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The Journal of Neuroscience, May 15, 2000, 20(10):3864-3873
Projections from the Rat Prefrontal Cortex to the Ventral
Tegmental Area: Target Specificity in the Synaptic Associations with
Mesoaccumbens and Mesocortical Neurons
David B.
Carr and
Susan R.
Sesack
Departments of Neuroscience and Psychiatry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260
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ABSTRACT |
Excitatory projections from the prefrontal cortex (PFC) to the
ventral tegmental area (VTA) play an important role in regulating the
activity of VTA neurons and the extracellular levels of dopamine (DA)
within forebrain regions. Previous investigations have demonstrated that PFC terminals synapse on the dendrites of DA and non-DA neurons in
the VTA. However, the projection targets of these cells are not known.
To address whether PFC afferents innervate different populations of VTA
neurons that project to the nucleus accumbens (NAc) or to the PFC, a
triple labeling method was used that combined peroxidase markers for
anterograde and retrograde tract-tracing with pre-embedding
immunogold-silver labeling for either tyrosine hydroxylase (TH) or
GABA. Within the VTA, PFC terminals formed asymmetric synapses onto
dendritic shafts that were immunoreactive for either TH or GABA. PFC
terminals also synapsed on VTA dendrites that were retrogradely labeled
from the NAc or the PFC. Dendrites retrogradely labeled from the NAc
and postsynaptic to PFC afferents were sometimes immunoreactive for
GABA but were never TH-labeled. Conversely, dendrites retrogradely
labeled from the PFC and postsynaptic to PFC afferents were sometimes
immunoreactive for TH but were never GABA-labeled. These results
provide the first demonstration of PFC afferents synapsing on
identified cell populations in the VTA and indicate a considerable
degree of specificity in the targets of the PFC projection. The
unexpected finding of selective PFC synaptic input to GABA-containing
mesoaccumbens neurons and DA-containing mesocortical neurons suggests
novel mechanisms through which the PFC can influence the activity of
ascending DA and GABA projections.
Key words:
dopamine; GABA; nucleus accumbens; prelimbic cortex; infralimbic cortex; ultrastructure
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INTRODUCTION |
Ascending projections of midbrain
dopamine (DA) neurons to the nucleus accumbens (NAc) and prefrontal
cortex (PFC) play important roles in motivation, reward, and cognitive
functions. Extracellular DA levels within these regions are
characterized by a tonic basal concentration, on which phasic increases
in DA levels occur in response to behaviorally relevant stimuli (Finlay
et al., 1995 ; Westerink, 1995; Wilson et al., 1995; Bassareo and Di
Chiara, 1997; Rebec et al., 1997). These phasic increases in
extracellular DA are likely caused by increased single spike and burst
firing of midbrain DA neurons (Streckler and Jacobs, 1987; Schultz et al., 1997). Burst firing is especially associated with enhanced DA
release from terminals (Gonon, 1988; Bean and Roth, 1991) and is
critically dependent on afferent input, because DA neurons do not
exhibit this firing pattern in vitro (Grace, 1987, 1988). Thus, determining the sources of afferent input that are responsible for the generation of burst firing is crucial in understanding the
function of ascending DA systems. Burst firing in DA neurons is
dependent, at least in part, on glutamate input, because blockade of
glutamate receptors suppresses this activity pattern in these cells
(Grenhoff et al., 1988; Charlety et al., 1991; Overton and Clark, 1992;
Chergui et al., 1993). One of the principal glutamate inputs to the
ventral tegmental area (VTA) arises from the PFC (Christie et al.,
1985; Sesack et al., 1989; Hurley et al., 1991; Sesack and Pickel,
1992; Lu et al., 1997). Moreover, PFC stimulation increases burst
firing of DA neurons (Gariano and Groves, 1988; Murase et al., 1993;
Tong et al., 1996), whereas inactivation of the PFC produces the
opposite effect (Svensson and Tung, 1989; Murase et al., 1993). These
effects may be mediated by the known monosynaptic projection from the
PFC to DA neurons within the VTA (Sesack and Pickel, 1992).
