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

  • Hofstra Northwell School of Nursing and Physician Assistant Studies


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
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 Dendritic spines Golgi impregnation
Prefrontal cortex Hippocampus Striatum Nucleus
accumbens Ventromedial Sex differences
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
© 2009 S. Karger AG, Basel
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Dev Neurosci 2009;31:71–75
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
° 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%
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
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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Prenatal Cocaine Increases Dendritic
Spine Density
Dev Neurosci 2009;31:71–75
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 ).
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
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-
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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Dev Neurosci 2009;31:71–75
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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... Administration of cocaine in utero induces morphological changes in brain regions associated with drug addiction, such as the prefrontal cortex and the nucleus accumbens, the central region in the reward pathway. However, as we have demonstrated, increased dendritic spine density following prenatal cocaine exposure is not limited to these regions (Frankfurt, Wang, Marmolejo, Bakshi, & Friedman, 2009). In our studies, timed pregnant rats were injected subcutaneously with 30 mg/kg cocaine HCl in 0.9% saline or saline beginning at day two of gestation until they gave birth. ...
... In addition, prenatal cocaine increased spine density on dendrites of medium spiny neurons in the striatum, nucleus accumbens, and on cells in the ventromedial hypothalamic nucleus (Table 25. 1;Frankfurt et al., 2009). When pregnant rats were administered cocaine in this model and the animals examined in adulthood, increased dendritic spine density persisted in the basal tree of pyramidal cells in the medial prefrontal cortex (Fig. 25.1), both apical and basal trees of CA1 pyramidal cells and the medium spiny neurons of the nucleus accumbens (Table 25.1; Salas-Ramirez, Frankfurt, Alexander, Luine, & Friedman, 2010). ...
... At 21 days male and female data were combined because there were no sex differences. For 21 days: data analyzed by 2-way ANOVA followed by Bonferroni test for post hoc comparisons (p , 0.05,Frankfurt et al., 2009). For 75 days: data analyzed by 2-way ANOVA followed by t-tests for post hoc comparisons (p , 0.05,Salas-Ramirez et al., 2010); and male (m) and female (f) data are shown separately. ...
Prenatal cocaine exposure has profound consequences on neurobehavioral parameters, which persist into adulthood. The underlying mechanisms for cocaine’s immediate and long-term effects, although not completely understood, appear to involve plasticity of specific neural circuits. Both dendritic spine turnover and glutamatergic neurotransmission are key to synaptic plasticity. In this chapter we review these parameters in the rat hippocampus and cortex following in utero exposure to cocaine. Prenatal cocaine increases dendritic spine density and induces alterations in glutamate receptor-mediated signaling via inotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors through their respective scaffolding proteins. Exposure to prenatal cocaine also results in translocation of protein kinase C to the synaptic membrane. Given that glutamate receptors are concentrated on dendritic spines, we propose that a possible mechanism underlying the neurobehavioral effects of prenatal cocaine may involve alterations in glutamate receptor signaling and protein kinase C translocation, which provide the basis for dendritic spine plasticity.
... Cocaine exposure during gestation causes impaired synaptic plasticity [5] that may be related to developmental delays in the excitatory glutamatergic systems [6]. There is also evidence indicating prenatal cocaine exposure leads to increased spine density in the cortical and subcortical regions [7] as well as hypertrophic dendritic outgrowth with atypical, tortuous dendritic profile [8]. Although the latter change in dendritic structure has been attributed to uncoupling of the dopamine D 1 receptor from its associated Gs/olf protein, BDNF-TrkB signaling is one of the prominent upstream modulators of the glutamatergic function and dendritic health in brain areas such as neocortex and hippocampus [9][10][11]. ...
... Progeny were cross-fostered and group housed with treatment-naïve surrogate mothers until they were sacrificed at 21 days of age (P21). Because neurotrophins play an important role in regulating dendritic dynamics and excitatory neurotransmission, and because we observed significant changes in dendritic spin morphology [7] and AMPAR transmission/signaling [21] in our previous rodent studies using P21 rats (an age when adult excitatory glutamatergic receptors are found), we selected P21 so that this investigation can also assess crosstalk between neurotrophin and NMDAR systems. Food and water were freely available. ...
