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Neuroscience and Biobehavioral Reviews 27 (2004) 751764

www.elsevier.com/locate/neubiorev

Review

Cocaine effects on the developing brain: current status


John A. Harvey*
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia PA 19102-1192, USA

Abstract
The present paper reports on the results obtained in a rabbit model of prenatal cocaine exposure that mimics the pharmacokinetics of crack
cocaine in humans, and relates these findings to studies in other species including humans. A general finding is that prenatal exposure to
cocaine during neurogenesis produces dysfunctions in signal transduction via the dopamine D1 receptor and alterations in cortical neuronal
development leading to permanent morphological abnormalities in frontocingulate cortex and other brain structures. Differences in the
precise effects obtained appear to be due to the dose, route and time of cocaine administration. Related to these effects of in utero cocaine
exposure, animals demonstrate permanent deficits in cognitive processes related to attentional focus that have been correlated with
impairment of stimulus processing in the anterior cingulate cortex. The long-term cognitive deficits observed in various species are in
agreement with recent reports indicating that persistent attentional and other cognitive deficits are evident in cocaine-exposed children as
they grow older and are challenged to master more complex cognitive tasks.
q 2003 Elsevier Ltd. All rights reserved.
Keywords: Prenatal cocaine; Neurogenesis; Dopamine; Frontocingulate cortex; Learning; Attention; Eyeblink conditioning, rabbit, rodent, primate, human

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Choice of animal model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Pharmacology of cocaine actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Development of the dopaminergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. In utero cocaine exposure produces a permanent uncoupling of the dopamine D1 receptor. . . . . . . . . . . . . . . . . . . .
6. Anatomic consequences of dopamine D1 receptor uncoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Behavioral consequences of prenatal exposure to cocaine: relationship to dopamine D1 receptor uncoupling and altered
cortical morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Comparison of behavioral effects of prenatal cocaine in other species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9. Relationship of animal studies to human clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. 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
* Fax: 1-215-762-2299.
E-mail address: john.harvey@drexel.edu (J.A. Harvey).
0149-7634/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2003.11.006

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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,

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J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

and actual exposure during term generally involves a range


of drug dosage and exposure to many other drugs [4 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.

2. 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 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 of cocaine via the marginal ear vein
of the rabbit and thus mimicking the pharmacokinetics of
smoking crack cocaine, the primary route of administration by pregnant women [14]; (5) the sensitivity of the
rabbit to the behavioral effects of various drugs is quite
similar to that of humans and this allowed us to employ
doses equivalent to those of pregnant women, approximately 2 4 mg/kg/day [8,15,16]; (6) the rabbit is a reflex
ovulator and thus natural mating can be used to initiate
pregnancy; (7) classical conditioning of the rabbits
nictitating membrane (NM) response, a component of the
eyeblink, has become a standard method for examining
associative learning and has been demonstrated to exhibit
all of the cognitive processes that have been observed in
humans [15,17]; and (8) the rabbit has been extensively
employed to examine the electrophysiological correlates of
learning [18]. A centralized breeding program was maintained using the protocol summarized in Table 1. There

were no significant or consistent differences between


cocaine and saline injected dams in body weight gain or
in the duration of pregnancy, thus obviating the need for
pair-fed controls [19]. In addition, there were no detectable
effects of prenatal exposure to cocaine on: (1) litter size; (2)
ratio of male to female births; (3) brain or body weights of
the kits at birth or during subsequent postnatal development;
(4) frequency of birth abnormalities; or (5) any other grossly
observable physical characteristics. The unique aspect of
this research program was that a large group of investigators
could obtain rabbits from the same centrally located core
facility so that prenatal drug exposure was identical for each
investigator and results across many different anatomical,
neurochemical, electrophysiological and behavioral experiments could be easily compared.

