Neurotoxicology and Teratology, Vol. 20, No. 4, pp. 401–409, 1998 © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0892-0362/98 $19.00 + .00 PII S0892-0362(98)00002-6 401 The Effects of Clonidine on Rat Pups Neonatally Exposed to Cocaine SUSAN BARRON, C. MICHELE STATON, JENNIFER A. WILLFORD AND LYNNE S. HANSEN-TRENCH Psychology Department, University of Kentucky, Lexington, KY Received 1 August 1996; Accepted 23 December 1997 BARRON, S., C. M. STATON, J. A. WILLFORD AND L. S. HANSEN-TRENCH. The effects of clonidine on rat pups neonatally exposed to cocaine. NEUROTOXICOL TERATOL 20(4) 401–409, 1998.—This study examined the effects of neonatal cocaine exposure on responsivity to the  2 noradrenergic agonist clonidine in 11-day-old rat pups. On postnatal day (PND) 4 neonatal rats were assigned to one of four treatment groups: artificially reared (AR) receiving 40 mg/kg/day co- caine hydrochloride, AR receiving 20 mg/kg cocaine, AR control receiving no drug, and a normally reared control group. Pups were maintained in this fashion from PND 4 to 9 and received no drug on PND 10. On PND 11 subjects received an IP injection of either 0, 0.25, or 1.0 mg/kg clonidine hydrochloride and were observed for locomotor activity and wall-climbing during a 15-min test session. Subjects exposed to the 40 mg/kg dose of cocaine demonstrated an enhanced sensitivity to the lo- comotor stimulating effects of clonidine relative to both control groups. This cocaine-related enhanced sensitivity was not ob- served on the wall-climbing measure. All groups showed evidence of wall-climbing, although this behavior was somewhat dampened among AR groups. The 20 mg/kg cocaine-exposed males also took longer to display wall-climbing behavior than their respective females regardless of clonidine dose, although this sex difference was not apparent for any other treatment group. These findings suggest that neonatal cocaine exposure may alter response of the noradrenergic system. © 1998 Elsevier Science Inc. Neonatal cocaine exposure Wall-climbing Locomotor activity ANIMAL models including rodent, sheep, chick [e.g., (8)], rabbit [e.g., (48)], and monkey [e.g., (38)] have been devel- oped to study the potential consequences of prenatal cocaine exposure. The advantages of these animal models are that they can control for many of the confounding factors inherent in clinical populations including polydrug use, lack of ade- quate nutrition and/or prenatal care, and impoverished post- natal environment that can make interpretation of clinical studies difficult. One important function that these animal models serve is to provide information regarding the possible physiological effects and/or mechanisms by which cocaine could affect the developing offspring. It is well known, for example, that co- caine can produce vasoconstriction, and sheep models have shown that prenatal cocaine exposure reduces fetal oxygen- ation and can result in fetal hypoxia and hypertension (19,36, 42,62). One of cocaine’s primary mechanisms of action is to block reuptake of the monoaminergic neurotransmitters, dopamine (DA), norepinephrine (NE), and serotonin (5-HT) from the synapse (11). Consequently, a number of animal studies have examined the effects of prenatal cocaine exposure on these monoaminergic neurons. To date the majority of studies have focused on DA function. Although prenatal cocaine exposure may alter aspects of the DA system, there is not a strong con- sensus emerging from this literature. For example, increased (29) and decreased (9) binding of the DA transporter have been reported following prenatal cocaine exposure. Increased D 1 (52) and D 2 receptors (24,51) and no change in postsynap- tic receptors or DA turnover (18) have also been reported. Possible explanations proposed for these inconsistent results include such factors as the variability across studies in the route and dose of cocaine administered as well as variations in the time points sampled following cocaine exposure. Although fewer published studies have examined the sero- tonergic or noradrenergic (NE) system after prenatal cocaine exposure, the available evidence suggests that prenatal co- caine exposure can affect development of the 5-HT system Requests for reprints should be addressed to Susan Barron, Ph.D., Psychology Department, Kastle Hall, University of Kentucky, Lexington, KY 40506-0044. Tel: (606) 257-5401; Fax: (606) 323-1979; E-mail: sbarron@pop.uky.edu