... Rats were subjected to the minimum handling associated with routine animal husbandry. Since we did not find gender differences in our earlier studies conducted in rabbit and rats [7], [8], [21], both sexes from separate litters were employed in these experiments. To prevent oversampling, only one pup from each litter was used in each experiment [22]. ...
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Prenatal cocaine exposure causes profound changes in neurobehavior as well as synaptic function and structure with compromised glutamatergic transmission. Since synaptic health and glutamatergic activity are tightly regulated by brain-derived neurotrophic factor (BDNF) signaling through its cognate tyrosine receptor kinase B (TrkB), we hypothesized that prenatal cocaine exposure alters BDNF-TrkB signaling during brain development. Here we show prenatal cocaine exposure enhances BDNF-TrkB signaling in hippocampus and prefrontal cortex (PFCX) of 21-day-old rats without affecting the expression levels of TrkB, P75NTR, signaling molecules, NMDA receptor—NR1 subunit as well as proBDNF and BDNF. Prenatal cocaine exposure reduces activity-dependent proBDNF and BDNF release and elevates BDNF affinity for TrkB leading to increased tyrosine-phosphorylated TrkB, heightened Phospholipase C-γ1 and N-Shc/Shc recruitment and higher downstream PI3K and ERK activation in response to ex vivo BDNF. The augmented BDNF-TrkB signaling is accompanied by increases in association between activated TrkB and NMDARs. These data suggest that cocaine exposure during gestation upregulates BDNF-TrkB signaling and its interaction with NMDARs by increasing BDNF affinity, perhaps in an attempt to restore the diminished excitatory neurotransmission.
... These modifications in dendritic spine density may have a negative impact on the function of the CNS at the time of pruning. Frankfurt et al. (2009) also investigated the impact of COC supplementation during gestation on pregnant rats and reported a significant dendritic spine density increase in pyramidal cells in the CA1 region of the hippocampus, in the medium spiny neurons of the striatum, and in the core of the NAc as well as in the neurons of the ventromedial hypothalamic nucleus. These effects of prenatal COC exposure seem to be independent of sex (Frankfurt et al., 2009); according to Salas-Ramirez et al. (2010), they might be related to increased anxiety and significant impairments of cognitive functions including locomotion, visual memory, and spatial memory. ...
... Frankfurt et al. (2009) also investigated the impact of COC supplementation during gestation on pregnant rats and reported a significant dendritic spine density increase in pyramidal cells in the CA1 region of the hippocampus, in the medium spiny neurons of the striatum, and in the core of the NAc as well as in the neurons of the ventromedial hypothalamic nucleus. These effects of prenatal COC exposure seem to be independent of sex (Frankfurt et al., 2009); according to Salas-Ramirez et al. (2010), they might be related to increased anxiety and significant impairments of cognitive functions including locomotion, visual memory, and spatial memory. ...
... Learning and memory processes (Riedel et al., 1996;Simonyi et al., 2005) are affected by prenatal COC exposure, and any changes may also be attributed to a compromised glutamatergic system. COC exposure during gestation largely affects the glutamatergic system by targeting glutamatergic receptors, such as the metabotropic glutamate receptor-type 1 (mGluR1), the NMDA, or the AMPA receptor (Frankfurt et al., 2009;Bakshi et al., 2011). Impaired mGluR1 function after prenatal COC administration results in delayed postnatal synaptic maturation (Bellone et al., 2011). ...
It is estimated that approximately 0.5%–3% of fetuses are prenatally exposed to cocaine (COC). The neurodevelopmental implications of this exposure are numerous and include motor skill impairments, alterations of social function, predisposition to anxiety, and memory function and attention deficits; these implications are commonly observed in experimental studies and ultimately affect both learning and IQ. According to previous studies, the clinical manifestations of prenatal COC exposure seem to persist at least until adolescence. The pathophysiological cellular processes that underlie these impairments include dysfunctional myelination, disrupted dendritic architecture, and synaptic alterations. On a molecular level, various neurotransmitters such as serotonin, dopamine, catecholamines, and γ-aminobutyric acid seem to participate in this process. Finally, prenatal COC abuse has been also associated with functional changes in the hormones of the hypothalamic-pituitary-adrenal axis that mediate neuroendocrine responses. The purpose of this review is to summarize the neurodevelopmental consequences of prenatal COC abuse, to describe the pathophysiological pathways that underlie these consequences, and to provide implications for future research in the field.
