A mouse model of transplacental cocaine exposure. Clinical implications for exposed infants and children.
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.
Kosofsky
B E
BE
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital-East, Charlestown 02129, USA. Kosofsky@helix.mgh.harvard.edu
Wilkins
A S
AS
D000818:Animals; D001245:Association Learning / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D002648:Child; D003042:Cocaine / Q000633:toxicity*; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D006128:Growth / Q000187:drug effects*; D006801:Humans; D007223:Infant; D051379:Mice; D009748:Nutrition Disorders / Q000209:etiology; D010646:Phentolamine / Q000494:pharmacology; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D019966:Substance-Related Disorders
D003042:Cocaine; D010646:Phentolamine