Autoradiographic Study of Pre- and Postnatal Distribution
of Cannabinoid Receptors in Human Brain1
Anat Biegon and Ilan A. Kerman2
Functional Imaging Center, Lawrence Berkeley National Laboratory, Berkeley, California 94720
Received March 28, 2001; published online October 24, 2001
Cannabinoid receptors have been characterized
and localized in the brain of several species, includ-
ing human. T he pre- and postnatal distribution of
human brain CB1 receptors was investigated using
quantitative autoradiography with [3H]CP 55,940 as
a ligand. Normal fetal brains (N ? 8, gestational
age 14–24 weeks) were obtained from voluntary
abortions. Normal (drug and pathology free) adult
human brains (N ? 16, age 18–78) were obtained
from the medical examiner’s offices in New Y ork
City and J affa, Israel. Brains were stored frozen
at ?70°C and sectioned (40 ?m) at ?15°C. T he radio-
ligand (5 nM) was incubated with the sections for 3 h
at room temperature. Washed and dried sections
were exposed to tritium-sensitive film along with
standards for 7–28 days and autoradiograms quan-
titated using NIH Image software. In the fetal hu-
man brain, low densities of T HC-displaceable, re-
gion-specific binding could be observed as early as
14 weeks gestation. R eceptor
slowly with gestational age but did not reach adult
levels by the end of the second trimester (24 weeks
gestation). In addition, the distribution pattern in
the fetal brains was markedly different from the
adult pattern. T he most striking difference was the
very low density of binding in the fetal caudate
and putamen. In contrast, the globus pallidus pars
medialis has almost-adult levels of cannabinoid re-
ceptors by 17–18 weeks gestation. T he relatively
low and regionally selective appearance of canna-
binoid receptors in the fetal human brain may ex-
plain the relatively mild and selective nature of
infants exposed to cannabinoids in utero.
Academic P ress
Although cannabis-derived drugs have been used for
thousands of years, brain receptors and endogenous
ligands for cannabinoids are a relatively recent discov-
ery (e.g., Devaneet al., 1988, 1992; Howlett et al., 1990;
Matsuda et al., 1990; Martin et al., 1999). In adult
mammalian brain, autoradiography has revealed high
densities of cannabinoid receptors in many brain re-
gions, which presumably subserve the known behav-
(Herkenham et al., 1990, 1991).
Marijuana is one of the most widely used recre-
ational drugs in our society. Drug dependence is more
common in men than in women, peaks in young adults,
and goes down steadily with age (Burke et al., 1990).
However, there is evidence that a significant percent-
age of pregnant women, 3–27% according to various
reports (e.g., Zuckerman et al., 1985, 1989; Hatch et al.,
1986; MacGregor et al., 1990; Lee, 1998), use the drug
during pregnancy. THC (the active component of mar-
ijuana) crosses the placenta readily in rodents (Idan-
appan-Heikkila et al., 1969) and primates (Bailey et al.,
1987), peaking in fetal blood within 15 min of admin-
istration. THC has also been found in the umbilical
cord blood at delivery of women who used marijuana
regularly during pregnancy (Blackard and Tennes,
1984), which indicates that THC crosses the placenta
in humans as well. Interestingly, reports on CNS ef-
fects of cannabinoid exposure during pregnancy are
contradictory and overall, marijuana appears to have
only minor effects on the offspring, in contrast with the
effects of other addictive substances that cross the
placenta, such as nicotine, alcohol, opiates, and cocaine
(e.g., Fried, 1980; Fried and Watkinson, 1990; Zucker-
man et al., 1989; Balle et al., 1999). In the present
study we have examined the neuranatomical distribu-
tion and developmental pattern of cannabinoid recep-
1The U.S. Government’s right to retain a nonexclusive royalty-
free license in and to the copyright covering this paper, for govern-
mental purposes, is acknowledged.
2Present address: Department of Otolaryngology, University of
Pittsburgh, 203 Lothrop Street, EEINS 113, Pittsburgh, PA 15213.