The efferent targets of DA neurons that receive PFC input are not
known. PFC afferents may target DA neurons that project to the NAc or
those that project back to the PFC, because there is substantial
overlap between the distribution of PFC terminals and the soma and
dendrites of both mesoaccumbens and mesoprefrontal neurons within the
VTA (Swanson, 1982; Sesack et al., 1989; Hurley et al., 1991; Sesack
and Pickel, 1992). In addition, PFC stimulation produces excitatory
responses in mesocortical or mesoaccumbens neurons that exhibit the
physiological characteristics of DA cells (Thierry et al., 1979;
Gariano and Groves, 1988). Neurochemical studies also indicate that PFC
afferents target the DA cell populations that project to the NAc or to
the PFC. Stimulation of the PFC increases levels of extracellular DA
within the NAc (Murase et al., 1993; Taber and Fibiger, 1995; Taber et
al., 1995; Karreman and Moghaddam, 1996), an effect that is blocked by
infusion of glutamate antagonists into the VTA but not into the NAc
(Taber and Fibiger, 1995; Taber et al., 1995; Karreman and Moghaddam, 1996). Inactivation of the PFC produces the opposite response (Murase
et al., 1993), indicating a role of the PFC in the regulation of tonic
levels of NAc DA. Stimulation of the PFC by local infusion of glutamate
agonists also increases DA levels within the PFC (Jedema and Moghaddam,
1996), whereas glutamate antagonist infusion has the opposite effect
(Takahata and Moghaddam, 1998). These effects may be attributable to
changes in the activity of PFC neurons that project to mesoprefrontal
DA cells, although mechanisms that are local to the cortex cannot be excluded.
Finally, in addition to the extensively studied DA projections of the
VTA, recent studies have also demonstrated that GABA-containing neurons
project from the VTA to both the NAc (Van Bockstaele and Pickel, 1995)
and to the PFC (Carr and Sesack, 2000). It is not known if these
GABA-containing projection systems receive synaptic input from the PFC.
However, both anatomical (Sesack and Pickel, 1992) and
electrophysiological (Tong et al., 1998) studies have demonstrated
monosynaptic contacts of PFC afferents onto non-DA neurons in the VTA.
Thus, both GABA mesoaccumbens and mesocortical neurons may receive PFC
synaptic input.
In this study, we have combined anterograde and retrograde tract
tracing with immunocytochemistry and electron microscopy in a
triple-labeling approach to examine the projections and neurochemical phenotypes of VTA neurons that receive synaptic contacts from PFC terminals.
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MATERIALS AND METHODS |
Tracer injection and immunocytochemical processing.
Five adult male Sprague Dawley rats, anesthetized with chloral hydrate (420 mg/kg, i.p.), received bilateral injections of the anterograde tracer biotinylated dextran amine (BDA) into the medial PFC and the
retrograde tracer FluoroGold (FG; Fluorochrome, Englewood, CO) into the
NAc. Four rats received combined injections of BDA and FG into the PFC.
BDA (10,000 MW; Molecular Probes, Eugene, OR) was dissolved as a 10%
solution in 10 mM sodium phosphate buffer, pH 7.4, and
injected into the PFC via glass micropipettes using a
controlled pressure device (PicoPump; World Precision Instruments). The
coordinates for bilateral PFC injections were 3.0 mm anterior to
bregma, 0.7 mm lateral to the midline, and 3.5 and 4.5 mm ventral to
the skull surface, according to the atlas of Paxinos and Watson
(1986). Approximately 100 nl of BDA was injected at each of the
four sites at a rate of 10 nl/min. FG was dissolved as a 1% solution
in 100 mM cacodylate buffer and injected into the NAc via
iontophoresis to minimize tissue damage and potential uptake by fibers
of passage (Pieribone and Aston-Jones, 1988). The coordinates for
bilateral NAc injection were 1.7 mm anterior to bregma, 3.4 mm lateral
to the midline, and 7.3 and 6.8 mm ventral to the skull surface. FG was
iontophoretically injected (+5 mA pulsed 10 sec on/off) for 20 min at
each of the four locations through glass micropipettes lowered at a
15° angle in the coronal plane. For FG injections into the PFC, the
tracer was pressure-injected using the same methods and coordinates as BDA injections, but using separate micropipettes.
After a 5-7 day survival period, animals were deeply anesthetized with
Nembutal (100 mg/kg, i.p) and perfused with 10 ml of 0.9% saline
containing 1000 U/ml heparin, followed by 50 ml of 3.75% acrolein and
2% paraformaldehyde and 400 ml of 2% paraformaldehyde in 0.1 M phosphate buffer (PB), pH 7.4 . The brains were removed, and 4-6 mm coronal blocks containing the PFC, NAc, and VTA were post-fixed in 2% paraformaldehyde for 45 min. Vibratome (50 µm) sections from these blocks were collected in PB and incubated in 1%
sodium borohydride in PB to enhance immunocytochemical labeling (Leranth and Pickel, 1989).
