA COLEMAN-HARDEE AND WILLIAM J. MILLARD University of Florida, Gainesville, FL 32610 Received 16 December 1991 PERIS, J., M. COLEMAN-HARDEE AND W. J. MILLARD. Cocaine in utero enhances the behavioral response to cocaine in adult rats. PHARMACOL BIOCHEM BEHAV 42(3) 509-515, 1992.--The effects of cocaine exposure in utero on cocaine-induced behaviors and dopamine (DA) transmission in the nigrostriatal and mesolimbic pathways were measured in adult rats. Pregnant rats received either saline or cocaine (1 or 3 mg/kg, IV) daily throughout gestation. When offspring were 3 months of age, locomotor and stereotypic behaviors were rated after an injection of either saline or cocaine (10 mg/ kg, IP). Cocaine in utero increased the response to cocaine in adult offspring and increased basal locomotion in female offspring. Cocaine in utero increased amphetamine-stimulated release in female offspring but decreased release in males. On the other hand, male rats that had received cocaine in utero exhibited greater basal tritium release. One injection of cocaine increased amphetamine-stimulated [3H]DA release from striatal slices of male rats but not female rats. Neither cocaine in utero nor in vivo affected D2 DA receptor binding in striatum nor nucleus accumbens. Thus, cocaine in utero behaviorally sensitized animals to subsequent cocaine exposure and increased [3H]DArelease from nigrostriatal endings, but the relation- ship of these two variables depended upon gender. Cocaine In utero Dopamine Striatum Stereotypy Locomotion COCAINE use has increased significantly in young women in their child-bearing years and unfortunately as many as 17070 of these women continue to use cocaine during pregnancy (14,25). The effects of cocaine use during pregnancy include shorter gestationai periods and offspring with decreased birth weights, increased incidence of urogenital malformations, and observable behavioral deficits (5-7,29). These findings have been reproduced in laboratory animals such that fetal expo- sure of at least 60 mg/kg/day decreases birth weight and in- creases physical malformations (8,13,26) while lower doses decrease learned behaviors and increase spontaneous locomo- tor activity up to 30 days postnataily (15,38,39). Similarly, exposure to cocaine in rats during postnatal days 1-10 (a time period comparable to third trimester exposure in humans) re- sults in a slight increase in basal locomotion but a twofold increase in amphetamine-induced locomotion (20). Thus, in utero exposure to low doses of cocaine appears to increase locomotor activity, especially in response to another stimu- lant, and this effect may persist into adulthood. These data suggest that cocaine in utero may affect the adult response to cocaine although this has not yet been measured. Cocaine exposure in adult rats increases the degree of loco- motion and stereotypy induced by subsequent cocaine admin- istration and this sensitization is long lasting [see (41)]. The mesolimbic and nigrostriatal dopaminergic pathways in the brain are thought to mediate the behavioral effects of cocaine (9) and increased dopamine (DA) transmission in these path- ways has been proposed as a mechanism for cocaine sensitiza- tion. More specifically, cocaine sensitization results in en- hanced striatai DA release (1,22,32-35) and postsynaptic D~ and D2 DA receptor responsiveness in nucleus accumbens (16,17,32). If the behavior response to cocaine in adult rats is sensitized by in utero exposure to cocaine, then it is also possible that DA transmission in nigrostriatai or mesolim- bic pathways may be enhanced after cocaine exposure in utero. The purpose of the work reported here was to test whether in utero cocaine can result in sensitization either behaviorally or neurochemicaily in adult offspring. Specifically, we asked whether the initial behavioral response to cocaine as an adult was affected by in utero exposure to cocaine and whether nigrostriatal and mesolimbic DA terminals were affected by in utero exposure to cocaine. We measured locomotor activity and stereotypy, [3H]DA release from striatum, and D2 DA receptor binding in striatum and nucleus accumbens both after a saline or cocaine in vivo challenge in adult rats that had been treated in utero with either saline or one of two doses of cocaine. Requests for reprints should be addressed to Joanna Peris, Ph.D., Box 100487, J. Hillis Miller Health Center, University of Florida, Gainesville, FL 32610. 509