NeuroImage 14, 1463–1468 (2001)
doi:10.1006/nimg.2001.0939, available online at http://www.idealibrary.com on
Copyright © 2001 by Academic Press
All rights of reproduction in any form reserved.
tors in brains of normal fetuses and adults by quanti-
the specific ligand
MATERIALS AND METHODS
Normal fetal brains (N ? 8, gestational ages 14, 17,
18, 20, 22, and 24 weeks) were obtained from saline-
induced voluntary abortions. Normal (drug and pathol-
ogy free) adult human brains (N ? 16, age range 18 to
78) were obtained from the medical examiner’s offices
in New York City and J affa, Israel. The brains were
frozen in dry ice and stored at ?70°C. Both the fetal
and the adult brain populations have been previously
described in detail (Bar Peled et al., 1991a,b, 1997;
Biegon et al., 1988; Gross-Isserof et al., 1990).
Thin (40 ?m) sections of one hemisphere, cut in the
coronal or sagittal plane, were obtained using a whole-
body cryotome (Bright) at ?15°C. The sections were
thaw mounted onto gelatin–chromalum-coated slides
and stored at ?20°C at least overnight prior to the
A 5 nM concentration of [3H]CP55,940 (NEN, sp act
104 Ci/mmol) was incubated with thesections for 3 h at
room temperature in a 120 mM Tris–HCl buffer, pH
7.4, containing 5% BSA. The incubation was followed
by 2 ? 90-min washes in thesamebuffer containing 1%
BSA, at 4°C. Nonspecific binding was determined on
consecutive sections in the presence of 100 ?M unla-
beled THC. The washes were followed by a short dip in
double-distilled water to remove buffer salts.
Dried sections were exposed totritium-sensitive film
for 1 to 4 weeks, alongside commercial (Amersham)
tritium standards. Films were developed manually us-
ing Kodak developer and fixer. The sections were
stained with cresyl violet for anatomical reference.
Autoradiograms and tritium standards were quanti-
fied using a computerized, video camera-based image
analysis system and the NIH Image software. Regions
were identified in reference to the histologically
stained sections and human brain atlases.
In the fetal human brain, low densities of THC-
displaceable, region-specific binding could be observed
as early as 14 weeks gestation. Receptor density in-
creased slowly with gestational age but did not reach
adult levels by the end of the second trimester (24
weeks gestation). In addition, the distribution pattern
in the fetal brains was markedly different from the
adult pattern. The most striking difference was the
very low, patchy density of binding in the fetal caudate
and putamen. The globus pallidus is the only region in
fetal brain demonstrating relatively high levels of can-
nabinoid receptors by 17–18 weeks gestation (Fig. 1).
In contrast, the distribution of cannabinoid receptors
in the adult human brain is widespread although het-
erogeneous with high levels of specific binding in many
brain regions (Fig. 2). Thus, very high densities were
found in the substantia nigra, medial portion of the
globus pallidus, and basal ganglia. Moderate densities
were found in the cortex and hippocampus. Low den-
sities were observed in most of the thalamus. Cortical
binding is laminar, such that a thin high-density band
over layer I is followed by lower binding in intermedi-
ate layers and high binding in inner cortical layers.
Nonspecific binding is relatively low and uniform over
gray matter areas of the brain (Fig. 2).
Quantification of fetal receptor levels was possible
only in the few regions showing a density consistently
higher than nonspecific binding (Table 1). Thus, bind-
ing density in both parts of the fetal globus pallidus
was approximately half of the mean value in young
adults (Table 1). The distribution of binding within the
globus pallidus in thefetal brains was similar tothat of
the adult as well, with the pars medialis demonstrat-
ing consistently higher levels than pars lateralis. How-
ever, binding in the caudate was patchy and low. Hip-
pocampal binding, although visible, was only slightly
above the level of nonspecific binding. Cortical levels of
cannabinoid binding in the fetus were higher over in-
ner cortical layers, reminiscent of the adult pattern,
but practically nondetectable in the outer cortical lay-
In this study of fetal human brains, cannabinoid
receptors were detectable as early as 14 weeks gesta-
tion. However, receptor levels were very low through-
out the second trimester and the only region demon-
strating receptor density close to that seen in adults
was the globus pallidus. The highest densities of can-
nabinoid receptors in the adult brain, as previously
reported by us and others (Herkenham et al., 1990;
Biegon and Kerman, 1995), are associated with ele-
ments and outflow regions of the dopaminergic system.