A dual-labeling method was used in which PFC terminals anterogradely
labeled with BDA and mesoaccumbens or mesocortical neurons retrogradely
labeled with FG were visualized by peroxidase immunocytochemistry, whereas the neurochemical phenotype of retrogradely labeled neurons was
revealed by pre-embedding immunogold labeling for either tyrosine hydroxylase (TH) or GABA. Vibratome sections were incubated for 30 min
in blocking solution containing 3% normal goat serum and 1% bovine
serum albumin in 0.1 M Tris-buffered saline (TBS), pH 7.6. To enhance antibody penetration, blocking solution contained Triton
X-100 (Sigma, St. Louis, MO) at 0.04% for electron microscopic examination or 0.2% for light microscopy. Sections were then incubated for 12-15 hr in blocking solution containing polyclonal antiserum raised in rabbit against FG (1:4000; Chemicon, Temecula, CA) and monoclonal antibody raised in mouse against either TH (1:5000; Chemicon) or GABA (1:1000; Sigma).
For peroxidase localization of BDA and FG, sections were incubated for
30 min in biotinylated goat anti-rabbit antiserum (1:400; Vector
Laboratories, Burlingame, CA) diluted in blocking solution. After
several rinses in TBS, sections were incubated for 30 min in
avidin-biotin peroxidase complex (1:200; Vectastain Elite kit; Vector
Laboratories) in TBS. The peroxidase reaction was visualized by
incubating the sections in 0.022% diaminobenzidine and 0.003% hydrogen peroxide in TBS for 2-4 min. The peroxidase reaction was
terminated by several rinses in TBS. For immunogold localization of TH
or GABA, sections were incubated for 30 min in blocking solution
containing 0.8% bovine serum albumin and 0.1% fish gelatin in 10 mM PBS, pH 7.4. Sections were then incubated in
blocking solution containing goat anti-mouse antiserum conjugated to 1 nm gold particles (1:50; Amersham, Arlington Heights, IL). After several rinses in blocking solution and PBS, the size of the gold particles was subsequently enhanced by incubation in silver solution (Amersham) for 5-7 min.
Sections for light microscopy were mounted on glass slides, dehydrated,
and coverslipped. Sections for electron microscopic examination were
post-fixed for 1 hr in 2% osmium tetroxide in PB, dehydrated through
successive alcohols and propylene oxide, and embedded in Epon (EM bed
812; Electron Microscopy Sciences). Sections were mounted on Epon
blocks, and ultrathin sections were taken from the outer surface of the
tissue and collected on copper mesh grids. Sections were counterstained
with uranyl acetate and lead citrate and examined with a Zeiss 902 transmission electron microscope.
Pseudorabies virus-Bartha strain injection. Although
FG extensively labels the dendritic tree of VTA neurons, it is
sometimes confined to lysosomes within retrogradely labeled cells (Carr and Sesack, 2000). Thus, some of the dendrites of retrogradely labeled
neurons may have been misclassified as unlabeled. Therefore, to confirm
the results obtained with retrograde transport of FG from the NAc,
additional experiments were performed in which pseudorabies virus-Bartha strain (PRV) was used to retrogradely label mesoaccumbens neurons. PRV produces extensive labeling within infected neurons, with
no evidence of anterograde transport or uptake by fibers of passage
(O'Donnell et al., 1997; Card et al., 1998; Carr et al., 1999). BDA
was injected into the PFC of three male Sprague Dawley rats as
described above. After a 5 d survival period, PRV injection was
performed as described previously (Carr et al., 1999). Briefly, 100 nl
of PRV (1.4 × 109 pfu/ml) was
stereotaxically injected into the medial NAc of three male rats. After
a 36 hr survival period, the animals were killed, and the tissue was
processed for electron microscopic examination as described above,
substituting polyclonal antiserum raised in rabbit against PRV
(1:10,000; gift of Dr. L.W. Enquist) for the anti-FG antiserum in the
primary antibody step. This postinoculation survival period was chosen
based on results from preliminary studies that this time period
produces maximal labeling of first-order neurons without significant
second-order infection (Carr et al., 1999) (P. O'Donnell, D. Carr, and
J. Card unpublished observations). This protocol has been used
extensively to determine the time course of neuronal infection in a
variety of central systems (O'Donnell et al., 1997; Card et al., 1998;
Carr et al., 1999; Leak et al., 1999).
