Prenatal Cocaine Increases Dendritic Spine Density in Cortical and Subcortical Brain Regions of the Rat

Abstract

Alterations in dendritic spine density following prenatal cocaine exposure were examined in the present study. Timed pregnant rats were injected daily with 30 mg/kg cocaine or saline during gestation. At postnatal day 21, male and female animals were separated and spine density was assessed following Golgi impregnation. In prenatal cocaine-exposed rats, significant increases in dendritic spine density were observed on pyramidal cells in the CA1 region of the hippocampus, basal dendrites of layer II/III of the medial prefrontal cortex, medium spiny neurons of the striatum and the core of the nucleus accumbens, as well as in neurons of the ventromedial hypothalamic nucleus. No differences were observed in either apical or basal dendrites of pyramidal cells in layer III of the sensory cortex or layer V of the medial prefrontal cortex, or in apical dendrites of layer II/III pyramidal cells of the medial prefrontal cortex. Moreover, there were no sex differences in any region examined. These results demonstrate that prenatal cocaine exposure increases spine density in many brain regions at postnatal day 21, and this effect is independent of sex.

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Original Paper
Dev Neurosci 2009;31:71–75
DOI: 10.1159/000207495
Prenatal Cocaine Increases Dendritic
Spine Density in Cortical and Subcortical
Brain Regions of the Rat
Maya Frankfurt Hoau-Yan Wang Naydu Marmolejo Kalindi Bakshi
Eitan Friedman
Department of Physiology/Pharmacology, City University of New York Medical School at CCNY, New York, N.Y. , USA
Introduction
Prenatal cocaine exposure has been shown to result in
multiple functional deficits in brains and in behavior of
offspring [reviewed by Harvey, 2004]. Given that prenatal
cocaine-induced effects persist long after exposure [Is-
mail and Bedi, 2007; Kalivas and O’Brian, 2007; Stan-
wood et al., 2001], it is likely that cocaine induces mor-
phological alterations in certain brain regions. This is
supported by studies in several species. In nonhuman
primates, prenatal cocaine exposure disrupts the devel-
opment of cortical layers [Lidow, 2003]. Prenatal cocaine
exposure has been shown to increase dendritic length
[Jones et al., 1996] and decrease dendritic bundling [Stan-
wood et al., 2001] in rabbit cortical pyramidal cells, and
to increase the dendritic arbor in mouse pyramidal cells
[Lloyd et al., 2003].
Since prenatal cocaine exposure results in a number of
cognitive defects [Morrow et al., 2002; Singer et al., 2002]
many of the morphological studies have targeted the pre-
frontal cortex (PFC). Prenatal cocaine has been demon-
strated to decrease axo-axonic synapses [Morrow et al.,
2003] and increase spine synapses [Morrow et al., 2007]
in the medial PFC of 21-day-old rat pups. However, there
exists ample evidence that cocaine also has profound ef-
fects on brain regions that have extensive interconnec-
tions with the PFC. In addition, sex differences in re-
Key Words
Cocaine, prenatal ⴢ Dendritic spines ⴢ Golgi impregnation ⴢ
Prefrontal cortex ⴢ Hippocampus ⴢ Striatum ⴢ Nucleus
accumbens ⴢ Ventromedial ⴢ Sex differences
Abstract
Alterations in dendritic spine density following prenatal co-
caine exposure were examined in the present study. Timed
pregnant rats were injected daily with 30 mg/kg cocaine or
saline during gestation. At postnatal day 21, male and female
animals were separated and spine density was assessed fol-
lowing Golgi impregnation. In prenatal cocaine-exposed
rats, significant increases in dendritic spine density were ob-
served on pyramidal cells in the CA1 region of the hippocam-
pus, basal dendrites of layer II/III of the medial prefrontal cor-
tex, medium spiny neurons of the striatum and the core of
the nucleus accumbens, as well as in neurons of the ventro-
m ed ia l hy po th a la mi c nu cl e us . N o di f fe re n ce s w er e ob se r ve d
in either apical or basal dendrites of pyramidal cells in layer
III of the sensory cortex or layer V of the medial prefrontal
cortex, or in apical dendrites of layer II/III pyramidal cells of
the medial prefrontal cortex. Moreover, there were no sex
differences in any region examined. These results demon-
strate that prenatal cocaine exposure increases spine den-
sity in many brain regions at postnatal day 21, and this effect
is independent of sex. Copyr ight © 2009 S. Karger AG, B asel
Rece ived: March 21, 2008
Accepted a fter revision: Septem ber 25, 2008
Published online: April 17, 2009
Maya Fra nkfur t, PhD
Depar tment of Physiology/Pharmacology, City University of N Y Medical School
138th Street and Convent Ave.