3. 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 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 into two major categories, the
D1-like family which includes D1A and D1B (D5) and the
D2-like family (D2, D3, D4). Dopamine receptors are located
both postsynaptically as well as presynaptically on dopamine and non-dopamine axon terminals. Signal transduction
in the dopamine-receptor system is initiated by stimulation
of guanine nucleotide regulatory protein (G-protein)coupled cell surface receptors that are characterized by
seven transmembrane domains. As noted in Fig. 1, the D1

Table 1
Protocol for breeding of Dutch belted rabbits
Day

Procedures

Gestational day 0

Proven breeders are mated using


natural breeding methods
Begin twice a day i.v. saline
or cocaine (68 mg/kg/day)
Last injection day
Kits are born. Birthday is considered
to be postnatal day zero
Kits are weaned and housed one
per cage
Initiation of behavioral testing

Gestational day 8
Gestational day 29
Gestational day 3031
Postnatal day 56
Postnatal day 40144

Fig. 1. Top panel: signaling mediated by the neurotransmitter dopamine is


transduced by the D1 [D1A and D1B (D5)] and D2 (D2, D3, and D4) receptor
families. These receptors are seven transmembrane helices that couple to
effectors (E in figure) via G-proteins. Second messengers generated by
these receptor systems mediate physiologic and nuclear or genomic
responses (see text).

J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

and D2 family of dopamine receptors couple to separate


G-proteins to produce second messenger signaling. D1
receptors bind to Gas to produce an increase in cAMP,
while D2 receptors bind to Gai and produce a decrease
in cAMP [23 25]. The D1 dopamine receptor can
also influence phospholipase C through coupling to Gq
[26,27]. In addition to the physiological responses mediated
by these receptors, dopamine also produces down stream
events that regulate nuclear and genomic responses known
to be critical for neuronal development and synaptic
plasticity.
Fig. 2 shows the four important dopamine projections in
the adult animal: (1) the neostriatal pathway arises from
dopamine cells in the substantia nigra pars compacta and
regulates motor movement through its projections to the
neostriatum; (2) the mesolimbic pathway originates from
dopamine cells in the ventral tegmentum and innervates the
nucleus accumbens where it can regulate mood and
reward; (3) the mesocortical pathway also arises in the
ventral tegmentum and innervates structures such as the
anterior cingulate cortex that are part of the circuitry
mediating cognitive processes; and (4) the tuberohypophysial pathway originating from dopamine cells located in the
arcuate nucleus that innervate the median eminence from
which dopamine is transported by the pituitary portal
system to lactotrophs on the anterior pituitary via the
circulation, and inhibits prolactin release. Thus, alterations
in the functioning of these pathways might be expected
to be manifested by alterations in motor performance,
cognitive abilities, mood, and endocrine balance. Our
research focused primarily on the possible effects of
prenatal cocaine on mesocortical projections that influence
cognitive processes.

Fig. 2. Cartoon showing four major projections of the dopamine system and
their targets (dotted circles) in a sagittal view of the brain. Each projection
system is numbered: (1) nigrostriatal bundle, (2) mesolimbic pathway, (3)
mesocortical pathway, and (4) tuberoinfundibular pathway. Abbreviations:
NA, nucleus accumbens; SN, substantia nigra pars compacta; VTA, ventral
tegmental area.

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4. 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 developmental period. Because of
its effects on the dopamine transporter and consequently its
postsynaptic effects on dopamine receptors due to increased
extracellular dopamine, cocaine would be expected to alter
the development of the dopamine system and the targets at
which dopamine acts.