Ultrastructural analysis. Ultrathin sections were taken from
the outer surface of Vibratome sections through the parabrachial and
paranigral regions of the anterior VTA. Within single, nonconsecutive thin sections, tissue contained within grid squares (boundaries of the
grid mesh, 3025 µm2) along the
Epon-tissue interface was examined at a magnification of 12,000×. All
synaptic contacts of BDA-labeled terminals were photographed at a
magnification of 12,000-20,000×. In animals receiving FG injections
into the NAc, 1,104,125 µm2 of tissue
was examined from TH-labeled sections and 828,850 µm2 from GABA-labeled sections. In
animals receiving FG injections into the PFC, 1,022,450 µm2 of tissue was examined from
TH-labeled sections and 1,016,400 µm2
from GABA-labeled sections. In animals receiving NAc PRV injections, 553,575 µm2 of tissue was examined from
TH-labeled sections and 463,780 µm2 from
GABA-labeled sections. To reduce false-negative results caused by
inadequate antibody penetration, only those areas at the surface of the
tissue (Epon-tissue interface) where antibody penetration is
maximal were examined. In addition, only micrographs that contained
both peroxidase and gold markers within the same 32.5 µm2 area (area contained within a single
micrograph taken at 12,000× magnification) were analyzed.
Neuronal elements were identified in electron micrographs according to
the criteria described by Peters et al. (1991). Neuronal somata were
identified by the presence of a nucleus. Dendrites exhibited densities
postsynaptic to axon terminals and contained mitochondria,
microtubules, and/or rough endoplasmic reticulum. Axon terminals had
cross-sectional diameters of at least 0.2 µm and contained numerous
synaptic vesicles. Asymmetric synapses (Gray's type 1; Gray, 1959)
exhibited thickened postsynaptic densities, whereas symmetric synapses
(Gray's type II) had thin postsynaptic densities.
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RESULTS |
Light-microscopic observations
Within the PFC, BDA injections were centered in the prelimbic and
infralimbic cortices, but also extended dorsally into the anterior
cingulate cortex. Within the VTA, BDA-labeled axons were distributed
throughout the parabrachial and paranigral divisions (Fig.
1A). No somatodendritic
BDA labeling was observed, consistent with a purely anterograde
transport of the tracer in this system. In those animals receiving FG
injections into the PFC, the spread of these injections typically
encompassed the same area as BDA labeling. Injections of either FG or
PRV into the NAc were centered in the medial portion of this nucleus,
including both the core and shell subdivisions. Within the VTA,
labeling for either FG or PRV was extensively distributed within
retrogradely labeled neurons extending into the proximal and distal
portions of the dendrites (Fig. 1B). There was
extensive overlap of the terminal field of BDA-labeled axons with the
somata and dendrites of VTA neurons retrogradely labeled from either
the NAc (Fig. 1B) or PFC (data not shown).
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Figure 1.
Light micrographs of coronal sections through the
rat VTA showing the overlap of the somatodendritic field of
mesoaccumbens neurons and PFC afferents. A, Bright-field
micrograph showing the distribution of axons and terminals after
injection of BDA into the medial PFC. B, Fluorescence
micrograph displaying the distribution and extent of labeling of VTA
neurons after an injection of FluoroGold into the medial NAc.
SNr, Substantia nigra, zona reticulata;
mp, mammilary peduncle. Medial is to the
right. Scale bar, 140 µm.
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Electron microscopy
Relationship between BDA-labeled terminals and TH- and
GABA-labeled dendrites
Within the rostral VTA, BDA labeling was confined to terminals and
preterminal axons. No somatodendritic BDA labeling was observed,
consistent with light-microscopic observations. BDA-labeled terminals
(Fig. 2; see Figs. 4-6) exhibited
morphological features consistent with previous observations of PFC
terminals within the VTA (Sesack and Pickel, 1992). These terminals
were sparsely distributed, requiring examination of a large area of
tissue to obtain a reasonable sample of BDA-labeled synaptic terminals
in each experimental condition (see Materials and Methods). Many BDA-labeled axons were of small diameter, contained few synaptic vesicles, and did not form synaptic contacts when examined in serial
sections. These profiles are probably PFC axons passing through the VTA
to more caudal targets. When BDA-labeled terminals were observed to
form distinct synaptic contacts, these were exclusively of the
asymmetric axodendritic type.
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Figure 2.
Electron micrographs showing synaptic contacts
(curved arrows) of BDA-labeled PFC terminals
(Pt) onto dendrites containing immunogold-silver
labeling for TH (A, TH-d) or GABA (B,
GABA-d). In B, the synapse formed by the Pt on
the GABA-d is also prominent in an adjacent section
(inset). Scale bar, 0.25 µm.