... Sholl analysis was performed to identify Golgi-stained and Doublecortin-positive (DCX + ) granule cells with tertiary, relatively untruncated dendritic branches (n = 5 cells per brain, n = 5 each group) using camera lucida at 40× magnification (Neurolucida, Microbrightfield, Williston, Vermont). NeuroExplorer (Microbrightfield) was adopted to evaluate dendritic length and number of intersections (branch points) [28]. ...
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Low-frequency repetitive transcranial magnetic stimulation (1-Hz rTMS) is a promising noninvasive tool for the treatment of depression. Hippocampal neuronal plasticity is thought to play a pivotal role in the pathophysiology of depressive disorders and the mechanism of action of antidepressant treatments. We investigated the effect of 1-Hz rTMS treatment on hippocampal dentate gyrus structural plasticity and related emotional behaviors modifications. Experimentally, adult male mice received either five days of 1-Hz rTMS or Sham stimulation. After stimulation, the mice underwent a battery of tests for anxiety-like and depression-like behaviors. We also tested the effect of treatment on mature and newly generated granule cell dendritic complexity. Our data showed that 1-Hz rTMS induced structural plasticity in mature granule cells, as evidenced by increased dendritic length and number of intersections. However, the stimulation did not increase the proliferation of the dentate gyrus progenitor cells. On the contrary, the stimulated mice showed increased dendritic complexity of newly generated neurons. Moreover, 1-Hz rTMS resulted in antidepressant-like effects in the tail suspension test, but it did not affect anxiety-like behaviors. Therefore, our results indicate that 1-Hz rTMS modulates dentate gyrus morphological plasticity in mature and newly generated neurons. Furthermore, our data provide some evidence of an association between the antidepressant-like activity of 1-Hz rTMS and structural plasticity in the hippocampus.
... However, some papers assessed multiple time points including Dumitru et al. [5], who measured dendritic spine density at 3 time points and reported changes after 4 hours, 24 hours, and 28 days of cocaine withdrawal. Reports of cocaine-induced spine alterations in transgenic animals were excluded, along with studies reporting spines changes after in utero cocaine exposure (although some show increases in accumbal spine density in later developmental stages [44,45]). This methodology helped ensure a fair and unbiased comparison across published studies. ...
Many reports show that repeated cocaine administration increases dendritic spine density in medium spiny neurons of the nucleus accumbens, but there is less agreement regarding the persistence of these changes. In this review we examine these discrepancies by systematically categorizing papers that measured cocaine-induced changes in accumbal spine density. We compare published reports based on withdrawal time, short versus long duration of cocaine administration, environmental pairing with cocaine, and core/shell subregion specificity. Together, these studies suggest that cocaine exposure induces rapid and dose-dependent increases in spine density in accumbens neurons that may play a role in the maintenance of cocaine use and vulnerability to early relapse, but are not a factor in behavioral changes associated with longer abstinence.
... For example, some studies have reported that cocaine exposure increases spines in cortical neurons, 43,47 whereas others have shown opposite effects in the same cells. 48,49 Our findings suggest no observable change in the spine density in cortical neurons exposed to cocaine. However, we did observe changes in spine morphology, with increased numbers of thin and fewer numbers of stubby and mushroom spines in cortical neurons following cocaine exposure. ...
