cocaine effects on the developing brain current status 2004 neuroscience biobehavioral reviews

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751

2. Choice of animal model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752

3. Pharmacology of cocaine actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752

4. Development of the dopaminergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753

5. In utero cocaine exposure produces a permanent uncoupling of the dopamine D1 receptor. . . . . . . . . . . . . . . . . . . . 753

6. Anatomic consequences of dopamine D1 receptor uncoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755

7. Behavioral consequences of prenatal exposure to cocaine: relationship to dopamine D1 receptor uncoupling and altered

cortical morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756

8. Comparison of behavioral effects of prenatal cocaine in other species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759

9. Relationship of animal studies to human clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760

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

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,

0149-7634/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.

doi:10.1016/j.neubiorev.2003.11.006

Neuroscience and Biobehavioral Reviews 27 (2004) 751–764

www.elsevier.com/locate/neubiorev

* Fax: þ1-215-762-2299.

E-mail address: [email protected] (J.A. Harvey).

http://www.elsevier.com/locate/neubiorev

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 adminis-

tration 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, approxi-

mately 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 rabbit’s

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 main-

tained 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 exper-

iments 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 concen-

trations 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 dopa-

mine 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

Gestational day 8 Begin twice a day i.v. saline

or cocaine (6–8 mg/kg/day)

Gestational day 29 Last injection day

Gestational day 30–31 Kits are born. Birthday is considered

to be postnatal day zero

Postnatal day 56 Kits are weaned and housed one

per cage

Postnatal day 40–144 Initiation of behavioral testing

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) 751–764752

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 tuberohypophy-

sial 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.

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 D1 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 nucleo-

tide 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

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.

J.A. Harvey / Neuroscience and Biobehavioral Reviews 27 (2004) 751–764 753

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 amphetamine’s 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. 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].

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].


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

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 organiz-

ation 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

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 ðn ¼ 7Þ demonstrate

a robust increase in amphetamine-induced head bobs, but this response is

virtually absent in rabbits ðn ¼ 7Þ exposed to cocaine prenatally. ANOVA

p , 0:001:

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 depho-

sphorylation 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.


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 concen-

tration 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 frontocin-

gulate 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 CSþand CS2 just prior to the

acquisition of an instrumental [18] or classically con-

ditioned [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 rabbit’s NM reflex to examine associative and atten-

tional 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

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].


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 particu-

larly 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 CSþ , 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 CSþ 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 CSþ and the less salient light as the CS2 (Fig. 9, upper

panel). Although the additional attentional demands in this

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 CSþ . 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 CSþ 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

CSþ [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

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).

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 þ 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 þ and the more salient tone stimulus was the CS 2 than did

controls [79].


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

intense and thus a more salient 1 kHz tone served as the

CSþ 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 CSþ

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 discrimi-

nation when the more salient, more intense tone was the

CSþ , however, they were severely impaired in acquisition

of the discrimination when the less intense, less salient tone

was the CSþ . Regardless of the nature of the discrimi-

nation, either cross modal or intramodal, prenatal cocaine

exposure significantly retarded the rate of CR acquisition to

a less salient CSþ 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 CSþ 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

CSþ and CS2 during the first session of training, there was

an absence of any differential responses to CSþ and CS2

in cocaine progeny (Fig. 10, middle row). Both groups

attained equivalent asymptotic levels of behavioral per-

formance 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 multi-

unit 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 þ and CS 2 occurred at the leftmost

position on the horizontal axis of each panel. Dark bars indicate the neural

response to the CS þ 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].


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 frontocin-

gulate 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 para-

digms. 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 precondi-

tioning was impaired. Similarly, adult rats exposed

prenatally to cocaine were able to form a conditional

discrimination based on odor cues but showed a signifi-

cantly 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

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].


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

deficits appear to be short lived [95–97] and/or gender-

dependent [97,98]. Similarly, spatial learning in the eight-

arm 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 stimu-

lation [123,124], and disordered regulation of behavioral

state [4].

Although the extent of cocaine’s prenatal influence on

children remains unsettled [125–129], substantial progress

that has been made recently in documenting the neuro-

cognitive 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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