Cocaine exposure during the brain growth spurt: Studies of neonatal survival, somatic growth, and brain development

doi:10.1016/0892-0362(93)90008-C

Neurotoxicology and Teratology

Volume 15, Issue 4, July–August 1993, Pages 267-273

https://doi.org/10.1016/0892-0362(93)90008-C Get rights and content

Abstract

Neonatal Sprague-Dawley rat pups were assigned to one of five groups. Three cocaine-treated groups were injected SC with either 40, 60, or 80 mg/kg/day of cocaine from postnatal day (PND) 4 through 9. Control groups were either injected with equivalent volumes of sterile dH₂O (vehicle control) or received no injections (normal control) from PND 4 through 9. This early postnatal period, corresponding to the third trimester of pregnancy in humans, is characterized as a period of rapid development within the central nervous system (CNS), generally termed the brain growth spurt. The survival rate, somatic growth, and brain development in response to the various dosages of postnatal cocaine administration were assessed. There was a dose-dependent relationship between cocaine administration and survival rate. Furthermore, significantly reduced somatic growth, assessed in terms of body weight, was found in animals given 80 mg/kg cocaine daily, as compared with controls. With respect to brain weight, no significant differences were obtained among the various doses of cocaine-treated and control animals and there was no evidence of regional vulnerability (forebrain, cerebellum, or brainstem) to the cocaine insult. Additionally, neither an effect of gender, nor the interactions of gender with various doses of cocaine treatment was found on somatic growth and brain development. Taken together, the present results suggest that the brain exhibits a greater resistance to the cocaine insults than does somatic growth. Several possible explanations regarding the somatic growth retardation are discussed.