5. 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 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.
However, prenatal exposure to cocaine in the rabbit produced
a functional uncoupling of the D1 dopamine receptor from its
G-protein in caudate nucleus, frontal cortex and cingulate
cortex. Basal and dopamine-stimulated binding of
[35S]GTPgS to Gas and Gai proteins was determined by
monitoring [35S]GTPgS in Gas protein immunoprecipitates
of specific Ga antisera. As expected, in all three brain regions
of the rabbit, the D1 dopamine receptors were found to couple
to Gs while the D2 dopamine receptors were associated with
Gi protein. While basal guanine nucleotide binding to these
Ga proteins was not altered, dopamine-induced increases in
guanine nucleotide binding to Gas protein were reduced in
all three brain regions of in utero cocaine-exposed offspring,
suggesting an uncoupling (desensitization) of the D1
receptor. This uncoupling of the D 1 receptor could
be observed in frontal cortex as early as embryonic day 22
(Fig. 3) and was still present at postnatal day 100. (Fig. 4). It is
important to note that the reduction in dopamine-stimulated
GTP binding to Gas did not result from a decrease in
concentration of membrane Gas protein [32,33]. The
uncoupling of the D1 receptor from its Gas protein was
highly specific since dopamine-stimulated guanine nucleotide binding to Gai was unchanged (Fig. 4), suggesting that
there was no effect on coupling of the D2 receptor in these
brain regions [32,33,41].
The uncoupling of the D1 dopamine receptor was further
confirmed by examination of cocaine-induced c-fos

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J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

Fig. 3. In utero exposure to cocaine produces a decreased coupling of the


dopamine D1A receptor. Basal and dopamine-stimulated coupling of D1A
dopamine receptor to GaS in rabbit frontal cortex at various embryonic and
postnatal ages. Co-immunoprecipitated D1A receptor protein expressed as
mean ^ sem of optical densities. Prenatal exposure to cocaine had no effect
on basal coupling of the D1A receptor but prevented the normal increase in
coupling produced by dopamine (1 mM). * p , 0:01; E, embryonic age, P,
postnatal age [52].

expression in both the mesolimbic and neostriatal brain


regions at postnatal day 20. The induction of c-fos in control
animals was shown to be due to activation of D1 dopamine
receptors since the D1 antagonist SCH 23390 completely
blocked this gene expression in both striatum and cortex.
Prenatal cocaine exposure significantly reduced the ability
of cocaine to induce c-fos gene expression in both brain
regions as compared with saline-exposed controls [42,43].
It has been demonstrated that the dopamine agonist
amphetamine elicits repetitive head movements in the rat
and head bobbing in the rabbit both of which are mediated
by activation of the D1 receptors in the striatum [44,45]. The
uncoupling of the D1 receptor and the decreased c-fos
expression demonstrated in rabbits prenatally exposed to

cocaine suggests that these rabbits should also demonstrate


a behaviorally blunted response to amphetamines ability to
elicit head bobbing. In agreement with this hypothesis,
prenatal cocaine exposure virtually eliminated the
stereotyped head bobbing elicited by amphetamine [45],
see Fig. 5. This result further confirms that prenatal
exposure to cocaine impairs signal transduction at the D1
receptor. The uncoupling of the D1 dopamine receptor
occurred in both neostriatum and in mesolimbic cortex,
brain areas that are strongly innervated by dopaminergic
fibers, suggesting that the uncoupling may reflect an
adaptive reaction to the persistent increase in synaptic
dopamine during brain development. This uncoupling of the
D1 dopamine receptor was also confirmed in primates that
had been exposed to cocaine in utero [46].
The equilibrium between coupled and uncoupled states
of the dopamine D1 receptor are determined by the balance
between protein kinase activity that phosphorylates serine to
produce the uncoupled state and phosphatase activity that
returns the G-protein to its coupled state (Fig. 6). It has been
demonstrated that dopamine acting at the D1 receptor can
initiate a phosphorylation of DARPP-32 on Thr34 which in
turn becomes an inhibitor of protein phosphatase 1
(PP1) thus decreasing the ability of PP1 to dephosphorylate
the D1 receptor [47]. Consequently more of the D1 receptor
remains in the phosphorylated (uncoupled) state and less in
the dephosphorylated (coupled) state. It was found that the
frontal cortex of rabbits exposed to cocaine in utero
demonstrated an increased content of phosphorylated
DARPP-32 (Thr34), a decreased content of PP1 and an
increased content of phosphoserine residues in the D1
receptor [48]. Thus, prenatal cocaine exposure produced a
selective inhibition of protein phosphatase 1 pathway thus
leading to an equilibrium in favor of the uncoupled state of
the receptor [48]. These results are in agreement with a
previous demonstration of increased phospho-DARPP-32
(Thr34) after acute cocaine administration in mice [49]. It
would appear, therefore, that the cocaine-induced increase

Fig. 4. In utero exposure to cocaine produces a long-lasting decrease in coupling to the dopamine D1 but not to the D2 receptor in frontal cortex of the rabbit.
Data are expressed as percent of basal (unstimulated) coupling [33].