New York, NY 10031 (USA)
Tel. +1 212 650 6994, Fax +1 212 650 7726, E-Mail mf rank@med.cuny.edu
© 2009 S. Karger AG, Basel
Accessible online at:
www.karger.com/dne
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72
sponse to cocaine have been reported in both humans
and experimental animals [Becker and Hu, 2008; Lynch
et al., 2002]. Therefore, in the present study, prenatal co-
caine effects on dendritic spine density were assessed in
several cortical and subcortical regions in the brains of
21-day-old male and female rats.
Materials and Methods
Timed pregnant rats weighing 200–225 g were purchased (Ta-
conic Farms, Hudson, N.Y., USA) and housed singly. Rats were
maintai ned at constant temperature and hum idity under a 12-hour
light/dark light cycle, with free access to food and water. The ani-
mal protocol used was approved by the Institutional Animal Care
and Use Commit tee at CCNY, and is in accord with t he NIH Guide
for the Care and Use of Laboratory Animals. Animals were inject-
ed daily subcutaneously with 30 mg/kg cocaine HCl in 0.9% saline
or saline alone from gestation day 2 until they gave birth. Follow-
ing each injection, the pregnant rats were observed and increases
in locomotor activity were seen in cocaine-treated rats. To mini-
mize skin lesions and tissue necrosis in the cocaine-injected rats,
the injection sites were rotated over different sites on the back. As
has been previously demonstrated [Choi et al., 1998; Yablonsky-
Alter et al., 2004], cocaine injections (40 mg/kg) did not affect ma-
ternal weight, litter size or body weight of the pups. A minimum of
4 pregnant rats were used for each group, and litters were between
8 and 14 pups. At postnatal day 21, the pups were sexed (minimum
6 per group) and killed by rapid decapitation, with the brains re-
moved, blocked and placed in solutions provided in the FD Rapid
GolgiStain Kit (FD NeuroTechnologies , Ellicott City, Md., USA).
Golgi impregnation was performed according to the direc-
tions from FD NeuroTechnologies, with minor modifications
[Luine et al., 2006]. Blocks were placed directly into solutions A
and B, wit hout rinsing, and remai ned there for 2 weeks in the da rk
at room temperature. Forty-eight hours after placing the blocks
in solution C (4
° C), the blocks were frozen on dry ice and stored
at –70
° C until sectioning. Cryostat sections (100 ␮ m) were c ut at
–25
° C and mounted onto gelatinized slides. Slides were allowed
to dry in the dark, and the rest of the staining process done as
previously described [Wallace et al., 2006].
Secondary basal dendrites and tertiary apical dendrites were
analyzed from pyramidal cells from the CA1 region of the dor-
sal hippocampus, layer II/III and layer V pyramidal cells of the
PFC, and layer III pyramidal cells of the somatosensory cortex
(ParCtx). In the striatum and core of the nucleus accumbens
(NAc), dendrites from medium spiny neurons were analyzed. In
the hypothalamus, cells in the ventrolateral part of the ventrome-
dial nucleus (VMN) were analyzed. Regions were defined with
the aid of The Rat Brain Atlas in Stereotaxic Coordinates [Pa xi nos
and Watson, 1998]. Cells chosen for analyses had to be well im-
pregnated, clearly distinguishable from adjacent cells and have
continuous unbroken dendrites. Spines were counted under oil
( ! 100), using a Leitz Diaplan microscope, and the entire den-
dritic le ngth visible mea sured using Image Pro Plus s oftware (Me-
dia Cybernetics, Bethesda, Md., USA) with a Nikon DXM 1200F
camera (Tokyo, Japan). Spine density was calculated by dividing
the number of spines by the length of the dendrite. Six cells/re-
gion/brain were averaged, and differences assessed by 2-way
ANOVA (treatment, sex) followed by the Bonferroni test for post
hoc comparisons (p ! 0.05 considered significant). Data are ex-
pressed as spines/10 ␮ m dendrite. A 1-way ANOVA showed a lack
of across-litter and within-litter variability of spine density with-
in treatment groups for all areas examined (data not shown).
