Prenatal Drug Exposure and Drug-Abusing Environments

Research Findings from September, 2003 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.

Perinatal Lead Exposure and Relapse to Drug-Seeking Behavior in the Rat: A Cocaine Reinstatement Study

Prior work published by Dr. Jack Nation and his colleagues at Texas A&M University has shown that perinatal lead exposure enhances cocaine-induced locomotor sensitization. He now reports that perinatal lead exposure enhances cocaine reinstatement, measured in a paradigm that is regarded to be a preclinical model of drug-seeking and relapse. Female rats were gavaged with either 0 or 16 mg lead prior to mating and this exposure procedure was continued through gestation and postnatal day 21. At postnatal day 120, male offspring were trained to self-administer cocaine. Following acquisition of steady-state responding, cocaine restatement was assessed over a 5-hour session in which cocaine self-administration occurred during the first hour, extinction via replacement of cocaine with saline occurred in hours 2-4, followed by a priming i.p. injection of either 0.00, 5.00, 10.00, or 20.00 mg/kg cocaine with assessment of drug-induced reinstatement in hour 5. During hour 5, both the lead-exposed and non-lead-exposed rats exhibited a dose-related increase in saline responding, indicative of "drug-seeking" behavior elicited by environmental cues previously paired with drug reward. The lead-exposed group, however, exhibited more saline responding than the non-lead-exposed group following priming doses of 5.00 and 10.00 mg/kg. These results indicate that low levels of lead exposure during gestation and lactation are associated with enhanced vulnerability to cocaine relapse in response to reintroduction of the drug cue. In the same paper, Dr. Nation cites unpublished data from his research program showing that adult rats with a history of perinatal lead exposure self-administer more low-dose cocaine than non-lead-exposed rats. The mechanism underlying perinatal lead exposure's effects on cocaine sensitivity and vulnerability in adulthood is not known, but Dr. Nation suggests that it could be mediated by lead's direct effects on maternal behavior or by lead's direct effects on the pups which then modulate maternal behavior. Such early pup/dam behavioral interactions could alter motivational circuits expressed in adulthood as enhanced cocaine vulnerability. In view of human data indicating that lead exposure during pregnancy and lactation can produce significant developmental and neurological abnormalities, the present data are particularly important, especially given that 1999 survey data shows approximately 70% of inner-city children have "unsafe" blood lead levels and that this percentage is even higher for urban minority children. Nation, J.R., Cardon, A.L., Heard, H.M., Valles, R., and Bratton, G.R. Perinatal Lead Exposure and Relapse to Drug-Seeking Behavior in the Rat: A Cocaine Reinstatement Study. Psychopharmacology, 168, pp. 236-243, 2003.

The Fetal Brain has a Different Pattern of Expression of Cannabinoid Receptor mRNA Compared to Adult

Yasmin Hurd at Karolinska Institute and colleagues at SUNY, Downstate have for the first time determined the expression of the cannabinoid receptor in the fetal (20 week) brain. While the adult brain showed high expression throughout the brain, expression in fetal brain was much more heterogeneous. The highest concentration was in the limbic structures of the hippocampus and amygdala. It is not clear what this might mean functionally; it is speculated that these might be the most vulnerable to prenatal exposure. Wang, X., Dow-Edwards, D., Keller, E., and Hurd, Y.L. Neuroscience, 118, pp. 681-694, 2003.

Effect of Maternal Smoking on Fetal Catecholamine Concentrations at Birth

Pregnant women who were self-identified as smokers (>/=10 cigarettes per day throughout pregnancy) or nonsmokers were recruited for study participation. Maternal blood was collected for cotinine concentrations. Umbilical artery cord blood was collected at delivery for arterial pH and catecholamine concentrations. Cord blood was obtained from 51 subjects, including 21 smokers and 30 nonsmokers. Median epinephrine concentrations [304 pg/mL versus 597 pg/mL (Mann-Whitney U = 170; p = 0.006)] and median norepinephrine concentrations [3148 pg/mL versus 6558 pg/mL (Mann-Whitney U = 191; p = 0.006)] were significantly lower in smokers compared with nonsmokers, respectively. After controlling for gestational age, route of delivery, and arterial pH, log-transformed epinephrine concentrations between smokers and nonsmokers were statistically significant (p = 0.03), with a similar trend for log-transformed norepinephrine concentrations (p = 0.07). Analyses of the data using cotinine <20 ng/mL to classify nonsmokers also showed differences in epinephrine concentrations between groups (p = 0.02). These results are consistent with results from animal studies showing that catecholamine concentrations may be affected by prenatal nicotine exposure. Further studies are needed to validate these findings and to examine the specific mechanism by which these differences may arise. Oncken, C.A., Henry, K.M., Campbell, W.A. et al. Effect of Maternal Smoking on Fetal Catecholamine Concentrations at Birth. Pediatr. Res., 53, pp. 119-124, 2003.