J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

Fig. 5. Effects of amphetamine on head bobbing in adult rabbits that had


been exposed to cocaine prenatally [45]. Head bobbing in 140-day-old
rabbits elicited by acute administration of D -amphetamine sulfate
(5 mg/kg, s.c.). Animals exposed to saline prenatally n 7 demonstrate
a robust increase in amphetamine-induced head bobs, but this response is
virtually absent in rabbits n 7 exposed to cocaine prenatally. ANOVA
p , 0:001:

in dopamine during fetal development has led to a persistent


increase in the uncoupled state of the D1 receptor due to
altered signaling in the DARPP-32/PP1 cascade [48].

6. 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

Fig. 6. Proposed basis for the uncoupling of the D1 receptor by prenatal


exposure to cocaine. The equilibrium between coupled and uncoupled
(desensitized) states of the D1 receptor is determined by the rate of
phosphorylation of serine by a protein kinase and the rate of dephosphorylation by phosphatase 1. Prenatal cocaine exposure produces a
dysregulation that results in a permanent decrease in protein phosphatase 1.
Consequently the equilibrium shifts to an increase in the phosphorylated
(desensitized) state of the receptor [48]. See text for further details.

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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 54]. These developmental abnormalities
were associated with uncoupling of D1 receptors in these
brain regions [52]. Exposure to cocaine during embryonic
days 16 25, the time of peak corticogenesis, appearance of
cortical dopamine and onset of dopamine D1 receptor
expression, was found to be the necessary and sufficient
condition for producing long-term effects on the organization of excitatory pyramidal neurons and inhibitory
interneurons [54]. As shown in Fig. 7, a significant
difference in neurite outgrowth between saline and cocaine
prenatally exposed rabbits was observed in embryonic
neurons obtained as early as E21 from anterior cingulate
cortex, but no differences were detectable in neurons taken
from visual cortex [52]. Also, in the adult, primary
somatosensory, motor, auditory and visual cortices, areas
receiving little if any dopaminergic inputs, exhibited normal
cortical structure [50 54].
It has been demonstrated that stimulation of D1 and D2
dopamine receptors influences neuronal development in
opposing manners [55]. Dopamine D1 receptor stimulation
suppressed axonal and neurite outgrowth in primary cortical
embryonic neurons in culture, while D2 dopamine receptors
promoted process elongation. In cultured retinal cells,
dopamine was also shown to cause neurite retraction via a
D1 dopamine receptor mediated mechanism [56]. In
cultured PC12 cells, activation of the D1 receptor directly
by dopamine or by the increase in dopamine produced by
cocaine (but not NE, 5-HT and acetylcholine) led to an
inhibition of neurite outgrowth [57 59]. The uncoupling of
the D1 receptor produced by prenatal exposure to cocaine
can be assumed to have affected its normal inhibitory
regulation of neurite outgrowth thus leading to the abnormal
dendritic length of the excitatory pyramidal neurons. The
altered expression of GABA and parvalbumin expression by
the inhibitory interneurons may have been a reaction to an
increased excitability of pyramidal neurons. Interestingly,
prenatal cocaine exposure in the rat resulted in a reduction
in neurite length of locus coeruleus neurons [60]. This result
suggests that cocaine inhibition of norepinephrine uptake
may also have consequences on the development of
noradrenergic neurons.
A greater alteration in brain cytoarchitecture than that
seen in rabbits has been reported in mice [61,62], rats [63],
and primates [64] exposed to cocaine in utero. These effects
include loss of neurons and a lack of discernable lamination
in cerebral cortex and hippocampus. However, as in the case
of the rabbit model, the effects of cocaine on cortical
development in the primate occurred only if it was
administered during the time of cortical neurogenesis [65].
The greater effects of cocaine in the developing brain
observed in these studies may well be related more to the
differences in the pharmacokinetics of cocaine when it is
injected intravenously (rabbit and rat), orally (primate) or