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In VTA tissue labeled for TH, gold-silver immunolabeling was observed
within neuronal somata as well as in large- and small-caliber dendritic
processes. Within this tissue, 37% (39 of 105) of BDA-labeled terminals formed asymmetric synapses onto dendrites containing gold-silver labeling for TH (Fig. 2A, Table
1). In tissue labeled for GABA, the
distribution of gold-silver labeling was more broad, being observed in
axon terminals forming symmetric synaptic contacts, as well as in
neuronal somata and dendrites. Within this GABA-labeled tissue, 37%
(35 of 95) of BDA-labeled terminals formed synapses onto dendrites
containing gold-silver labeling for GABA (Fig. 2B,
Table 1).
Relationship between BDA-labeled terminals and retrogradely labeled
mesoaccumbens dendrites
Within the VTA, immunoperoxidase labeling for FG or PRV
retrogradely transported from the NAc was diffusely distributed within neuronal somata as well as in large- and small-caliber dendritic profiles (Figs.
3-5).
Occasionally, immunoreactivity for FG was confined to lysosomes (Fig.
4A). Peroxidase immunoreactivity for FG or PRV was
distinct from gold-silver labeling for TH or GABA, and profiles dually
labeled with both peroxidase and gold-silver markers were readily
distinguishable from those singly labeled for either marker alone (Fig.
3). No significant differences were observed in data obtained in
animals receiving either PRV or FG injections into the NAc, so data
from both groups was pooled together. In both TH- and GABA-labeled
tissue from animals receiving injections of either tracer into the NAc,
the majority of BDA-labeled terminals formed synaptic contacts onto
unlabeled dendrites (Fig. 4A). In TH-labeled tissue
from these animals, BDA-labeled terminals synapsed onto dendrites
containing only peroxidase labeling for FG or PRV (Fig.
4B) and onto dendrites containing only gold-silver
labeling for TH, but not onto dendrites containing both markers.
BDA-labeled terminals were often observed in the same area of neuropil
as dendrites dually labeled for TH and FG or PRV, but in every instance these terminals formed synaptic contacts onto other targets (Fig. 4A). In GABA-labeled tissue from these animals,
BDA-labeled terminals synapsed on dendrites containing gold-silver
labeling for GABA alone, as well as dendrites containing both
peroxidase labeling for FG or PRV and gold-silver labeling for GABA
(Figs. 4C, 5). No terminals synapsed onto dendrites
containing only peroxidase labeling for FG or PRV. These results are
summarized in Table 1.
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Figure 3.
Electron micrograph showing the distribution of
immunoperoxidase labeling for FG, retrogradely transported from the
NAc, and immunogold-silver labeling for TH within the neuropil of the
VTA. A dendrite (FG/TH-d) contains both peroxidase
labeling for FG as well as gold-silver labeling for TH. Within the
same area of neuropil are dendrites singly labeled for either FG
(FG-d) or TH (TH-d). Scale bar, 1.0 µm.
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Figure 4.
Electron micrographs showing the associations of
PFC terminals (Pt) with VTA dendrites retrogradely
labeled from the NAc. In A, a Pt is within the same area
of neuropil as a dendrite containing both immunoperoxidase labeling for
FG, retrogradely transported from the NAc, as well as immunogold
labeling for TH (FG/TH-d). The FG/TH-d exhibits FG
labeling concentrated in a lysosome (note flocculent precipitate around
the structure at the open arrow) and receives a synaptic
contact from an unlabeled terminal (Ut). The Pt does not
contact the FG/TH-d but instead contacts an unlabeled dendrite
(Ud). The oblique synapse (curved arrow)
formed by the Pt on the Ud is more evident in an adjacent section
(inset). In B, a Pt forms a synaptic
contact (curved arrow) onto an FG-labeled dendrite
(FG-d) that does not contain gold-silver labeling for
TH. In C, a Pt synapses (curved arrow) on
a dendrite (PRV/GABA-d) that contains both
immunoperoxidase labeling for PRV retrogradely transported from the NAc
and immunogold-silver labeling for GABA. The PRV/GABA-d is adjacent to
a dendrite that contains only peroxidase labeling for PRV
(PRV-d). Scale bar, 0.5 µm.
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Figure 5.