The substantia nigra, the major dopamine-producing
region, contains the highest density of binding, fol-
lowed by the medial part of the globus pallidus, the
caudate, and the putamen. However, many other brain
regions contain moderately high concentrations of ra-
dioactivity, including theserotonergic raphenuclei and
the noradrenergic nucleus locus coeruleus. This pat-
tern suggests that cannabinoids may be powerful,
though indirect, modulators of dopaminergic activity in
the brain. The moderately high densities of binding in
the raphe and locus ceoruleus suggest that cannabi-
BIEGON AND KERMAN
noids may also modulate serotonergic and noradrener-
gic activity, although probably to a lesser degree than
The developmental results reported here are com-
patible with recent developmental studies in rodents
showing a slow progression of receptor density during
prenatal and postnatal development in the rat (Belue
et al., 1995; Romero et al., 1997; Berrendero et al.,
1999). The single human study reporting high fetal
brain levels of cannabinoid receptors (Glass et al.,
1997) included only one fetal brain, so it is difficult to
speculate on the reasons for the apparent discrepancy.
Slow and relatively late development of cannabinoid
receptors in the brain may explain the paucity of post-
natal developmental effects observed in rats treated
perinatally with cannabinoids and in children born to
women who have used marijuana during pregnancy.
Thus, some researchers have found that prenatal mar-
ijuana exposure may affect fetal growth while having
no teratogenic, neurobehavioral, or other developmen-
tal effects following birth (Tennes et al., 1985; Miro-
chnik et al., 1997; Balleet al., 1999). Others havefound
that offspring born to heavy (?5 joints a week) mari-
juana users had a significantly higher occurrence of
tremors and startles (Fried, 1985; Fried and Mackin,
1987), which alsodiffered in their nature from those of
non- and light users. As part of the same study, it has
also been reported that the prenatally exposed off-
spring showed poorer habituation tolight stimulus and
poorer visual responsiveness at 3, 9, and 30 days of age.
These infants also showed a trend toward greater in-
cidence of myopia, strabismus, and abnormal oculomo-
tor functioning (Fried et al., 1987). Furthermore, these
infants performed significantly worse than the controls
on a number of motor tests (Fried et al., 1987), which,
along with the reported trend toward greater irritabil-
ity, is consistent, though milder in nature, with post-
natal opioid withdrawal (Fried and Watkinson, 1988,
1990; Zuckerman et al., 1989).
In rats, chronic cannabinoid administration to adult
males and females results in widespread and signifi-
cant decreases in cannabinoid receptor density (Oviedo
et al., 1993; Romeroet al., 1998; Breivogel et al., 1999).
In contrast, exposure of fetal brains tocannabinoids in
F IG. 1.
photographs of the cresyl violet sections used to produce the matching autoradiograms on the right. The top row is from gestational age 14
weeks, the middle row is from a 17-week-old fetus, and the bottom row represents a 24-week-old fetus. The sections are in the sagittal plane
and were exposed to film, together with a tritium standard scale strip (right) for 28 days. The scale bars (from top to bottom) correspond to
[3H]CP55,940 in fm/mg (calculated from the nCi/mg content of the standards and the specific activity of the ligand used in the experiment).
Abbreviations: f, frontal cortex; b, basal ganglia; g, globus pallidus; m, medial part of globus pallidus; h, hippocampus; t, thalamus.
