Prenatal Drug Exposure and Drug-Abusing Environments

Research Findings from May, 2002 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.

Prenatal Exposure to Cocaine Decreases the Survival and Growth of Neurons Involved in
Attentional Processes

Problems of attention can arise in the young children of individuals who use cocaine during pregnancy. Dr. Diane Snow and her collaborators at the University of Kentucky are using a clinically relevant rodent model of prenatal cocaine exposure to investigate dysfunction in noradrenergic neurons of the locus coeruleus (LC), an area that has been associated with attentional deficits in previous studies. Dr. Snow is using a unique approach in which she measures cell survival and neurite outgrowth in LC neurons cultured from fetal rat brains. With this technique, she can compare the consequences of in vivo prenatal exposure, which could result from either direct or indirect effects on the cells of interest, with the direct effects of cocaine applied in vitro to neurons cultured from fetuses of untreated dams. Another virtue of this approach is that it permits the delineation of critical periods of drug exposure during prenatal development. In her first study, Dr. Snow found that both in vivo and in vitro cocaine exposure decreased neuron survival, the number of cells that extended neurites, the number of neurites elaborated per neuron and total neurite length. The two treatments produced consistent results, which suggests that prenatal exposure may alter the growth potential of LC neurons via direct effects on these cells. Snow, D.M., Smith, J.D., Booze R.M., Welch, M.A., and Mactutus, C.F. Cocaine Decreases Cell Survival and Inhibits Neurite Extension of Rat Locus Coeruleus Neurons. Neurotoxicology and Teratology, 23, pp. 225-234, 2001.

Drug Use During Pregnancy and Short-Term Maternal Outcomes

Findings from the largest study of illicit drug use during pregnancy have replicated many of the associations found in studies involving smaller samples. Over a 2-year period, 19,079 mother-infant pairs were screened after delivery for cocaine and opiate exposure at four clinical centers, located in Detroit, Memphis, Miami, and Providence. Of those screened, 16,988 met eligibility criteria, and 11,811 agreed to participate. Analyses involved 8,627 mother-infant pairs, based on ability to confidently classify participants as exposed or not exposed. Exposure was defined as admission of use of cocaine or opiates or both, or the presence of cocaine or opiate metabolites in meconium (using gas chromatography-mass spectroscopy methodology). Nonexposure was defined as a negative drug use history by interview and a negative immunoassay screen. Exposed mothers had a significantly higher risk of infections, including syphilis, gonorrhea, hepatitis, and HIV; psychiatric, nervous, and emotional disorders; and abruptio placenta. However, it should be noted that in this large, sociodemographically diverse cohort study, the prevalence of these risk outcomes was lower than typically reported in previous reports. The authors point out that although the prevalence of serious and life-threatening medical outcomes is low in drug-abusing pregnant women, disadvantaged social and environmental conditions that are often characteristic of the lifestyle of these women may compound these problems. Bauer, C.R., Shankaran, S., Bada, H.S., et al. The Maternal Lifestyle Study: Drug Exposure During Pregnancy and Short-Term Maternal Outcomes. American Journal of Obstetrics and Gynecology, 186, pp. 487-495, 2002.

Effects of Fetal and Adolescent Nicotine Exposure on CNS Vulnerability

It is widely believed that nicotine is a neuroteratogen that targets synaptic function during critical developmental stages. Recent studies indicate that central nervous system (CNS) vulnerability extends into adolescence, the time that smoking typically commences. In the past year, NIDA supported researchers, Dr. Theodore Slotkin and his associates at Duke University Medical Center have demonstrated that nicotine administration during development alters the functioning of the serotonergic (5-HT) systems, the neurotransmitter pathway closely associated with depression, throughout the brain. Dr. Slotkin examined indices of the development of 5-HT projections and 5-HT presynaptic activity following prenatal and adolescent nicotine exposure of rats. These studies used the nicotine dose rates that replicate the plasma nicotine levels found in smokers. Fetal nicotine exposure (gestational days 4-21) showed a decrease in the cerebrocortical binding of paroxetine (PXT), a marker for the 5-HT transporter, indicative of a decrease in nerve terminals in that region. This effect lasted into adulthood. There was a corresponding increase in PXT binding in the midbrain and brainstem, the region containing the 5-HT cell bodies that project to the cerebral cortex, a pattern typical of reactive sprouting in response to nerve terminal damage. After adolescent nicotine treatment (postnatal days 30-47), PXT binding was reduced in the hippocampus and striatum instead of the cerebral cortex, again accompanied by increased binding in the midbrain and brainstem. These effects within each region were gender selective, although both males and females displayed abnormalities. Superimposed on this overall effect, there were transient changes of 5-HT transporter expression likely due to the acute stimulant effects of nicotine. Additional studies showed that withdrawal from adolescent nicotine treatment led to suppression of activity in the cerebral cortex and activation in the midbrain. These results indicate that both fetal and adolescent nicotine exposure elicit apparent damage to 5-HT projections with reactive increases in regions containing 5-HT cell bodies. These findings are important as long-term changes in 5-HT innervation and /or synaptic activity may play a role in the subsequent development of depression in the offspring of women who smoke during pregnancy or in adolescent smokers. Xu, Z., Seidler, F.J., Ali, S.F., Slikker Jr., W., and Slotkin, T.A. Fetal and Adolescent Nicotine Administration: Effects on CNS Serotonergic Systems. Brain Research, 914, pp.166-178, 2001.

Offspring of Women who Smoke during Pregnancy Show Behavioral Abnormalities

Behavioral abnormalities, including increased incidence of attention deficits, learning disabilities, and cognitive dysfunction are shown by the offspring of women who smoke. Researchers at Duke University Medical Center, Dr. Theodore Slotkin and his team recently reported alterations in cellular morphology and regional architecture in the juvenile and adolescent brain regions involved in learning and memory (hippocampus) and in pain pathways (somatosensory cortex) in rats previously exposed to nicotine prenatally. These investigations were designed to compare the vulnerabilities of neuronal populations arising from different germinal zones as well as similar types of cells located in different regions. Their data showed that prenatal nicotine exposure, at blood levels comparable to those seen in human smokers or in user of transdermal nicotine patches, elicited structural abnormalities in the hippocampus and somatosensory cortex before the reemergence of functional deficits. Nicotine appeared to target specific sub-regions and cell types, including cells with postnatal birth dates, indicating that exposure alters the program for brain cell development and for architectural assembly of critical regions involved in learning and memory. Roy, T.S., Seidler, F.J. and Slotkin, T.A. Prenatal Nicotine Exposure Evokes Alterations of Cell Structure in Hippocampus and Somatosensory Cortex. J. Pharmacology Experimental Therapeutics, 300, pp. 124-133, 2002.