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J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

Fig. 7. Photomicrographs of MAP2-stained embryonic day E21 medial frontal cortical (including the anterior cingulate cortex) (A, B) and visual cortical (C, D)
culture preparations from saline-exposed (A, C) and cocaine-exposed (B, D) embryos. Neurons taken from the anterior cingulate cortex (ACC) of cocaine
(COC)-exposed embryos (B) demonstrate an exuberant growth of neurites as compared to those taken from saline (SAL)-exposed embryos (A). There were no
differences between neurons taken from the visual cortex (VIS) of saline (C) and cocaine (D)-exposed embryos [52].

subcutaneously (rat and mouse) than to the species of


animal employed. Intravenous administration is equivalent
to inhalation of crack cocaine producing a rapid and high
content of cocaine in plasma and in the brain with a short
plasma half life. In contrast, oral and subcutaneous
administration of cocaine produces a slow increase,
persistent duration, and slow decline in plasma concentration and thus a lower brain concentration but longer
duration of exposure of brain to cocaine. The longer
duration of exposure of the brain to cocaine may thus be
responsible for the more damaging effects observed.

7. 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 frontocingulate
cortex. Damage to the rabbit frontocingulate cortex
impairs associative learning [72] and, in normal rabbits,
neurons in the anterior cingulate cortex begin to respond
differentially to a CS and CS2 just prior to the
acquisition of an instrumental [18] or classically conditioned [73] discrimination, a task requiring attentional

focus. Similarly, in humans, imaging studies have shown a


robust activation of the anterior cingulate cortex during the
performance of tasks that provide measures of attentional
processes such as the Stroop attentional conflict task [74],
a noun verb conflict task [75] or a stimulus change
detection task [76]. For these reasons, we hypothesized that
the reduced coupling of the D1 receptor and consequent
structural abnormalities in the frontocingulate cortex might
be associated with deficits in attentional and associative
processes. Therefore, we examined the attentional and
associative abilities of cocaine progeny during acquisition
of the classically conditioned eyeblink response and the
instrumental avoidance response.
We first employed classical (Pavlovian) conditioning of
the rabbits NM reflex to examine associative and attentional processes that might have been affected by prenatal
exposure to cocaine. Rabbits were trained using both a
75 dB tone conditioned stimulus (CS) and a flashing
houselight CS in an 800-ms delay procedure. The CSs
were presented in a semi-random fashion with each
conditioning session consisting of 30 pairings of the
800-ms tone and 30 pairings of the 800-ms light CS with
a 100 ms corneal air puff unconditioned stimulus (US). All
animals, both saline and cocaine progeny, showed a faster
rate of conditioned response (CR) acquisition to the tone CS
compared to the light CS (Fig. 8). By convention, this
difference in the rate of learning given different conditioned
stimuli has been attributed to differences in stimulus
salience. The CS associated with the faster rate of
conditioning (in this case, the tone) is said to be the more
salient of the two. Cocaine offspring learned significantly
faster than saline offspring when rate of learning was

J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

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Fig. 8. Acquisition of CRs to a light or tone CS by rabbits prenatally


exposed to cocaine or saline [77]. Cocaine progeny acquired CRs to the
light CS at the same rate as controls, but demonstrated a significant
acceleration of learning to the tone CS (see text for more details).

