ReviewCocaine effects on the developing brain: current status
Introduction
Approximately 12 years ago, NIDA funded a program project grant that was the first to examine the effects of in utero exposure to cocaine in an animal model from an integrated neuroscience perspective. This project was possible because of the development of a neuroscience section at NIDA under the leadership of Roger Brown. There were four separate components to this project that involved PIs who were experts in neuroanatomy (E. Hazel Murphy), developmental neurobiology (Pat Levitt), molecular Biology (Eitan Friedman) and behavioral neurobiology (John A. Harvey, Kenny J. Simansky, Anthony G. Romano, Vincent J. Aloyo, Wei Du and Michael Gabriel). This endeavor was initiated in order to understand the risks of in utero exposure to cocaine that have been reported among childbearing women [1], [2]. It has been estimated that prenatal exposure to cocaine occurs in 30,000–160,000 infants each year [3] and this has raised serious concerns about the impact of cocaine use during pregnancy on human fetal and postnatal development. At the time of initiation of these studies, the extent of prenatal cocaine effects on the postnatal development of the neonate was controversial. This was due to the fact that assessment problems are difficult because early deficits are often transient, pre- and postnatal care and nutrition may be inadequate, assessment instruments vary in their sensitivity, and actual exposure during term generally involves a range of drug dosage and exposure to many other drugs [4], [5], [6]. We, therefore, employed an animal model in order to examine the effects of in utero exposure to cocaine on the developing brain in terms of its neurobiological and neurobehavioral consequences [7]. This paper presents and synthesizes the current status of findings concerning the long-term consequences of prenatal cocaine exposure in our rabbit model and the relationship of these findings to research employing rodents and non-human primates. Finally, the relationship between findings in animal models is compared with current clinical studies.
Section snippets
Choice of animal model
A rabbit model was chosen for these studies for a variety of reasons: (1) the prior history of the rabbit as a model of behavioral teratology following drug treatment [8], [9], [10], [11]; (2) rabbits exhibit patterns of brain development and growth that parallel those of humans [10], [12]; (3) the rabbit metabolizes dopamine, the neurotransmitter through which cocaine acts, in a similar manner to that in humans and other primates [13]; (4) the ease of performing multiple intravenous injections
Pharmacology of cocaine actions
Cocaine, in mature animals as well as in the fetus, is known to bind to the dopamine, norepinephrine and serotonin transporters, thus increasing the synaptic concentrations of these monoamines [20], [21], [22]. The blockade of the norepinephrine transporter in sympathetic neurons accounts for the peripheral autonomic effects of cocaine, while its ability to bind to the dopamine transporter appears to be primarily responsible for its central nervous system effects [20]. Dopamine receptors fall
Development of the dopaminergic system
The monoamine neurons, including those containing dopamine, appear and become operational prenatally, and mature during early postnatal life. Cell bodies of dopamine neurons are present in rat brainstem at gestational day 14 and their axons extend rostrally thereafter [28]. Dopamine is also present in human fetal brains as early as gestational week 7 [29] and in the rabbit forebrain by gestational day 19 [30], [31]. In rat brain, postsynaptic dopamine receptors also appear during this early
In utero cocaine exposure produces a permanent uncoupling of the dopamine D1 receptor
Prenatal cocaine exposure in the rabbit had no effect on the density of either the D1 or D2 receptor in the caudate or in prefrontal/cingulate cortex [32], [33]. This finding was in agreement with previous studies in rats that failed to observe consistent or persistent changes in dopamine receptor densities [34], [35], [36], [37], [38]. In some cases, changes in dopamine receptor densities were observed in the primate [39] or guinea pig [40] fetus but postnatal effects were not measured.
Anatomic consequences of dopamine D1 receptor uncoupling
Although prenatal cocaine exposure produced no gross teratological effects in the rabbit, there were a number of permanent developmental abnormalities in the anterior cingulate, entorhinal, and piriform cortices, areas receiving strong dopaminergic innervation. Of special interest was the finding of abnormally increased length and decreased bundling of layer III and V pyramidal neuron dendrites and alterations in GABA and parvalbumin expression by interneurons [50], [51], [52], [53], [54].
Behavioral consequences of prenatal exposure to cocaine: relationship to dopamine D1 receptor uncoupling and altered cortical morphology
It is well known that the DA projections to frontocingulate cortex are important for associative and attentional processes [66], [67]. Associative conditioning of the NM response (a component of the eyeblink) in the rabbit is severely retarded by DA receptor blockade [68] or by depletion of DA by means of neurotoxic lesions [69], [70] and robustly enhanced by the DA agonist amphetamine [71]. The acquisition of the eyeblink response is also critically dependent on the integrity of the
Comparison of behavioral effects of prenatal cocaine in other species
The findings described above employing both classical and instrumental discrimination learning in the rabbit are consistent with the more general hypothesis that frontocingulate cortex is importantly involved in the mediation of associative attention [18], [73], [72] and that normal functioning of the dopamine system in frontal cortex is critical for normal attentional processes. This conclusion is further supported by studies in a variety of species indicating that prenatal exposure to cocaine
Relationship of animal studies to human clinical findings
Prenatal exposure to cocaine has been reported to produce a variety of abnormalities in the newborn infant that may reflect the sympathomimetic effects of cocaine. These include impaired development of fetal renal arteries [111], vascular injury to the neonatal central nervous system [112], alterations in heart rate variability and diastolic filling [113], [114], [115], [116], increased risk for manifesting a constellation of central nervous system and autonomic nervous system effects [117].
Acknowledgements
This research was supported by NIDA Grant DA 11164 and MH16841.
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