Prenatal Cocaine Administration Research Articles

Prenatal cocaine administration increases glutathione and alpha-tocopherol oxidation in fetal rat brain

Recent findings suggest that prenatal cocaine exposure results in significant attenuation of uterine and placental blood flow. The extent of blood flow reduction to fetuses positively correlates with reductions in glial-derived neurotrophic factor (GDNF) and dopamine (DA). However, whether such changes in uterine blood flow are sufficient to induce oxidative stress have yet to be determined. In the following experiments, the impact of prenatal cocaine exposure on fetal brain levels of the endogenous antioxidant glutathione (GSH and its oxidized form GSSG) or the exogenous antioxidant α-tocopherol (α-T and its oxidized quinone form) was investigated. It was hypothesized that cocaine exposure would result in greater oxidation of both GSH and α-T. Results indicated that a single injection of cocaine to a drug-naive pregnant dam results in significant (−16.38%) reductions in the levels of GSH. GSSG can be either raised or reduced as a result of fetal uterine position: fetuses at the ovarian extremes show significant increases in GSSG in response to cocaine (+64.73%), whereas cervically situated fetuses show decreased GSSG (−47.91%). Additionally, cocaine significantly decreased the levels of α-T (−15.9%) and increased the levels of its oxidative product α-Tquinone (α-Tq, +34.05%). Levels of α-T were not affected by fetal uterine position. These data collectively suggest that cocaine exposure increases the utilization of both endogenous and exogenous anti-oxidants in the fetal rat brain. Along with previous studies, these data support the hypothesis that cocaine-induced vasoconstriction results in oxidative stress in the gestating fetus.

Neuronal instability: implications for Rett's syndrome

The maturational changes in the brain and spinal cord do not linearly proceed from immature in infants to mature in adults. Dendrites dynamically extend or retract as neurotrophic factors fluctuate. In certain cases mature neurons can be seen soon after birth, and in other cases immature neurons can be identified in the aged brain. Monoamine ‘neurotransmitter’; such as serotonin (5-HT), dopamine and norepinephrine appear to function as Maintenance Growth Factors since they must be present in order to produce their maturational actions. Serotonin neurons contain TRK-B receptors and are sensitive to availability of the trophic factor, BDNF. 5-HT also functions by promoting the release of the glial extension factor, S-100β. 5-HT and S-100β can provide maturational signals to a variety of neurons, in both cortical and subcortical areas, and appear to be involved in regulating the maturation and release of acetylcholine and dopamine. We have shown that activation of the 5-HT1A receptor is particularly effective in inducing growth of stunted neurons. The mechanism of action of the 5-HT1A receptor involves both a direct inhibition on c-AMP and pCREB formation in postsynaptic neurons and a release of S-100β from glial cells. Both these events are capable of stabilization and elaboration of the cytoskeleton of the neuron and inhibition of apoptosis. 5-HT1A receptors have been shown to effectively reverse stunted neurons and microencephaly produced in animal models of fetal alcohol syndrome and prenatal cocaine administration. I discuss the implications for regressive disorders such as Rett's syndrome and autism, and the feasibility of treatments with 5-HT1A agonists in children with developmental disorders.

Enduring effects of prenatal cocaine administration on emotional behavior in rats

The present studies sought to determine whether prenatal cocaine administration (15 mg/kg b.i.d. between gestational ages 1–20) had enduring effects on emotional behavior of rats. Rats prenatally treated with cocaine interacted less with other rats in the social interaction test of anxiety at both 30 and 120 days of age. However, there were no differences in the elevated plus maze test of anxiety. Rats prenatally treated with cocaine were significantly more immobile in the forced-swim test at 60 and 120 days of age. In addition, animals exposed to prenatal cocaine were more sensitive to the enhancing effect of phencyclidine (2.0 mg/kg) on startle responses to an acoustic stimulus. The cocaine-treated animals tested at 50 to 60 days of age showed higher levels of prepulse inhibition, in comparison to the saline group, after vehicle pretreatment, but not after phencyclidine. Although there were gender differences in the expression of some of these behavioral tasks, there were no gender differences in the effects of cocaine. These findings indicate that when emotional behavior is altered by prenatal cocaine administration, the effects are enduring.

Enduring effects of prenatal cocaine administration on emotional behavior in rats

Enduring effects of prenatal cocaine administration on emotional behavior in rats

A Mouse Model of Transplacental Cocaine Exposure: Clinical Implications for Exposed Infants and Childrena.