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Cocaine is a highly addictive narcotic associated with dendritic spine plasticity in the striatum. However, it remains elusive whether cocaine modifies spines in a cell type-specific or region-specific manner or whether it alters different types of synapses in the brain. In addition, there is a paucity of data on the regulatory mechanism(s) involved in cocaine-induced modification of spine density. In the current study, we report that cocaine exposure differentially alters spine density, spine morphology, and the types of synapses in hippocampal and cortical neurons. Cocaine exposure in the hippocampus resulted in increased spine density, but had no significant effect on cortical neurons. Although cocaine exposure altered spine morphology in both cell types, the patterns of spine morphology were distinct for each cell type. Furthermore, we observed that cocaine selectively affects the density of excitatory synapses. Intriguingly, in hippocampal neurons cocaine-mediated effects on spine density and morphology involved sigma-1 receptor (Sig-1 R) and its downstream TrkB signaling, which were not the case in cortical neurons. Furthermore, pharmacological inhibition of Sig-1 R prevented cocaine-induced TrkB activation in hippocampal neurons. Our findings reveal a novel mechanism by which cocaine induces selective changes in spine morphology, spine density, and synapse formation, and could provide insights into the cellular basis for the cognitive impairment observed in cocaine addicts.
The placenta is a complex organ in terms of its structure and function. The structure varies vastly from species to species and according to the developmental stage. The placenta plays multiple roles in maintaining pregnancy and the development of the fetus by serving as the lungs, gut, kidneys, hematopoietic system, and endocrine/exocrine gland. In addition, it provides a flow of chemical information between the mother and fetus. Placental toxicology is a fascinating subject, as it deals with the toxic effects of drugs, chemicals, and biotoxins on mother, placenta, and fetus. Furthermore, the subject encompasses the knowledge of drug-/chemical-induced structural and functional changes in the placenta, placentation, implantation, embryotoxicity, fetotoxicity, growth retardation, teratogenesis, and neurochemical and functional deficits. The placenta and fetus appear to be more sensitive than the mother to chemical toxicity. This chapter describes the placental toxicity of some commonly abused drugs (alcohol, tobacco, opioids, and cocaine), heavy metals, and pesticides. Because of the chemical-induced structural and functional compromises in the placenta, biochemical, neurochemical, and behavioral deficits occur in the developing conceptus. Some of these deficits appear to persist during the postnatal stage, thereby predisposing the fetus to certain metabolic and neurodegenerative diseases.
Prenatal and postnatal exposure to cocaine can affect the development and function of the central nervous system in offspring. It also produces changes in cocaine-induced dopamine release and increases cocaine self-administration and cocaine-induced conditioned place preference. Further, prenatal cocaine exposure involves greater risk for development of a substance use disorder in adolescents. Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on locomotor sensitization in rats. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine pre-exposure group) and another group pregnant female rats were administered daily with saline (saline pre-exposure group). During lactation (PND0 to PND21) pregnant rats also received cocaine administration or saline, respectively. Of the litters resulting of the cocaine pre-exposed and saline pre-exposed pregnant female groups, only the male rats were used for the recording of the locomotor activity induced by different doses of cocaine (1, 5, 10, 20 and 40 mg/Kg/day) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90 and 120 days), representative of adolescence and adult ages. The study found that prenatal and postnatal cocaine exposure enhanced locomotor activity and locomotor sensitization, and such increase was dose- and age-dependent. This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to cocaine abuse in young and adult humans.
Lewis (LEW) and Fischer 344 (F344) rats are considered a model of genetic vulnerability to drug addiction. We previously showed important differences in spatial learning and memory between them, but in contrast with previous experiments demonstrating cocaine-induced enhanced learning in Morris water maze (MWM) highly demanding tasks, the eight-arm radial maze (RAM) performance was not modified either in LEW or F344 rats after chronic cocaine treatment. In the present work, chronically cocaine-treated LEW and F344 adult rats have been evaluated in learning and memory performance using the Y-maze, two RAM protocols that differ in difficulty, and a reversal protocol that tests cognitive flexibility. After one of the RAM protocols, we quantified dendritic spine density in hippocampal CA1 neurons and compared it to animals treated with cocaine but not submitted to RAM. LEW cocaine treated rats showed a better performance in the Y maze than their saline counterparts, an effect that was not evident in the F344 strain. F344 rats significantly took more time to learn the RAM task and made a greater number of errors than LEW animals in both protocols tested, whereas cocaine treatment induced deleterious effects in learning and memory in the highly difficult protocol. Moreover, hippocampal spine density was cocaine-modulated in LEW animals whereas no effects were found in F344 rats. We propose that differences in addictive-like behavior between LEW and F344 rats could be related to differences in hippocampal learning and memory processes that could be on the basis of individual vulnerability to cocaine addiction.