Electron micrographs showing a synaptic contact
(curved arrow) of a PFC terminal (Pt) on
a dendrite containing both immunoperoxidase labeling for FG
retrogradely transported from the NAc and immunogold-silver labeling
for GABA (FG/GABA-d). The postsynaptic dendrite is
proximal to the soma, [see Golgi apparatus
(ga)], and receives synaptic input from the Pt
(also shown in inset) and from unlabeled terminals
(Ut). A GABA-containing terminal (GABA-t)
lies adjacent to the dendrite. Scale bar, 0.5 µm.
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Relationship between BDA-labeled terminals and retrogradely labeled
mesoprefrontal dendrites
Similar to the results obtained in tissue from animals receiving
retrograde tracer injections into the NAc, the majority of BDA-labeled
terminals in VTA tissue from animals receiving FG injections into the
PFC formed synapses onto unlabeled dendrites. In TH-labeled tissue from
these animals, BDA-labeled terminals formed synaptic contacts onto
dendrites containing only gold-silver labeling for TH, as well as onto
dendrites containing both peroxidase labeling for FG and gold-silver
labeling for TH (Fig.
6A,B). No terminals
synapsed onto dendrites containing only peroxidase labeling for FG. In
GABA-labeled tissue, BDA-labeled terminals synapsed onto dendrites
containing only gold-silver labeling for GABA or onto dendrites
containing only peroxidase labeling for FG (Fig. 6C). No dendrites
dually labeled for both GABA and FG received synaptic contact from
BDA-labeled terminals. BDA-labeled terminals were observed in the same
area of neuropil as dendrites dually labeled for FG and GABA but formed
synaptic contacts onto other targets (Fig. 6C). These
observations are summarized in Table 1.
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Figure 6.
Electron micrographs showing the associations of
PFC terminals (Pt) with VTA dendrites retrogradely
labeled from the PFC. In A and B, two
different Pts form synaptic contacts (curved arrows)
onto dendrites that contain both immunoperoxidase labeling for FG
retrogradely transported from the PFC as well as immunogold-silver
labeling for TH (FG/TH-d). In C, a Pt
synapses on a dendrite (FG-d) that contains retrogradely
transported FG but does not contain gold-silver labeling for GABA.
Within the same area of neuropil, two other dendrites
(FG/GABA-d) contain both markers. One FG/GABA-d is
apposed to an unlabeled terminal (Ut). Scale bar, 0.25 µm.
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DISCUSSION |
This study used a novel triple-labeling method to examine the
projection targets and phenotypes of midbrain neurons synaptically targeted by the PFC. The results demonstrate that PFC terminals selectively synapse onto GABA cells that project to the NAc and DA
cells that project to the PFC. These data represent the first direct
demonstration of PFC terminals synapsing onto identified populations of
DA and GABA neurons within the rat VTA and demonstrate substantial
selectivity in the midbrain targets of the PFC. Through these
connections, the PFC can mediate a selective influence on the activity
of ascending DA and GABA projections. The findings are summarized in
Figure 7.
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Figure 7.
Schematic drawing of the observed relationships
between PFC terminals and mesoprefrontal, mesoaccumbens, and other
projection neurons of the VTA. 1, A small population of
PFC terminals form synaptic contacts onto DA neurons that project to
the PFC. 2, Another population of PFC terminals synapse
onto GABA neurons that project to the NAc. 3, The
majority of PFC terminals within the VTA appear to target DA and GABA
neurons that project to unknown target sites. It is also possible that
PFC terminals project onto VTA neurons that contain neither DA nor
GABA.
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PFC terminals within the VTA
The observation that PFC terminals formed exclusively asymmetric
axodendritic synapses is consistent with previous anatomical observations (Sesack and Pickel, 1992) as well as reports that this
pathway mediates an excitatory influence on target cells (Christie et
al., 1985; Gariano and Groves, 1988; Murase et al., 1993; Tong et al.,
1996, 1998). Approximately one-third (37%) of PFC terminals synapsed
onto TH- immunoreactive VTA dendrites, in close agreement with previous
quantitative observations (Sesack and Pickel, 1992). The present study
extends these findings by demonstrating that an additional one-third
(37%) of PFC terminals synapse onto GABA-immunoreactive VTA dendrites.
It is likely that these TH- and GABA-labeled dendrites arise from
separate neuronal populations, because Kosaka et al. (1987) have
reported that TH and GABA are not colocalized within VTA cells.
Although some GABA-labeled cells contacted by PFC terminals were
clearly projection neurons, as revealed by retrograde tracing, it is
possible that some GABA-labeled dendrites arose from local circuit
neurons. Thus, the PFC may alter cell activity within the VTA both by
directly synapsing onto projection neurons as well as indirectly via
contacts onto interneurons.