Home Intervention for Mothers and their Drug-Exposed Infants

This longitudinal randomized cohort study assessed the effects of a home intervention and ongoing maternal drug use on developmental outcomes of drug-exposed infants. Participants included 108 low-income, inner-city, drug-exposed children and their biological mothers (control, 54; intervention, 54). Results suggest that, compared to control infants, intervention infants had significantly higher Bayley Scales of Infant Development (BSID) Mental Development Index (MDI), and BSID Psychomotor Developmental Index (PDI) scores during the first 18 months post partum. Furthermore, ongoing maternal drug use was associated with worse developmental outcomes for both groups. Schuler, M.E., Nair, P., and Kettinger, L. Drug Exposed Infants and Developmental Outcome: Effects of a Home Intervention and Ongoing Maternal Drug Use. Archives of Pediatrics & Adolescent Medicine, 157, pp. 133-138, 2003.

Differential Effects on Cognitive Functioning in 13- to 16-Year-Olds Prenatally Exposed to Cigarettes and Marijuana

The ongoing effects of prenatal cigarette and marijuana exposure were explored in a study conducted by Fried and colleagues. Assessments were carried out in the areas of general intelligence, achievement, memory, and aspects of executive functioning. Maternal cigarette smoking during pregnancy was categorized into nonsmoking, light, and heavy ($16 mg nicotine/day), while maternal average marihuana use across pregnancy was categorized into two groups: no use plus infrequent/ moderate use, and heavy use ($6 joints/week). After controlling for confounding variables, the strongest relationship between maternal cigarette use and cognitive variables was seen with overall general intelligence and aspects of auditory functioning. Prenatal marijuana exposure was negatively associated with tasks that required visual memory, analysis, and integration. The areas that appear vulnerable to prenatal exposure to either cigarettes or marijuana are the same that were identified at earlier ages, and these two drugs continue to differentially impact varying aspects of cognition. Fried, P., Watkinson, B., and Gray, R. Differential Effects on Cognitive Functioning in 13- to 16-Year-Olds Prenatally Exposed to Cigarettes and Marijuana. Neurotoxicology and Teratology, 25, pp. 427-436, 2003.

Influence of Prenatal Cocaine Exposure on Early Language Development

Researchers at the University of Miami have recently reported effects of prenatal cocaine exposure on early language development. The Miami Prenatal Cocaine Study prospectively enrolled 476 African-American infants categorized as cocaine-exposed or non-cocaine exposed. The Bayley Scales of Infant Development were administered at 4, 8, 12, 18, and 24 months. At 3 years, the Clinical Evaluation of Language Fundamentals-Preschool was administered. Information was also collected from the primary caregiver at the time of child assessment. Prenatal substance exposure was measured by the number of cigarettes smoked, number of marijuana cigarettes smoked, number of drinks of beer, wine, or hard liquor, and number of cocaine lines or rocks recorded in increments of usual daily dose, usual days per week, and number of weeks used. Longitudinal analyses indicated evidence for a subtle, consistent pattern of cocaine-associated deficits in language functioning over the six intervals assessed during the first three years of life. This association remained stable after considering prenatal exposure to other substances, and important social-environmental factors. The investigators suggest that these subtle deficits may have important ramifications for long-term academic and social adaptation, especially when considered within the broader context of additional potential risk factors. Morrow, C.E., Bandstra, E.S., Anthony, J.C., Ofir, A.Y., Xue, L., and Reyes, M.B. Influence of Prenatal Cocaine Exposure on Early Language Development: Longitudinal Findings from Four Months to Three Years of Age. Developmental and Behavioral Pediatrics, 24(1), pp. 39-50, 2003.