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Prenatal cocaine treatment produces equivocal effects on spatial learning and memory; however, no data are available on neonatal treatment as a model of human third-trimester exposure. Sprague–Dawley rats were treated on postnatal days (P) 1–10 or 11–20 with cocaine (15 mg/kg × 4 per day at 2-h intervals) or saline (P1–P20) and evaluated as adults in the Morris water maze and on tests of activity, startle, scent marking, swimming immobility, and sequential learning. Neonatal cocaine had no effect on mortality; however, early treatment reduced body weight, whereas later treatment did not. Neonatal cocaine had no effects on exploratory activity, swimming ability, sequential learning, multiday activity rhythms, scent marking, or swimming immobility, but augmented acoustic startle amplitude in the early-treated group. Neonatal cocaine also produced an interaction on spatial learning in which the cocaine early-treated males performed slightly more efficiently than controls. Plasma cocaine concentrations were significantly higher in the early-treated group than the later-treated group despite receiving the same weight-adjusted doses. It was concluded that neonatal cocaine, when administered during a stage of brain development analogous to human third trimester, induces few behavioral effects based on the assessments used in this study.
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Prenatal cocaine exposure can result in neurobehavioral disturbances and structural modifications of the central nervous system. In the present study, cocaine was injected into pregnant rats and the brains of their offspring were examined at the light microscopic level. As adults, cocaine-exposed offspring exhibited subtle, but consistent, hippocampal abnormalities. In particular, the stratum pyramidale (particularly the CA1 region) was interrupted by frequent gaps in lamination, and ectopic pyramidal cells were found in stratum oriens and radiatum.
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CD-1 mice received daily subcutaneous injections of either cocaine (20 mg/kg or 40 mg/kg) or saline solution (0.9% NaCl) from postnatal days 2 to 15. Pups were tested on days 16–17 for learning and 24-h retention of a passive avoidance task, where entering a dark compartment was punished with a mild foot shock. Locomotor activity and general behaviour in an open field arena were assessed on day 21, following administration of either the muscarinic blocker scopolamine (0.8 mg/kg) or saline solution. In addition, immunostaining for the enzyme choline acetyltransferase (ChAT) was measured in different basal forebrain areas (medial septum, striatum, and nucleus basalis) on day 30. Cocaine treatment failed to affect either learning or retention capabilities. Nonetheless, neophobic behaviour during the learning session was enhanced in control nonpunished mice exposed to the 20-mg/kg dose. In the open field test, although baseline activity levels were unaffected by cocaine exposure, the 40-mg/kg cocaine-treated pups showed decreased sensitivity to the hyperkinetic effects of scopolamine. ChAT immunocytochemistry revealed a significant reduction of the number of ChAT-immunopositive neurons in the nucleus basalis but not in the other cholinergic basal forebrain regions.
Effects of cocaine on the rat cerebral commissure
1996, International Journal of Developmental Neuroscience
We investigated the effects of cocaine on the corpus callosum, the nerve fibre bundle that connects the bilateral cerebral hemispheres. Our experiments in rats confirmed that, in the control group, the mid-sagittal area of the corpus callosum in the adult male was significantly larger than this area in the female. Early postnatal exposure to cocaine abolished this sexual dimorphism, that is, cocaine-treated males had a significantly smaller callosal area than the control males. Cocaine induced no significant changes in the weight of the body or brain. There were no significant sex differences in the midline sagittal area of the anterior commissure, and no apparent effects of cocaine exposure were determined in this structure. These findings suggest that early postnatal exposure to cocaine abolishes the sexual differentiation of the corpus callosum in male rats.
Neonatal cocaine exposure and activity rhythms in rats
1996, Behavioural Brain Research
This study looked at the effects of neonatal cocaine exposure on activity rhythms over a 48-h period in rats. Subjects were artificially-reared from postnatal days (PN) 4–10 via intragastric cannulas. The four treatment groups included two cocaine doses (20 and 40 mg/kg per day), an artificially-reared control and a normally reared suckled control. Subjects were tested at PN 38–40 in an automated running wheel. Neonatal cocaine exposure did not alter activity rhythms over the 48-h test period. However, there was a gender-specific effect of neonatal cocaine exposure on response to the novel test chamber and to the experimenter. The 20 mg/kg cocaine-exposed females showed increased running wheel activity relative to all other groups after placement in the running wheel. During the second 24-h period, cocaine-exposed females from both cocaine groups showed increased activity relative to controls following the entry of an experimenter to the test room. These findings suggest that female rats exposed to cocaine neonatally show an increased response to novel environments and stimuli.
Effects of prenatal cocaine exposure on postnatal growth patterns of male Wistar rats
1995, Neurotoxicology and Teratology
The purpose of this study was to investigate basic parameters regarding the postnatal effects of prenatal exposure to cocaine. Timed-pregnant Wistar rats were injected SC with 60 mg/kg body weight/day of cocaine from gestational day 8 to 22. Control females were nonmanipulated and given food ad lib; saline females received saline injections and pair-fed received saline and were nutritionally controlled to the cocaine-treated rats. Litters were restricted to 8 pups, weighed every other day until postnatal day (PND) 30 and every week from PND 30 to PND 90. The rats were perfused at PND 14, 30, and 90. The adequacy of adjustment of the logistic and Gompertz models to the body weights of the offspring was tested for the whole experimental period. The results from the Gompertz curve showed a higher growth rate and less time to reach 37% of expected mature body mass for the offspring of cocaine and pair-fed dams as compared with that of control and saline dams. No significant differences in the estimated adult weight were found among the experimental groups. The allometric relationship between forebrain and body weight is described by two postnatal growth phases with a first phase of rapid growth between PND 14 and 30 and a decelerating phase between PND 30 and 90. This relationship was not different among the experimental groups; however, the cocaine and pair-fed offspring showed a constant deficit in the forebrain weight as compared with the control and saline off-spring. An analogous two- phase allometric relationship was found between cerebellum and body weight in the control and saline groups in contrast with a single phase for the cocaine and pair-fed groups. The low weight of the cerebellum until PND 30 in cocaine or pair-fed offspring is subsequently compensated by sustaining the high early relative growth between PND 30 and 90. These effects of prenatal cocaine exposure on growth patterns are not different from those detected in the offspring of pair-fed dams, suggesting effects on food intake rather than a direct drug effect. This longitudinal data analysis is of considerable value in the assessment of the effects of drug exposure on body and brain weights, suggesting a possible technique for further evaluation of the developmental processes of the central nervous system.

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ArticleCocaine exposure during the brain growth spurt: Studies of neonatal survival, somatic growth, and brain development

Abstract

Am. J. Obstet. Gynecol.

Neurotoxicol. Teratol.

Neurotoxicol. Teratol.

Neurotoxicol. Teratol.

Neurotoxicol. Teratol.

Early Hum. Dev.

Neurotoxicol. Teratol.

Dev. Brain Res.

Neurotoxicol. Teratol.

Neurotoxicol. Teratol.

Lancet

Neurotoxicol. Teratol.

Neurotoxicol. Teratol.

J. Nutr.

Reciprocity and resource exchange: A symbiotic model of parent-offspring relations

Alcohol concentration and microencephaly: A dose-response study in the neonatal rat

Teratol.

Article
Cocaine exposure during the brain growth spurt: Studies of neonatal survival, somatic growth, and brain development