This chapter focuses on some important placenta toxic drugs and toxicants. The subject embraces the knowledge of drug- and chemical-induced structural changes in the placenta, placentation, implantation, embryotoxicity, fetotoxicity, growth retardation, teratogenesis and biochemical, neurochemical and functional deficits. The first part explains the placental structure, function and species differences. During pregnancy, overall toxicity of a chemical can be influenced by maternal toxicity, placental transfer and placental-fetal metabolism, which are dealt in detail. Various types of chemicals are known to induce toxicity in the placenta by damaging either structure and/or function. Placental toxicity of some common types of drugs and environmental chemicals is described here in brief. Four classes of insecticides (organophosphates, carbamates, organochlorines and pyrethroids) are known to adversely affect the mother, placenta and conceptus in laboratory animals. Here, organophosphates and carbamates are discussed together because many of their effects are similar. As a result, a variety of abnormalities are seen in the developing conceptus. Furthermore, some of the neurochemical and behavioral deficits observed at birth appear to persist during adolescence and adulthood. This chapter describes in brief the important structural and functional aspects of the placenta, which follows the placental toxicity of commonly abused drugs, heavy metals, insecticides and environmental pesticides.
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Context Maternal use of cocaine during pregnancy remains a significant public health problem, particularly in urban areas of the United States and among women of low socioeconomic status. Few longitudinal studies have examined cocaine-exposed infants, however, and findings are contradictory because of methodologic limitations.Objective To assess the effects of prenatal cocaine exposure on child developmental outcomes.Design Longitudinal, prospective, masked, comparison birth cohort study with recruitment in 1994-1996.Setting Obstetric unit of a large US urban teaching hospital.Participants Four hundred fifteen consecutively enrolled infants (218 cocaine-exposed and 197 unexposed) identified from a high-risk, low–socioeconomic status, primarily black (80%) population screened through clinical interview and urine and meconium samples for drug use. The retention rate was 94% at 2 years of age.Main Outcome Measures The Bayley Mental and Motor Scales of Infant Development, assessed at 6.5, 12, and 24 months of corrected age.Results Controlled for confounding variables, cocaine exposure had significant effects on cognitive development, accounting for a 6-point deficit in Bayley Mental and Motor Scales of Infant Development scores at 2 years, with cocaine-exposed children twice as likely to have significant delay (mental development index <80) (odds ratio, 1.98; 95% confidence interval, 1.21-3.24; P = .006). For motor outcomes, there were no significant cocaine effects.Conclusions Cocaine-exposed children had significant cognitive deficits and a doubling of the rate of developmental delay during the first 2 years of life. Because 2-year outcomes are predictive of later cognitive outcomes, it is possible that these children will continue to have learning difficulties at school age.
Structure-activity relationships for cocaine and analog binding at the dopamine, norepinephrine and serotonin transporters were determined. Cocaine inhibition of ligand binding to each of these sites has a stereospecific requirement for the levorotatory isomer. Binding potencies of cocaine derivatives involving N-substitution, C2 and C3 substituent modifications, however, revealed differences in structure-activity relationships for cocaine binding at the transporters. Removal of the N-methyl groups produced little change in binding potency at the dopamine transporter site but produced increases in binding potency at norepinephrine and serotonin transporter sites. Changes in structure at the C2 substituent produced changes in binding potency at the dopamine transporter which were generally similar in direction, but not necessarily in magnitude at the norepinephrine and serotonin transporters. Modifications to the C3 substituent, especially substitution of a hydroxyl moiety, produce changes in affinity at norepinephrine and serotonin transporters which are much larger than those observed at dopamine transporters. In general, our results indicate that unique structural requirements exist for each transporter site, but that cocaine binding at norepinephrine and dopamine transporters can be described by more similar structure-activity relationships than those found for the serotonin transporter. Requirements for cocaine binding to the dopamine transporter, which we have previously shown to be associated with the reinforcing effects of cocaine, include levorotatory stereospecificity, the benzene ring at C3, at least some portions of the tropane ring, and the presence of the C2 methyl ester group in the beta conformation.
