Jeannine L. Gingras

Cocaine and development: mechanisms of fetal toxicity and neonatal consequences of prenatal cocaine exposure

As cocaine use during pregnancy has become increasingly recognized, there also has been increased concern about the toxic and teratogenic properties of cocaine on the fetus. A significant literature exists describing the adverse fetal and neonatal outcomes associated with in utero cocaine exposure. However, specific causality by cocaine on outcome in the human is difficult to ascertain because of multiple confounding variables associated with substance abuse including social factors and polydrug use as well as difficulty in confirming timing, dose and frequency of cocaine exposure. Most literature suggests that prenatal cocaine exposure is associated with developmental risk to the fetus. What is currently unknown is the extent of risk, the additive and/or synergistic factors contributing to cocaines toxicity and the reversibility of the injury. In this paper we review the pharmacologic properties of cocaine as related to a model of mechanisms for developmental injury secondary to cocaine exposure and the published literature on the adverse fetal and neonatal outcomes associated with cocaine use during pregnancy. Specific attention has been focused on the structural, neurobehavioral and respiratory control teratogenesis.

Prenatal cocaine and/or nicotine exposure in rats: Preliminary findings on long-term cognitive outcome and genital development at birth

Prenatal cocaine or nicotine exposure is associated with a variety of teratogenic effects. The current study was conducted to determine their effects alone and in combination on cognitive function and sexual differentiation. Pregnant Long-Evans rats (N = 19) were exposed to either cocaine (15 mg/kg/dose b.i.d. SC on GD 8-20); nicotine (4 mg/kg/day continuous SC infusion on GD 4-20); both nicotine + cocaine; or vehicle only. Birth weight and anogenital distance (AGD) were measured in all pups at birth. Learning and memory were tested in the Morris water maze (MWM) during prepubertal and pubertal ages in five daily consecutive sessions and a sixth session 1 week later and in the radial-arm maze (RAM) during adulthood. In the RAM, a drug challenge of the beta-noradrenergic antagonist propranolol (10-20 mg/kg) was given after acquisition training. Maternal weight gain was reduced 13-42% and offspring birth weight was reduced by 7-12% in all three exposure groups compared to controls. Cocaine decreased the AGD of males (2.68 mm) compared to 2.88 mm in noncocaine-exposed male pups (p < 0.025). A sex-selective cocaine effect was also seen after adjustment of AGD measurements for body weight. With this measure cocaine-treated females showed significantly (p < 0.05) greater AGD than those not exposed to cocaine. In the MWM, there were two types of trials: cued reference memory trials and uncued spatial working memory trials. On cued reference memory trials significant cocaine-induced latency deficits were seen on only the first session. On spatial working memory trials cocaine-induced latency deficits were seen throughout daily training on sessions 1-5, but not the retention session 6, 1 week later. During RAM acquisition, there were no significant differences in choice accuracy between exposure groups. Following propranolol challenge, deficits in choice accuracy were demonstrated in rats prenatally exposed to cocaine or nicotine. These rats did not show any response to propranolol, whereas the controls slightly improved their choice accuracy. The results of this study indicated that prenatal cocaine exposure altered long-term cognitive function under basal conditions in the MWM and drug challenge in the RAM, birth weight, and genital development. Cocaine-induced cognitive deficits were predominately in working memory rather than reference memory or long-term retention. Prenatal nicotine exposure was only observed to alter birth weight and cognitive function in response to propranolol challenge in the RAM.

Maternal polydrug use including cocaine and postnatal infant sleep architecture: preliminary observations and implications for respiratory control and behavior

Twelve-hour overnight pneumocardiograms were assessed for sleep architecture and sleep efficiency in two groups of healthy term newborn infants: a group exposed prenatally to cocaine alone or in combination with other drugs and a non-exposed group. Sleep was differentiated from wakefulness by an increase in heart rate, an increase in or variation in the duration and amplitude of the respiration and increased artifacts on the heart rate channel. Quiet and active sleep were determined by the regularity or irregularity of heart rate and respiration. In a sub-set of infants, the number of arousals during active sleep was calculated. Overall significance was confirmed by ANOVA followed by paired comparisons using the Students-test. When compared to non-exposed infants within the first week of life, infants exposed prenatally to cocaine alone or in combination with other drugs demonstrated more wakefulness and less sleep (P < 0.05), more frequent arousals during active sleep (P < 0.01), and the tendency of a higher proportion of active sleep compared to quiet sleep. These findings may have implications to both behavioral and respiratory control findings associated with prenatal cocaine exposure.