R e s u l t s
Two-way ANOVA demonstrated a significant treat-
ment effect in many areas and a lack of sex differences in
all regions examined. All treatment effects are shown in
table 1 . In the CA1 region of the hippocampus, prenatal
cocaine treatment increased dendritic spine density by
22% on basal dendrites (F
1,19 = 12.11, p ! 0.01) and 12%
on apical dendrites (F
1,19 = 8.33, p ! 0.01) as compared to
saline. In the striatum and NAc, prenatal cocaine expo-
sure increased dendritic spine density of medium spiny
neurons by 33% (F
1,22 = 44.034, p ! 0.01; fig. 1 ) and 13%
(F
1,18 = 11.67, p ! 0.01), respectively. In layers II/III of the
medial PFC, prenatal cocaine increased dendritic spine
density by 23% as compared to saline injected controls
(F
1,19 = 13.276, p ! 0.01), but had no effect on the spine
density of apical branches of these cells. In the VMN, pre-
natal cocaine exposure increased dendritic spine density
by 18% (F
1,18 = 9.059, p ! 0.01). Prenatal cocaine exposure
did not affect densities of either apical or basal dendrites
Tab le 1. Prenatal cocaine: effect on dendritic spine density in 21-
day-old rat pups
Brain region Saline Cocaine
CA1 apical 13.180.4 14.780.4*
CA1 basal 11.380.5 13.880.5*
Striatum 12.880.5 17.080.5*
NAc 11.680.3 13.180.3*
VMN 6.680.3 7.880.3*
PFC (II/III) basal 10.880.5 13.380.5*
PFC (II/III) apical 12.680.4 13.480.4
PFC (V) basal 16.480.5 15.380.9
PFC (V) apical 18.680.5 16.780.7
ParCtx (III) basal 14.480.5 14.180.4
ParCtx (III) apical 14.780.6 14.280.6
Value s refer to the number of spines/10 ␮m dendrites, and are
expressed as means 8 SEM. Apical = Tertiary dendrites; basal =
secondary dendrites. Analysis of 6–13 brains/group. Data ana-
lyzed by 2-way ANOVA followed by post hoc analysis using the
Bonferroni method. * p < 0.05.
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of pyramidal cells in layer III of the ParCtx or apical and
basal dendrites of pyramidal cells in layer V of the me-
dial PFC ( table 1 ).
Discussion
In the present study, alterations in dendritic spine den-
sity following prenatal exposure to cocaine have been
demonstrated in a number of brain regions. The greatest
increase in dendritic spine density was observed in the
striatum, but there were significant increases in spine
density in pyramidal cells of layer II/III of the PFC, the
CA1 region of the hippocampus, the core of the NAc and
the VMN. With the exception of the VMN, these regions
are part of the reward circuit that mediates the effects of
cocaine on the brain [Kalivas and O’Brian, 2007; Malan-
ga and Kosofsky, 2003].
These results extend previous studies in which prena-
tal cocaine exposure has been reported to alter the mor-
phology of neurons in the PFC [Jones et al., 2000; Mor-
row et al., 2003, 2007]. In addition, prenatal cocaine has
been demonstrated to increase dendritic volume in layer
III pyramidal cells and decrease dendritic volume in lay-
er IV granule cells of the frontal cortex of mice [Lloyd et
al., 2003]. While prenatal cocaine administration dis-
rupts the development of pyramidal cells in CA1 [Bara-
ban et al., 1999], perinatal cocaine exposure results in a
decrease in the number of pyramidal and granule cells in
the hippocampus at postnatal d ay 22 that persists th rough
adulthood [Ismail and Bedi, 2007].
Postnatal or adult administration of cocaine also re-
sults in alterations in neuronal dendritic trees. In the
adult rat, administration of cocaine, by several routes,
has repeatedly been demonstrated to increase dendritic
spine density in layer V pyramidal cells of the PFC and
medium spiny neurons of the NAc [Robinson et al., 2001;
Robinson and Kolb, 1997, 1999], while amphetamine has
been shown to increase spine density in the rat striatum
[Li et al., 2003]. In contrast to cocaine exposure in adult
rats, prenatal cocaine exposure in the present study did
not induce significant changes in spine density in layer V
pyramidal cells in the PFC. The differential effects seen
between the 2 layers of the medial PFC may be related to
laminar differences in neuronal circuitry. For example,
layer V pyramidal cells in the PFC receive a greater do-
pamine innervation than pyramidal cells in layer II/III
[Va n E de n e t a l., 1997] . I n a dd it ion, it ha s b ee n shown tha t
spine density may change during maturation and aging
[Kolb et al., 2003], so drug contact at any particular pe-
riod may differentially affect the same spine population.