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 α-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.

Transplacental cocaine exposure. 1: A rodent model.

To characterize the transplacental effects of cocaine on the developing brain, we have developed a mouse model of gestational cocaine exposure. Pharmacokinetic analysis revealed that cocaine and its metabolites (BE, BNE, and NC) were found in fetal brain and plasma at 30 and 120 min following SC administration to embryonic day (E) 17 pregnant Swiss Webster mice. Pregnant dams injected twice daily with cocaine HCl at 20 mg/kg SC from gestational day E8 to E17 (COC) demonstrated less food intake and lower percentage weight gain than vehicle-injected dams allowed access to food ad lib (SAL). A nutritionally paired control group of dams injected with saline vehicle and pair-fed with the COC dams (SPF) demonstrated the lowest percentage weight gain of all three groups. The surrogate fostered offspring of COC and SPF dams demonstrated persistent growth retardation [on postnatal days (P) 1, P9, and P50] and transient brain growth retardation (on P1 and P9) when compared to pups born to SAL dams. We conducted behavioral tests that 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 three 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 or P100. Unlike the SPF and SAL controls, COC mice (i.e., mice born to COC dams) were unable to acquire an aversion to an odor previously paired with shock on P9. This learning deficit was transient because on P12, COC mice trained on the same conditioning task displayed an aversion to the odor that was indistinguishable from the SPF and SAL controls. P50 and P100 COC mice (and to a lesser extent, SPF mice) demonstrated a persistent behavioral deficit in the 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.

Retinal lesions in rat fetuses prenatally exposed to cocaine.

The increased use of cocaine in the United States and worldwide has created great concern about its effects on fetuses and neonates of pregnant cocaine abusers. The effects on neonates are varied: fetal growth delay, microcephaly, abnormal neurological functions, microphthalmia, and maternal obstetric complications. In this study, the effect of prenatal cocaine administration was studied microscopically in the retina of rat fetuses. Twenty-five pregnant Wistar rats were injected i.p. with an aqueous cocaine solution using a 30 mg/kg daily dose for 45 days. Control group rats (15 pregnant animals) received saline solution for the same period. Day 0 of gestation was the day after mating. Dosing began on this day. The rats were killed on gestation day 21 and fetuses were obtained for examination. The histopathological light and electron microscope studies of the retinas showed interstitial oedema, areas depleted of cells, necrosis, and hyperchromatic ganglion cells. There also was a significantly lower number of retinal cells compared to control fetuses. In four cases, teratogenic lesions of the retina were observed whereas no changes were present in control fetuses. Results indicate that development of retina in fetuses prenatally exposed to cocaine was altered by cocaine exposure.

The effects of prenatal cocaine exposure on dopaminergic challenge and receptor binding in Wistar rats.

The behavioral teratogenic effects of prenatal cocaine administration in Wistar rats were assessed in dams treated throughout gestation via oral gavage with either 0 or 80 mg/kg of cocaine. A pair-fed (PF) cohort group for the 80-mg/kg dose was used to control for an anorexic effect of cocaine. Alterations in the dopaminergic system at maturity were evaluated using pharmacological challenges with amphetamine and cocaine and by measuring D1 and D2 receptor binding in the nucleus accumbens and caudate nucleus. No significant difference among the offspring of the treatment groups was found in amphetamine-induced locomotion. A cocaine-based conditioned taste aversion was established in all offspring, but no significant effect of prenatal cocaine treatment was seen. Dopamine receptor binding was not significantly influenced by prenatal treatment, although a decreased D1 binding in the caudate nucleus of the prenatal cocaine rats approached significance.

Prenatal cocaine delays astroglial maturation: immunodensitometry shows increased markers of immaturity (vimentin and GAP-43) and decreased proliferation and production of the growth factor S-100

Exposure to cocaine during fetal development has been demonstrated to produce a variety of brain and behavioral changes. Cocaine is a potent releaser of a variety of neurotransmitters, such as serotonin, which act as developmental signals. Since serotonin plays an important role in astroglial maturation, migration, and growth factor production (e.g. S-100β), we proposed that these properties of astroglial cells will be altered in a brain prenatally exposed to cocaine. To observe cocaine's effects on astroglial development, we performed immunocytochemical analyses of a variety of developmental protein markers including BrdU, Gap-43, vimentin, and S100β. Our results demonstrate that prenatal cocaine administration produces decreased cell proliferation as measured by BrdU staining, retarded neurite outgrowth as ascertained by increased Gap-43 immunoreactivity, increased density of vimentin-positive radial glial cells, and diminished tissue S100β immunoreactivity. Overall, these results suggest that cocaine delays astroglial development. This delay would have profound effects on neuronal development and outgrowth and, thus, development of the entire brain.

