A Mouse Model of Transplacental Cocaine Exposure: Clinical Implications for Exposed Infants and Children^a

Abstract

To characterize the effects of cocaine on developing brain we have developed a mouse model of gestational cocaine exposure. We studied pregnant dams injected twice daily with cocaine HCl at 40, 20, or 10 mg/kg/day sc from embryonic days (E)8 to E17 (COC 40, COC20, and COC10, respectively), vehicle-injected dams allowed access to food ad libitum (SAL) or pair-fed with the COC 40 dams (SPF 40), animals pretreated with the short-acting alpha-adrenergic antagonist phentolamine prior to each cocaine injection (P COC 40), and animals administered phentolamine prior to saline (PHENT). COC 40, P COC 40, and SPF 40 dams demonstrated the lowest percentage weight gain during gestation. The surrogate-fostered offspring of COC 40, P COC 40, and SPF 40 dams demonstrated transient brain and body growth retardation on postnatal days (P)1 and P9 when compared to pups born to SAL dams. We conducted behavioral tests which allowed us to dissociate the indirect effect of cocaine-induced malnutrition from a direct effect of prenatal cocaine administration in altering postnatal behavior. Pups from all groups were tested for first-order Pavlovian conditioning on P9 or P12 or for the ability to ignore redundant information in a blocking paradigm on P50. Unlike the SPF 40, PHENT, and SAL controls, COC 40 and P COC 40 mice were unable to acquire an aversion to an odor previously paired with shock on P9, a learning deficit that resolved by P12. However, on P50, COC 40 mice and, to a lesser extent, P COC 40 and SPF 40 mice demonstrated a persistent behavioral deficit in our blocking paradigm, which may reflect alterations in selective attention. We discuss how these findings in our rodent model have developmental implications for human infants exposed to cocaine in utero.

Dose-Response Effect of Cocaine on Newborn Head Circumference

“…These include the indirect effects of compromised nutrition and oxygenation resulting from cocaine-induced vasoconstriction of placental vessels, 20 as well as direct effects of cocaine on cell division, cell migration and neurotransmitter function within the developing brain. [21][22][23] The latter possibility is supported by findings of microcerebral dysgenesis in rodents exposed to cocaine, who also exhibit decreased head growth. 24 Our finding that impaired fetal head growth is independent of effects on somatic growth supports the hypothesis that cocaine acts directly to inhibit fetal brain growth.…”

Augmented D1 Dopamine Receptor Signaling and Immediate-Early Gene Induction in Adult Striatum After Prenatal Cocaine

“…However, the data remains elusive as to the independent contribution of prenatal cocaine vs. confounding variables such as poly-drug use, poor prenatal; care, adverse living situations, and compromised maternal health in contributing to adverse postnatal neuro-behavioral outcomes. To control for some of these variables we created an animal model of prenatal cocaine exposure which has provided support for the role of cocaine independently contributing to some but not all of the clinical findings (reviewed in (10)). Of note,, rodents exposed to cocaine in utero display an altered response to drugs of abuse when tested as adults including impaired conditioned place preference (11,12), increased acquisition to (13,14) and enhanced reinforcing ability of cocaine (13,14) in self-administration tests, augmented brain stimulation reward following administration of cocaine and D 1 agonists (15), and enhanced stereotypy during cocaine induced behavioral sensitization (16).…”

Similar and functionally typical kinematic reaching parameters in 7‐ and 15‐month‐old in utero cocaine‐exposed and unexposed infants

“…Based on the pathophysiology of cocaine's effect on the central nervous system (CNS) (Eyler & Behnke, 1999;Fetters & Tronick, 1996;Kosofsky & Wilkins, 1998;Mayes, 1994;Mayes, Granger, Frank, Schottenfeld, & Bornstein, 1993;Mirochnick, Meyer, Cole, Herren, & Zuckerman, 1991;Needlman, Zuckerman, Anderson, Mirochnick, & Cohen, 1993;Volpe, 1992), one might expect intrauterine cocaine exposure to have specific, permanent effects on infant motor functioning as well as on affect, attention, and arousal. Additionally, in utero exposure to cocaine also may indirectly affect infant outcome via the maternal fetal cardiovascular system with its resultant fetal hypoxic effects (Lester, LaGasse, & Bigsby, 1998;Lester & Tronick, 1994;Livesay, Ehrlich, & Finnegan, 1987;Villar, Smeriglio, Martorell, Brown, & Klein, 1984;Zuckerman, 1996).…”