In the present study the dopaminergic innervation of the prefrontal cortex was studied by means of a recently developed anti-dopamine serum. This method can demonstrate endogenous dopamine in a specific way, and offers the opportunity to study the distribution of dopaminergic fibres in the cortex in detail in counterstained sections. Furthermore, dopaminergic nerve endings can be visualized at the electron microscopic level. Light microscopic observations demonstrated that the highest density of dopaminergic fibres in the frontal cortex is found in the prefrontal cortex and the infralimbic cortex. Within the prefrontal cortex, a good correlation is found between regional differences in distribution of dopaminergic fibres and the cytoarchitectonic parcellation of this part of the cortex. Outside the prefrontal cortex dopaminergic fibres were observed in adjacent frontal areas, the cortex surrounding the entire rhinal sulcus and the retrosplenial cortex. Electron microscopic observations demonstrated dopaminergic terminals through all cortical layers. The majority of dopaminergic terminals in the prefrontal cortex from synaptic contacts with dendritic processes. The synaptic profiles were usually symmetric and were characterized by the presence of many clear vesicles and an occasional dense-core vesicle.
The effect of in utero exposure to cocaine on striatal dopamine receptors was assessed at postnatal days 10 through 100 by examining receptor-mediated increases in GTP binding to G alpha proteins. Pregnant Dutch-belted rabbits were injected with 4 mg/kg i.v. of cocaine HCl twice a day on gestational days 8 through 29, and striatal membranes were prepared from their progenies on days 10 through 100. Dopamine-stimulated [35S]GTP gamma S binding to membrane alpha subunits was measured and found to increase binding to G alpha s and G alpha i. Pharmacological characterization of the dopamine response revealed that enhanced [35S]GTP gamma S binding to G alpha s is associated with D1 receptor stimulation, whereas binding to G alpha i is linked to D2 receptor activation. The abilities of dopamine to stimulate the binding of [35S]GTP gamma S to G alpha s but not to G alpha i was reduced in striata obtained from cocaine-exposed animals when examined at 10, 50 or 100 days of age. Similarly, prenatal cocaine exposure also reduced dopamine-stimulated [alpha-32P]GTP binding to G alpha s without influencing binding to G alpha i. Fetal cocaine exposure did not change carbachol-induced increases in [35S]GTP gamma S binding to G alpha i and G alpha o. Immunoblot analyses showed no changes in the amounts of these alpha subunits in membranes from cocaine-exposed animals vs. controls. Moreover, prenatal cocaine did not affect [3H]SCH23390 binding to D1 dopamine receptors in the caudate, putamen or substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)
In this chapter, recent studies on gonadal steroid-induced neural plasticity in the adult rat hypothalamus have been described. Neurons in the VMN and DMN are capable of rapid, reversible structural alterations in response to a changing hormonal environment. Given the importance of the VMN in mediating lordosis in female rats, the present studies suggest that hormonally induced morphological changes in the VMN may be necessary for the manifestation of lordosis. This possibility is supported by the 5,7-DHT studies which indicate that the induction of dendritic spines on VMN neurons may somehow decrease the threshold of E needed to elicit lordosis. Moreover, the sex differences in hormonal requirements for lordosis in 5,7-DHT-treated rats are probably the result of organizational effects of gonadal steroids. Our data support the idea that activational effects can only be superimposed on existing brain circuitry to a certain degree. Finally, the neuronal plasticity seen in the hypothalamus may be an important physiological mechanism by which gonadal steroid feedback mediates reproductive and behavioral function.