assessed in the presence of the more salient, tone CS


whereas there was no difference in the rate of CR
acquisition to the less salient light CS [77]. Control
experiments indicated that the accelerated associative
learning to the tone CS, demonstrated by cocaine progeny,
could not be attributed to an increase in non-associative
responding, an increase in the intensive properties of the
tone CS or the air puff US. Moreover, since acquisition of
CRs to the light CS was not affected, prenatal cocaine could
not be having some general effect on learning. These results
suggest that the accelerated rate of CR acquisition in
cocaine-exposed offspring was due to an alteration in
attentional processing which is most evident when particularly salient stimuli are employed as CSs. Thus, an alteration
in attentional processing of the salient tone CS could
account for the more rapid entry of the tone CS into
associative learning [77].
A discrimination learning task was employed to test the
hypothesis that prenatal exposure to cocaine had affected
attentional processing. These are tasks in which attentional
processing plays a more critical role than in simple
acquisition of the CR. In the simplest discrimination learning
task, two CSs are employed. One CS, designated the CS , is
consistently paired with the US whereas the other CS,
designated the CS2 , is never paired with the US. A
commonly held view of discrimination learning is that
successful discrimination involves learning to attend and
respond to the CS and learning to ignore and not respond to
the CS2 [78]. If attentional processing was altered as a
consequence of prenatal cocaine exposure, then one would
expect to see some alteration in discrimination learning as
well. Animals were trained with the relatively salient tone as
the CS and the less salient light as the CS2 (Fig. 9, upper
panel). Although the additional attentional demands in this

Fig. 9. Acquisition of discrimination tasks by rabbits that had been exposed


prenatally to cocaine and their saline controls. Top panel, cocaine progeny
acquired the discrimination at the same rate as controls when to salient tone
stimulus was the CS and the less salient visual stimulus was the CS 2 .
Bottom Panel, cocaine progeny required approximately 2 more weeks to
acquire the discrimination when the less salient visual stimulus was
the CS and the more salient tone stimulus was the CS 2 than did
controls [79].

task slowed the rate of learning for both groups (compare


with Fig. 8), that effect was more pronounced in the cocaine
offspring so that there were no differences between them and
saline offspring in the acquisition of CRs to the tone CS . In
the next experiment, conducted in separate groups of
animals, the roles of the tone and light were switched. The
light now served as the CS and the more salient tone served
as the CS2 (Fig. 9, lower panel). This discrimination task
was more difficult than the previous one in that both groups
required more sessions to achieve asymptotic performance
when the more salient stimulus, the tone, was the CS2 . More
importantly, cocaine-exposed animals were significantly
retarded in their ability to acquire CRs to the less salient, light
CS [79].
We conducted two more discrimination experiments, this
time involving a discrimination between two tones differing
in both frequency and intensity [80]. The intensity
dimension was manipulated in order to produce differences
in stimulus salience between the two tones since it seemed
that differences in stimulus salience rather than modality
were contributing to the attentional alterations seen in

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J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

cocaine-exposed animals. In the first experiment, a more


intense and thus a more salient 1 kHz tone served as the
CS and a less intense and thus less salient 8 kHz tone
served as the CS2 . In the second experiment, these CSs
were reversed with the less intense tone serving as the CS
and the more intense tone serving as the CS2 . The results of
this intramodal discrimination confirmed those of the cross
modal discrimination. Cocaine progeny did not differ from
saline progeny in their rate of acquisition of the discrimination when the more salient, more intense tone was the
CS , however, they were severely impaired in acquisition
of the discrimination when the less intense, less salient tone
was the CS . Regardless of the nature of the discrimination, either cross modal or intramodal, prenatal cocaine
exposure significantly retarded the rate of CR acquisition to
a less salient CS when a more salient stimulus served as
the CS2 [79,80].
The results described above indicate that prenatal
exposure to cocaine produces a significant deficit in
attentional processes. The deficit is characterized by an
exaggerated tendency to attend to the more salient of two
stimuli regardless of its significance for the acquisition of
discrimination. Thus, rabbits prenatally exposed to cocaine
had difficulty only when they had to ignore a more salient
stimulus and attend to a less salient stimulus. Consequently,
learning was retarded when preferential attention to the
more salient stimulus was not appropriate for the task. These
findings also suggest that there might be a causal
relationship between the deficits in learned attentional
processes and the abnormal development of the anterior
cingulate cortex an area of the brain strongly implicated in
attentional processes. This possibility was investigated by
measuring the electrophysiological responses of the anterior
cingulate cortex during the acquisition of an instrumental
discrimination in the rabbit.
Previous research had demonstrated that, in normal
rabbits, neurons in the anterior cingulate cortex begin to
respond differentially to a CS and CS2 just prior to
behavioral acquisition of an instrumental discrimination
and that these differential responses reflect attentional
processes [18,81]. Discriminative avoidance training was
carried out using a tone stimulus that had either high or low
salience. Stimulus salience was manipulated by altering
stimulus duration with the more salient stimulus having a
500 ms duration and the less salient stimuli having a 200 ms
duration. Acquisition of the discriminated instrumental
response was measured in terms of the behavioral
acquisition of CRs and in terms of the training-related
multiple unit responses recorded simultaneously in the
anterior cingulate cortex. Under conditions employing
reduced stimulus salience (200 ms CS), cocaine progeny
demonstrated significantly fewer CRs than saline progeny
during the first session of training. In addition, while
controls demonstrated a significant difference in the
neuronal response of the anterior cingulate cortex to the
CS and CS2 during the first session of training, there was