Distribution of cannabinoid receptors in the second-trimester human fetal brains postmortem. The images on the left are
CANNABINOID RECEPTORS IN HUMAN FETAL BRAIN
utero had no effect on adult receptor levels (Garcia Gil
et al., 1999). Also in the rat, peak levels of receptors
appear between days 30 and 40 of postnatal life (Ro-
driguez de Fonesca et al., 1993) and aging is associated
with region-specific decline in receptor and mRNA lev-
els (e.g., Berrendero et al., 1998), which was especially
pronounced in deep cortical layers. We have reported a
similar declinein receptor binding in human prefrontal
and cingulate cortex (Biegon and Kerman, 1995).
Therefore, it appears that although the distribution of
cannabinoid receptors is not identical in rat, monkey,
and human (Biegon and Kerman, 1995; Ong and
Mackie, 1999), the age-dependent changes are similar
in rodents and man.
Further studies are necessary toextend the develop-
mental curve of cannabinoid receptors to infants and
children. Such data may explain another apparently
paradoxical observation in children given THC as an
antiemetic, who do not show the psychotropic profile
seen with the same drug in adults (Abrahamov et al.,
1995). These young (less than 10-year-old) patients
demonstrated a remarkable absence of psychotropic
effects. Correspondingly, it was found that behavioral
responses toTHC develop relatively late in mice (Fride
and Mechoulam, 1996). The fact that the antiemetic
effect of the drug was apparent in the pediatric pa-
tients does not contradict a relative lack of brain CB1
receptors, since the antiemetic properties of cannabi-
noids are not mediated by the cannabinoid receptor. In
fact, antiemetic activity can be elicited with nonpsy-
choactive synthetic cannabinoids which have an opti-
cal configuration opposite to the one favored by the
cannabinoid receptor (Feigenbaum et al., 1989a,b).
F IG. 2.
of the hippocampus is shown. The image on the left is the cresyl violet-stained section used to produce the autoradiogram in the center. The
image on the right is an autoradiogram of a consecutive section incubated with excess unlabeled THC representative of nonspecific binding.
The sections were exposed tofilm, together with a tritium standard scale strip (shown at the bottom) for 7 days. At this short exposure time
the lowest standard was not visible above film background. The concentrations of ligand corresponding to the bars are the same as in Fig.
1 above. The nonspecific autoradiogram was enhanced so it would be visible; radioactivity levels in those sections were below 20 fm/mg.
Abbreviations: T, thalamus; P, putamen; G, globus pallidus (note the higher density of binding in the medial compared to the lateral part
of the structure); S, substantia nigra; H, hippocampus.
Distribution of cannabinoid receptors in theadult human brain postmortem. A coronal section of theright hemisphereat thelevel
T ABL E 1
Comparison of Cannabinoid Receptor Density in Basal
Ganglia of Second-Trimester Fetuses and Young Adults
Specific binding, fmol/mg protein
Fetal brainsAdult brains
Globus pallidus, medial
Globus pallidus, lateral
77.2 ? 41.4
289.2 ? 114
140.9 ? 94.0
437 ? 203
567 ? 175
309 ? 124
Note. Results are means and standard deviations of six fetal and
three adult brains.
BIEGON AND KERMAN
From the perspective of brain development, it is
noteworthy that in consecutive sections from the same
brains used for these studies, we found densities of
cholinergic muscarinic and 5HT1a receptors that were
quite high, often higher than in adults. Subtypes of
glutamate transporters were also detected at high lev-
els in the same brains (Bar Peled et al., 1991a,b, 1997).
Thus, the late development of cannabinoid receptors is
not a common feature of brain neurotransmitter mark-
ers. This pattern may actually differentiate between
markers that mature in parallel with brain maturation
and those that play a specific role (e.g., guidance of
growth cones and synapse formation) in brain develop-
ment. It would appear that cannabinoid receptors be-
long to the former class, and the relatively low and
regionally selective appearance of cannabinoid recep-
tors in the fetal human brain may explain the rela-
tively mild and selective nature of postnatal deficits
observed in infants exposed to cannabinoids in utero.
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BIEGON AND KERMAN