Prenatal exposure to cocaine has the potential to modify normal brain development and result in behavioral dysfunction. We used a new animal model in which cocaine was administered intravenously during prenatal development in pregnant rabbits twice daily at low dosages. Analysis of brain development focused on two areas of the cerebral cortex, anterior cingulate and primary visual, in which dopamine afferents, a target of cocaine, are differentially distributed. All postnatal rabbits exposed to cocaine prenatally exhibited normal features of cortical organization, including thickness, lamination patterns, and cytoarchitectonic differentiation. General axonal and astroglial organization, assessed by neurofilament-H and glial fibrillary acidic protein immunostaining, also was unchanged in the cocaine-exposed animals. Analysis of dendritic organization was done using antibodies against microtubule-associated protein 2 (MAP2), which reveals mostly the larger apical shafts of cortical pyramidal cells. In the anterior cingulate cortex of adolescent rabbits exposed to cocaine in utero, there is a marked decrease in both dendritic bundling and typical long, straight MAP2-stained profiles. In normal animals, the long, bundled dendrites area readily traced in a single focal plane from layer III or V pyramidal cell somata to the pial surface in saline-treated animals. Instead, the drug-exposed animals contained many more short segments of MAP2-stained dendrites that could be viewed coursing in and out of the plane of focus in the sections. Apical dendrites in mature visual cortex appeared normal in the cocaine-exposed rabbits. Examination of MAP2 staining at various postnatal ages revealed that the dendritic changes expressed in the adolescent anterior cingulate cortex appeared less robust, but still evident at birth. By P10-14, dendritic modifications were similar to the adult. Counts of the number of MAP2-positive dendritic profiles crossing the layer II-III interface reached a nadir of 50% in the cocaine-exposed animals, indicative of a change in the organization of the apical dendrites compared to the control animals. Dendritic profiles of anterior cingulate neurons, filled by 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine percholate (Dil), confirmed that in the cocaine offspring, the dendrites coursed in an irregular, wavy manner from deep to superficial layers, suggestive of dendrites that were longer than normal, although cortical thickness was unchanged. The altered dendritic profiles also were seen in Golgi-impregnated neurons. The data indicate that prenatal exposure to cocaine can lead to specific alterations of neuronal growth that are long lasting. The lack of dendritic changes in visual cortex suggests that the drug does not modify development of cortical regions uniformly. This study also provides a new focus on the anterior cingulate cortex as a site in which aberrant structure-function relationships following prenatal cocaine exposure should be examined in both animal models and clinically.
The higher cognitive functions, working memory, mental imagery and willed action, are all intimately associated with consciousness. The common process underlying all these functions is that information is "held in mind" for a period of time. This information, which may be about stimuli or responses, can be derived from the past or generated for the future. Brain imaging studies show that "holding something in mind" is associated with activity in an extended system which involves both prefrontal cortex and more posterior areas whose location is determined by the nature of the information being held in mind. Automatic actions and perceptions which do not involve consciousness are associated with activity in the relevant posterior areas, but not in the prefrontal cortex. These studies demonstrate that activity occurs in the same posterior area whether the associated information comes from the outside world or is internally generated. This raises the problem of how we know whether our experience derives from mental imagery or from something happening in the outside world. There is evidence that patients with schizophrenia have precisely this problem since they perceive their own thoughts and even sub-vocal speech as coming from outside (hallucinations). Recent brain imaging studies suggest that there is a disconnection between prefrontal and posterior areas in these patients which could explain their characteristic misperceptions.
The early appearance of monoamine systems in the developing mammalian CNS suggests that they play a role in neural development. We review data from two model systems that provide compelling new evidence of this role. In one model system-in utero exposure to cocaine-specific and robust alterations are seen in dopamine-rich areas of the cerebral cortex, such as the anterior cingulate cortex: D1 receptor-G protein coupling is greatly reduced, the GABAergic system is altered and pyramidal dendrites undergo excessive growth. In a second model system-a transgenic mouse line in which the gene that encodes monoamine oxidase A (MAOA) is disrupted, resulting in excessively high 5-HT levels-barrels fail to form in the developing somatosensory cortex. Both models reveal the effects of very early manipulation of monoamines on forebrain development, and the long-term anomalies that persist into adulthood.