an absence of any differential responses to CS and CS2


in cocaine progeny (Fig. 10, middle row). Both groups
attained equivalent asymptotic levels of behavioral performance by the last block of training and this was mirrored
by the subsequent occurrence of equivalent discriminative
neuronal responses in saline- and cocaine-exposed rabbits.
However, as seen in the middle row of Fig. 10, cocaine
progeny trained under the less salient stimuli exhibited less
sustained firing of anterior cingulate neurons as compared
with controls. The fact that both the discriminative neuronal
and behavioral deficits associated with prenatal cocaine
exposure occurred in the first training session is consistent
with past results in the rabbit [81]. When the more salient
500 ms CS duration was employed, both cocaine and saline

Fig. 10. Multiple unit activity in the anterior cingulate cortex during
acquisition of an instrumental discrimination. Average integrated multiunit activity in 30 consecutive, 10 ms intervals after onset of brief
(200 ms) CSs in rabbits exposed to cocaine in utero and in saline-exposed
controls. The onset of the CS and CS 2 occurred at the leftmost
position on the horizontal axis of each panel. Dark bars indicate the neural
response to the CS and light (open) bars to the CS 2 . Data are shown
for pretraining in which tones and unpaired footshock presentations were
given, the first session of conditioning and the session of criterion
attainment. Note the absence of training-induced discriminative neuronal
activity in the first session of training (left panel, second row) in rabbits
exposed to cocaine in utero as compared to their saline-exposed controls
(right panel, second row) [83].

J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

759

Fig. 11. Average anterior cingulate cortical multi-unit spike frequency in 40 consecutive, 10-ms intervals after onset of brief (200-ms) CS in rabbits exposed to
cocaine in utero and in saline-exposed controls. Data in each histogram are averages for all rabbits and training stages from pretraining to the session of
criterion attainment. The onset of the CSs occurred at the leftmost position on the horizontal axis. Asterisks indicate the occurrence of significantly greater
discharges in the indicated condition (prenatal exposure to saline or cocaine) than in the corresponding interval in the other condition [83].

progeny acquired CRs at the same rate. However,


differences could still be detected between the neuronal
responses of cocaine and saline progeny during acquisition
[82]. A number of other alterations were observed in the
anterior cingulate cortex including an elimination of the
usually observed poststimulus inhibitory firing pause [83].
Specifically, as shown in Fig. 11, the histograms of the
cocaine-exposed rabbits lacked the expected inhibitory
pause, which occurred dramatically in controls from 40 to
80 ms after CS onset, and which is a consistent feature of
the CS-elicited temporal discharge profiles of neurons in
cingulate cortex [81]. This effect may be related to the
alterations in the inhibitory GABA interneurons and/or to
the loss of D1-mediated signaling in frontocingulate cortex
described above.