Prenatal cocaine exposure affects the development of aortic adrenergic innervation and contractile responses

This study examines the effects of prenatal cocaine administration on the development of vascular sympathetic innervation and contractile responsiveness. Rabbits received cocaine (4 mg/kg, iv, bid) or saline during gestational days 8 to 29. Aortas were obtained on postnatal days 10, 20, 30 and 50. Vascular smooth muscle responsiveness was assessed by measuring aortic contractile responses to norepinephrine (NE) and to other vasoconstrictors. Vascular adrenergic innervation was evaluated by measuring desipramine sensitive [ 3H]-NE uptake into aortic ring segments and aortic NE content. [ 3H]-NE uptake and NE content were reduced at postnatal days 10 and 20 in the rabbits exposed prenatally to cocaine. Differences were not observed at postnatal days 30 or 50. The contractile response to NE was reduced in rabbits exposed to cocaine prenatally. Maximal response and potency were decreased at postnatal day 10 and potency was still decreased at day 20, but not at the older ages. Contractile responses to serotonin (5-HT) and angiotensin II (AII) were not affected by prenatal cocaine exposure. These results suggest that prenatal cocaine exposure delays the development of aortic adrenergic innervation and alpha adrenoceptor responsiveness.

Prenatal cocaine administration stimulates fetal brain tyrosine hydroxylase activity

Functional effects of prenatal cocaine exposure may be mediated in part by changes in catecholaminergic development. The present study examined whether cocaine administration influenced fetal brain activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. Subcutaneous (s.c.) injection of pregnant rats with 40 mg/kg of cocaine HCl daily from gestational day (GD) 8 to GD20 resulted in an 8.7% stimulation of fetal whole-brain TH activity compared to controls. We then switched to a s.c. implantation procedure involving Silastic capsules filled with 80 mg of cocaine base dissolved in polyethylene glycol (PEG). Implantation of 2 such capsules on GD18 produced a 28% increase in fetal TH activity measured only 3 days later on GD21. Subsequent experiments demonstrated that GD14 implantation was equally effective in stimulating fetal TH activity on GD17, but that the enzyme was unaffected in the brains of the treated dams. When cocaine-containing capsules were implanted on GD18, removed on GD21, and the females were allowed to deliver normally, offspring TH activity was still elevated on postnatal day 10 but not later. Finally, the presence of cocaine implants from GD18 to GD21 had no influence on fetal brain neurotransmitter and metabolite concentrations, however, the treated dams exhibited significant reductions in dopamine (DA) and the serotonin metabolite, 5-hydroxyindoleacetic acid. We conclude that maternal cocaine implants rapidly but transiently stimulate TH activity in the fetal brain, and that such stimulation prevented the DA depletion observed in the dams.

Effects of prenatal cocaine on behavioral responses to a cocaine challenge on postnatal day 11

The purpose of this study was to investigate the effects of prenatal cocaine treatment on behavioral responsivity to a cocaine challenge on postnatal day (PD) 11. Timed-pregnant Sprague-Dawley rats were injected s.c. with 40 mg/kg/day of cocaine (20 mg/kg twice daily) from gestational day 11 to 20. Saline-control females received saline injections and were pair-fed to the cocaine-treated females, whereas untreated-control females were undisturbed and were fed ad lib. Litters were culled to eight pups on PD1 and fostered to normal lactating dams. On PD 11, subjects were given either saline or cocaine (1.25, 2.5, or 5.0 mg/kg s.c.) and then tested 15 min later for isolation-induced ultrasonic vocalizations and other behaviors. Prenatal cocaine-treated pups showed a reduced sensitivity to the stimulating effect of postnatal cocaine on wall climbing, which may reflect an underlying alteration in central dopaminergic and/or noradrenergic systems. Most of the other behaviors studied, including ultrasonic vocalizations, were unaffected by prenatal cocaine administration. However, one other notable finding was an increase in postnátal mortality among the cocaine-exposed pups. We hypothesize that prenatal cocaine treatment may alter pup behavior so as to produce abnormal maternal-offspring interactions and impaired development in some individuals.