In addition to targeting TH- and GABA-labeled dendrites, 26% of PFC
terminals formed asymmetric synapses onto dendrites that contained
neither marker. Although this finding may be attributable to inadequate
penetration of TH and GABA antibodies, it is also possible that these
dendrites arise from a distinct population of VTA neurons. For example,
some cholecystokinin-containing VTA cells do not colocalize DA (Seroogy
et al., 1989), and future studies may show that this population
receives synaptic PFC input.
Association of PFC terminals with mesoaccumbens neurons
The lack of observed synaptic contact of PFC terminals onto
TH-labeled mesoaccumbens neurons was contrary to our original hypothesis. Although examples of PFC synaptic contacts onto
mesoaccumbens DA cells may have been missed because of limitations
inherent in the methods, several observations suggest that a
significant innervation of mesoaccumbens DA neurons by PFC terminals
was not overlooked. (1) To avoid false-negative results caused by
inadequate antibody penetration, our investigation was confined to the
Epon-tissue interface where immunolabeling is maximal. (2) The
observation that PFC terminals were sometimes in the same area of
neuropil as mesoaccumbens TH-labeled dendrites confirms that all three markers could be detected within the same area of tissue. (3) PFC
terminals synapsed onto TH-labeled neurons that were retrogradely labeled from the PFC. (4) Whereas all the dendrites of every
retrogradely labeled neuron might not contain visible tracer in a
single section, the findings are strengthened by the observation of
comparable results using either FG or PRV to retrogradely label
mesoaccumbens neurons. Moreover, we know of no evidence for
differential transport of axonal tracers by subclasses of midbrain
neurons. (5) Finally, PFC terminals synapsed on GABA-labeled neurons
that project to the NAc, despite the fact that these cells represent a
minority of the mesoaccumbens projection (Swanson, 1982; Van Bockstaele and Pickel, 1995) and should have been more difficult to observe.
Although the evidence obtained in this study does not support a direct
excitatory projection from the PFC to mesoaccumbens DA neurons,
neurochemical data from several laboratories indicates that the PFC
influences DA levels within the NAc (Murase et al., 1993; Taber and
Fibiger, 1995; Taber et al., 1995; Karreman and Moghaddam, 1996). This
discrepancy can be reconciled if the excitatory effect of PFC
stimulation on mesoaccumbens DA cell activity was not produced by a
direct projection from the PFC to the VTA but rather by an indirect
projection in which the PFC activates another area that, in turn,
projects to the VTA. Such an indirect mechanism is consistent with the
findings of Tong et al. (1996) that PFC stimulation produces excitatory
responses in VTA cells with a latency inconsistent with a monosynaptic
projection. Moreover, such an intermediary is likely to involve a
glutamate projection to the VTA, because the effects of PFC stimulation
on NAc DA are blocked by glutamate receptor antagonists within the VTA
(Taber and Fibiger, 1995; Taber et al., 1995; Karreman and Moghaddam, 1996). The glutamate neurons of the pedunculopontine tegmentum (PPT)
are a likely cell group through which the PFC might mediate an indirect
excitatory influence on the VTA. The PFC projects to the PPT (Sesack et
al., 1989; Hurley et al., 1991), which in turn projects to the VTA
(Oakman et al., 1995) and, at least in primates, synapses on DA neurons
(Smith et al., 1996). Future examination is required to determine if
the excitatory effect of the PFC on mesoaccumbens DA neurons is
mediated via the PPT.
The observation of GABA-labeled neurons retrogradely labeled from the
NAc is consistent with the report of Van Bockstaele and Pickel
(1995) describing a GABA mesoaccumbens projection. We have extended
these findings to show that this GABA pathway receives a direct
synaptic innervation from the PFC. The functional significance of this
circuit is unclear, because little is known about the role of the GABA
mesoaccumbens pathway. Van Bockstaele and Pickel (1995) have suggested
that this pathway preferentially inhibits the activity of cholinergic
local circuit neurons within the NAc. Thus, the excitatory input to
these GABA cells could provide a mechanism through which the PFC can
indirectly inhibit the activity of NAc cholinergic neurons.
Alternatively, if mesoaccumbens GABA neurons synapse onto spiny NAc
projection cells, PFC afferents to GABA VTA neurons might exert a
feedforward inhibitory influence on NAc output cells. This inhibitory
circuit could act in concert with direct excitatory PFC projections to
medium spiny neurons (Sesack and Pickel, 1992; O'Donnell and Grace,
1994), with the net effect of exciting some NAc efferent projections
while inhibiting others.