8. 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 results in attentional deficits as
measured during discrimination and other learning paradigms. Prenatal exposure of rats to intravenous cocaine has
been reported to impair selective attention, an effect that
was linked to dysfunctions of the dopamine D1 receptor

[84 88]. In most instances, an increase in the demands of


the task have led to an increase in the severity of deficits
seen in cocaine progeny, similar to what we observed in our
rabbit NM preparation. Thus, it has been reported [89] that
first-order odor conditioning was intact in infant rats
prenatally exposed to cocaine whereas sensory preconditioning was impaired. Similarly, adult rats exposed
prenatally to cocaine were able to form a conditional
discrimination based on odor cues but showed a significantly slower reversal of that discrimination than control
animals [90]. Paradoxically, latent inhibition, a presumed
test of attentional abilities was enhanced in prenatally
exposed rats as compared with their saline controls [91].
The mouse model of prenatal cocaine exposure shows a
similar pattern of apparently normal learning during a
simple acquisition task but impaired learning when greater
attentional demands are placed on the organism [92]. Adult
mice exposed to cocaine prenatally demonstrate normal
aversion to an odor paired with a footshock but fail to show
blocking of associative learning when a redundant CS is
added to the original odor footshock pair [80,93]. Blocking
of associative learning when a redundant CS is added to an
already established CS US association is often regarded as
an attentional phenomenon whereby animals learn to ignore
the redundant CS [78].
Most of the cognitive behavioral deficits described above
suggest that prenatal exposure to cocaine disrupts learned,
attentional processing. Other learned behaviors, less
dependent upon attentional processing, should therefore be
spared. Spatial learning appears to fall into such a category.
Mixed results have been reported in spatial learning tasks
such as the Morris water maze and eight-arm radial maze.
Cocaine progeny sometimes fail to show deficits in

760

J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751764

the Morris water maze [94] or if they do show deficits, these


deficits appear to be short lived [95 97] and/or genderdependent [97,98]. Similarly, spatial learning in the eightarm radial maze is either unaffected by prenatal cocaine
exposure [95] or is impaired in only one gender [99].
However, non-spatial short-term memory was affected by
prenatal cocaine exposure in the rat [100]. Preliminary
evidence of deficits in monkeys prenatally exposed to
cocaine in a reversal learning task, a procedure that requires
attentional focus, has also been reported [101]. In utero
cocaine exposure has also been reported to produce altered
responses to stress and novelty in rodents [102 106] that
may be associated with altered sensory processing of
stressful stimuli in prefrontal cortex [107 109]. Finally,
another potentially serious concern is the latest finding of an
increased vulnerability to self-administer cocaine in mice
prenatally exposed to cocaine [110].

9. 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 [113 116], increased risk for manifesting a
constellation of central nervous system and autonomic
nervous system effects [117]. The well-documented
decreased head circumference may be related to nutritional,
early birth or other factors [118]. A variety of abnormalities
that may be related to the central nervous system
effects of cocaine include altered energy metabolism in
brain [119], altered muscle tone and motor competence
[120 122], retarded neuronal conduction to sensory stimulation [123,124], and disordered regulation of behavioral
state [4].
Although the extent of cocaines prenatal influence on
children remains unsettled [125 129], substantial progress
that has been made recently in documenting the neurocognitive changes that occur in children born of mothers
who abused cocaine during pregnancy [130 134], also see
Ref. [6]. Of relevance to the present review are the findings
of the second generation of studies. Thus The Toronto
Adoption Study has reported that cocaine exposure was
significantly associated with lower IQ and poorer language
development [135,136]. Similarly a Miami Prenatal
Cocaine Study reported impaired language functioning
though age 7 years [137]. Fetal cocaine exposure has also
been associated with impulsivity and impaired attention
[138], impaired auditory information processing and
habituation [139], impaired reaching behavior [140], as
well as impaired cognitive functioning and fine motor
control [141]. In summary, prenatal cocaine exposure in

experimental animals and in humans produces measurable


dysfunctions in behaviors that are regulated by the
dopamine system as shown in Fig. 2: cognitive abilities,
motor performance, reward and mood, and endocrine
reactions to stress.

Acknowledgements
This research was supported by NIDA Grant DA 11164
and MH16841.

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