Prenatal Drug Exposure and Drug-Abusing Environments

Research Findings from May, 2004 Director's Report

This section lists selected summaries from NIDA funded research projects that investigate the consequences of prenatal drug exposure. The summaries provided were selected from recent issues of the Director's Report to the National Advisory Council on Drug Abuse. For a more comprehensive listing of NIDA funded projects see the Director's Report.

Early Lead Exposure Enhances Vulnerability for Cocaine Self-Administration

Dr. Jack Nation at Texas A&M University has been studying the effects of prenatal exposure to metals and the subsequent effects of this exposure on indices of drug abuse vulnerability in an animal model. Previously he has demonstrated that developmental lead exposure enhances behavioral sensitization with repeated cocaine administration but reduces the behavioral effects of acute cocaine. In the present study, female rats received 30 days of 16mg oral lead exposure and were bred with non-exposed males. Lead dosing was continued during gestation and into the lactation period. Pups were weaned on post-natal day 21 and tested for i.v. cocaine self-administration beginning on day 70. After training on stable responding for doses between 0.030 and 0.500 mg/kg/infusion, a dose response curve was determined. Blood and tissue samples were then collected and analyzed for lead concentration. Comparisons between lead exposed rats and those from dams receiving only sodium acetate vehicle revealed that the lead group was more sensitive to low doses of i.v. cocaine. Thus, whereas little self-administration was seen with 0.030 mg/kg for either group, at 0.060 mg/kg lead exposed rats made responses to receive cocaine at a rate greater than two times that seen in vehicle exposed animals. Lead analysis indicated that high concentrations detected in littermates at post-natal days 1 and 21 had returned to control levels by the time of self-administration testing. These results suggest that lead exposure during development may enhance the vulnerability to acquire drug abuse behaviors, because there is an enhanced sensitivity to the drug. The mechanism for this change in sensitivity remains to be determined but the authors suggest that either pharmacokinetic changes or alterations in central mesocorticolimbic dopaminergic systems produced by lead may be responsible. Nation, J.R., Smith, K.R. and Bratton, G.R. Early Developmental Lead Exposure Increases Sensitivity to Cocaine in a Self-Administration Paradigm. Pharmacol Biochem Behav, 77, pp. 127-135, 2004.

Are There Critical Periods for the Effect of Methamphetamine-Induced Cognitive Deficits?

In an animal model of postnatal methamphetamine (MA) administration, exposure during post-natal (PN) days 11 to 20 produces lasting deficits in spatial learning and memory, while early exposure (PN days 1-10) is without effect. PN days 1-20 represent a pre-weaning period in the rat that corresponds to the third trimester of human gestation, and it is likely that drug effects on brain hippocampal development in particular underlie these cognitive effects. In particular, rapid neuronal growth and differentiation is seen in the hippocampus during PN days 11-15. The investigators suggest that since MA produces prolonged elevations of corticosterone on PN day 11, neurotoxic effects of this stress hormone on hippocampal development may be responsible for subsequent cognitive deficits. In the present study, Dr. Vorhees used the Morris water maze as a behavioral test of hippocampally-mediated learning and memory. MA in a dose of 10 mg/kg was administered to pregnant dams four times daily on either PN days11-15 or PN days 16-20. Behavioral testing in offspring began on PN day 50 using a modified Morris maze procedure with a small platform to test learning. Animals were first trained with the platform in a familiar underwater location, and then assessed in a "shifted platform" version of the task where they have to learn a new platform location. During acquisition several dependent measures of learning are collected, including time to locate the platform, path length and distance from the platform. "Probe" tests were conducted following acquisition to assess memory. Average distance from the platform and percent time in the target quadrant of the pool were measured during the probe tests. MA administration impaired the ability of animals to learn the maze task following PN exposure on days 11-15, and during probe tests MA rats tended to be further from the former platform site. Animals exposed later during the PN period showed no deficits in learning the task. When tested with the shifted platform, again rats exposed on PN days 11-15 showed deficits in learning, but there were no treatment-related group differences on the probe test for memory. No effects were seen on learning or memory in this shifted-platform test by animals exposed later during the PN period. These differences reveal a critical window for MA exposure to produce cognitive deficits seen in adulthood. Thus, spatial navigation deficits in both 'learning' and 'shifting' response sets were apparent in animals exposed to MA on PN days 11-15, whereas drug exposure beginning five days later was without effect. As this critical period corresponds to development in the central HPA axis that influences hippocampal integrity, it is possible that MA compromises this integrity via glucocorticoid release and its ensuing neurotoxic effects on hippocampal neurons. Williams, M.T., Moran, M.S. and Vorhees, C.V. Refining the Critical Period for Methamphetamine-Induced Spatial Deficits in the Morris Water Maze. Psychopharmacology, 168, pp. 329-338, 2003.

Severity of Prenatal Cocaine Exposure and Child Language through Age 7 Years

Results of data analyses from a longitudinal cohort study at the University of Miami suggest that greater severity of prenatal cocaine exposure is associated with increased (although modest) deficits in aptitude for language performance, but not with a trajectory of language development through 7 years of age. Within the framework of the latent growth curve analysis utilized, the intercept of the language growth curve was interpreted as reflecting a relatively time-invariant aptitude for language performance, and the slope was interpreted as indicating a time-varying trajectory of language performance. Language was assessed at ages 3, 5, and 7 years. The observed association was independent of multiple other possible sources of variation in language development, including the child's intellectual functioning and language stimulation in the home. Severity of prenatal cocaine exposure was characterized using a construct combining maternal self-report of cocaine use during pregnancy with maternal and infant bioassays. The statistical analytical model included gender, and prenatal alcohol, tobacco, and marijuana among the covariates. The researchers note that although the study has many strengths, the sample is relatively homogeneous (e.g., full-term, relatively healthy African-American children residing in socially disadvantaged inner-city neighborhoods), and caution should be exerted in generalizing the cocaine-language estimate to other populations or settings. Furthermore, they call for further investigation in other scientifically rigorous studies with sufficient sample sizes, in order to understand mechanisms by which prenatal cocaine exposure may affect child language functioning. Bandstra, E.S., Vogel, A.L., Morrow, C.E., Xue, L., and Anthony, J.C. Severity of Prenatal Cocaine Exposure and Child Language Functioning Through Age Seven Years: A Longitudinal Latent Growth Curve Analysis. Substance Use and Misuse, 39(1), pp. 25-59, 2004.