Maternal cocaine addiction. II: An animal model for the study of brainstem mechanisms operative in Sudden Infant Death Syndrome

Respiratory control abnormalities are mechanistic in Sudden Infant Death Syndrome (SIDS). In particular, arousal form sleep is an important component of respiratory regulation. Cocaine alters central neurotransmitter metabolism, particularly the monoamines. The locus coeruleus, the major Norepinephrine (NE) neuronal system, is involved in arousal from sleep related apnea and has extensive forebrain and brainstem projections. Thus, it is plausible that in utero cocaine exposure disrupts the normal maturation of transmitters and/or brain structures essential to sleep related respiratory regulation. Infants exposed to cocaine in utero may have an increased incidence of SIDS. We propose that cocaine use in pregnancy alters the normal maturation of centers and/or neurotransmitters involved in respiratory regulation thereby altering postnatal respiratory control. We hypothesize that the increased incidence of SIDS in cocaine exposed infants may be secondary to deficits in arousal. The study of prenatal brain development and of postnatal respiratory control in rabbit pups exposed to cocaine in utero will provide a useful model for the study of mechanisms operative in SIDS.

Maternal cocaine addiction and fetal behavioral state. I: A human model for the study of sudden infant death syndrome.

Abnormalities of respiratory regulation, such as apnea and abnormal hypoxic arousal during sleep, are mechanistic in the pathophysiology of SIDS. In utero cocaine exposure is associated with poor head growth, abnormal neurodevelopment, and an increased incidence of sudden, unexplained death, suggesting that in utero cocaine exposure disrupts the central regulation of breathing. It is likely that this disruption is due to altered CNS maturation. Indeed, cocaine alters norepinephrine metabolism within the locus coeruleus, important in arousal from sleep, suggesting that the increased incidence of SIDS in cocaine exposed infants may be secondary to sleep-related deficits in arousal. Since components of fetal behavioural state organization reflect the successful integration of the Central Nervous System, have a specific developmental timetable, and can be studied by fetal ultrasound techniques, we developed a strategy for assessing the state organization of the fetus by ultrasound techniques. We hypothesize that fetal evaluation of state will be a marker of abnormal CNS maturation and a predictor of risk, i.e. abnormal neurodevelopment and/or state related arousal deficits predisposing the cocaine exposed neonate to SIDS. We propose that the study of in utero cocaine exposed fetuses will provide a human model for examining the pathophysiology of SIDS.

Ontogeny of dopamine daily rhythms within rabbit brainstem regions

To examine the development of daily variations in dopamine levels, we measured dopamine concentrations within five distinct brainstem regions in 3- and 21-day-old, and adult rabbits at 09.30, 15.30, 21.30 and 03.30 h. Dopamine was measured by radioenzymatic assay and the dopamine concentration was expressed relative to wet tissue weight. In addition to defining the presence of a daily variation in the dopamine concentration in the whole brainstem, we were interested in identifying brainstem region-specific differences in this daily variation. Our data suggest that daily variations in dopamine concentrations are established by 3 days of life. Analysis of gross brainstem daily variation data suggest a peak in the dopamine concentration during the early light phase (09.30 h) for 3-day-old animals in contrast to a late light phase peak (15.30 h) for 21-day-old animals. Adult animals showed a peak in the early dark phase (21.30 h). These gross daily variations reflect the net sum of distinct region-specific patterns in the dopamine concentration. Analysis by region reflects a region-specific ontogeny in the development of daily variations for dopamine. Dopamine is involved in cardiorespiratory regulation. The observed developmental patterns may relate to the maturation and integration of these physiologic processes.

Nicotine and/or Cocaine Alters Postnatal Ventilatory Control in the Rat Pup Gestationally Exposed

Nicotine and/or Cocaine Alters Postnatal Ventilatory Control in the Rat Pup Gestationally Exposed

Maternal Cigarette-Smoking and Cocaine/Polydrug Use during Pregnancy: Comparable Disruptive Effects on Fetal Autonomic Regulation

Maternal Cigarette-Smoking and Cocaine/Polydrug Use during Pregnancy: Comparable Disruptive Effects on Fetal Autonomic Regulation

Development of the Hypoxic Arousal Response in Healthy Infants: Impact of Maternal Cigarette Smoking and Cocaine Use during Pregnancy

Development of the Hypoxic Arousal Response in Healthy Infants: Impact of Maternal Cigarette Smoking and Cocaine Use during Pregnancy

PRENATAL INTERVENTION FOR CHILDREN WITH IN UTERO EXPOSURE TO MATERNAL DRUG USE. 643

In our Infant Care Project we integrate prenatal, substance abuse, and child services for pregnant women who are abusing drugs and their children. Three groups are identified to study the intervention and the relative contributions of biological and environmental factors: women recruited prenatally (early intervention), those identified postnatally (late), and a matched comparison group with no known drug use.