The mechanism underlying the cocaine-induced in-
crease in dendritic spine density remains unclear. Co-
caine binds the dopamine transporter, and thus blocks
the uptake of this monoamine by presynaptic terminals
[Levitt et al., 1997; Ritz et al., 1990]. Additionally, in ute-
ro cocaine exposure has been shown to disrupt the D
1A
dopam ine receptor coupl ing to Gs/olf in the anterior cin-
gulate cortex and striatum [Friedman and Wang, 1998;
Jones et al., 2000; Levitt et al., 1997; Wang et al., 1995;
Zhen et al., 2001]. Since dopaminergic neurons have been
implicated in directing growth of neurons [Levitt et al.,
1997; Van Kampen et al., 2005], cocaine-induced dys-
functional neurotransmitter signaling may impact den-
dritic growth and morphology in brain areas innervated
by dopaminergic fibers.
In addition to the dopaminergic system, cocaine ex-
posure also has effects on glutamatergic transmission.
Acute cocaine injection has been shown to induce a re-
distribution of NMDA receptors subunits on synaptic
membranes of cells in the ventral tegmental area [Schil-
ström et al., 2006], and prenatal cocaine exposure reduc-
ab
Fig. 1. Golgi-impregnated neurons in stri-
atum. Photomicrograph illustrating the
cocaine-induced increase in dendritic
spines on medium spiny neurons of the
striatum. Dendritic segment from a prena-
tal cocaine exposed rat pup (
a ) has a great-
er spine density as compared to saline (
b ).
Arrows denote spines. Scale bar = 10 ␮ m .
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74
es synaptic membrane expression of AMPA receptors
[Bakshi and Wang, 2006]. Treatment with phencyclidine,
an NMDA antagonist, alters dendritic spine density on
pyramidal cells [Flores et al., 2007] and spine synapses in
the PFC [Hajszan et al., 20 06]. Existing data a lso indicate
that glutamate plays a role in dendritic remodeling, at
least in the medial PFC. Glutamate synaptic activity pro-
motes the initial development of the dendritic tree [Rajan
and Cline, 1990], and subsequent activity in these excit-
atory synapses induces and influences the adult spine
population [Kossel et al., 1997]. Given the role of gluta-
mate neurotransmission on spine plasticity, and the co-
caine-induced alterations in this transmitter system, it is
possible that glutamate neurotransmission may, at least
in part, be responsible for the dendritic arbor alterations
observed in the present study.
No sex differences in spine density were observed in
prenatal cocaine-exposed rats. Sex differences in many
aspects of drug abuse have been shown [Becker and Hu,
2008; Lynch et al., 2002]. In experimental animals, sex
differences in cocaine-induced behaviors have been dem-
onstrated [Festa et al., 2004]; cocaine seeking [Larson et
al., 2005] and behavioral sensitization [Zhen et al., 2007]
are sensitive to changes in estrogen levels. The VMN was
examined in the present study because it is known to be
sexually dimorphic [Todd et al., 2007] and dendritic
spines in the VMN change with gonadal state [Frankfurt,
1994]. Therefore, it is particularly interesting that there
was no sex difference in the VMN. The lack of sex differ-
ences in dendritic spine density noted in t he present study
indicates that activational rather than organizational ef-
fects of gonadal steroids are responsible for the sex differ-
ences observed after cocaine exposure in the adult.
Longitudinal studies have shown that children who
have been exposed to cocaine in utero develop learning
and cognitive deficits which become more evident with
advancing age [Singer et al., 2002]. In addition to the
functions mediated by the PFC and hippocampus [Frith
and Dolan, 1996], the present study supports the idea that
many other brain areas also form part of the neuronal
architecture/circuitry involved in mediating the effects of
prenatal cocaine.
A c k n o w l e d g m e n t s
This work was supported by a grant from NIDA (DAO18055)
to E.F. and a CUNY collaborative grant to H.-Y.W. and K.B.
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