It is also possible that PFC synaptic inputs to VTA GABA neurons
indirectly regulate mesoaccumbens DA cells through local collaterals.
Such an arrangement is consistent with the short-latency inhibition
typically evoked in DA neurons by PFC stimulation (Tong et al., 1996).
Whereas this inhibition may originate from the basal ganglia,
preliminary evidence suggests that VTA GABA neurons regulate DA cell
activity (S. Henriksen, personal communication). Future
anatomical studies will need to investigate the presence of local
connections from GABA cells to mesoaccumbens DA neurons. Such a
synaptic organization has important implications for models of
schizophrenia pathophysiology (Laruelle et al., 1996; Bertolino et al.,
1999), which hypothesize loss of inhibitory control of mesostriatal DA
neurons as a result of PFC functional deficits.
Association of PFC terminals with mesoprefrontal neurons
The finding that PFC terminals synapse onto the dendrites of
mesocortical DA neurons is consistent with neurochemical evidence that
the infusion of glutamate receptor agonists into the PFC elevates
extracellular DA within this cortical area (Jedema and Moghaddam, 1996)
and further suggests that this effect may be caused by excitation of
the PFC cells that synapse onto mesoprefrontal DA neurons. These
results are also consistent with electrophysiological data that PFC
stimulation produces a short-latency response in DA cells
antidromically activated from the PFC (Thierry et al., 1979; Gariano
and Groves, 1988). This reciprocal projection may mediate an inhibitory
feedback mechanism because most in vivo studies report that
DA suppresses PFC cell activity (Thierry et al., 1988; Sesack and
Bunney, 1989). This projection may also play a role in the unique
response of this pathway to stress (Horger and Roth, 1996), because
both PFC cells (Mantz et al., 1988) and mesocortical DA neurons
(Thierry et al., 1976; Mantz et al., 1989; Deutch et al., 1991) are
activated by stressful stimuli. Finally, the finding of synaptic input
from prefrontal association cortex to mesocortical DA neurons has
important significance for understanding the role of DA in facilitating
learning by the communication of future expectations (Schultz,
1997).
In addition to the well-characterized DA projection to the PFC, the VTA
also sends a substantial GABA projection to this area, comprising 58%
of all mesoprefrontal neurons (Carr and Sesack, 2000). Within the PFC,
VTA GABA terminals synapse on both pyramidal cells and GABA local
circuit neurons and are thus positioned to mediate both direct
inhibitory and indirect disinhibitory influences. The observation that
mesoprefrontal GABA neurons did not receive synaptic innervation from
the PFC suggests that this pathway does not participate in a direct
feedback mechanism. It is possible that a minor input from the PFC to
GABA mesocortical cells was overlooked. However, many of the same
arguments as provided for the mesoaccumbens DA cells are also
applicable here. In particular, PFC terminals synapsed on
mesoprefrontal DA neurons, despite the fact that these cells make up a
minority of the projection population (Swanson, 1982; Carr and Sesack,
2000) and should have been more difficult to detect than GABA-labeled
neurons. Future studies are necessary to understand the sources of
afferent input that drive activity in the newly discovered GABA
mesocortical pathway.
In tissue from animals receiving retrograde tracer injections into
either the PFC or the NAc, most PFC terminals formed synaptic contacts
onto TH- or GABA-labeled neurons that were not retrogradely labeled. It
is thus likely that PFC terminals also target VTA cells that project to
other regions, although the projection targets of these neurons are not
known. Based on previous studies of the distribution of VTA projection
neurons, as well as the terminal field of PFC axons within the VTA,
other likely targets are the septum, amygdala, or entorhinal cortex
(Swanson, 1982). Future investigation is required to identify the other
efferent populations of VTA neurons that are synaptically driven by the PFC.
Conclusions
The findings of this study that PFC terminals synapse selectively
onto mesoaccumbens GABA neurons and mesoprefrontal DA neurons were
unexpected. Given that ~80% of the VTA projection to the NAc
contains DA (Swanson, 1982) and ~60% of mesoprefrontal cells contain
GABA (Carr and Sesack, 2000), one would expect that these two
populations would have the highest probability of receiving PFC
synaptic contacts. The observation that in both systems, PFC terminals
target the cell population that makes up the minority of the overall
projection (GABA projections to the NAc and DA projections to the PFC)
strongly suggests that the synaptic contacts of PFC terminals within
the VTA are not randomly distributed but are targeted to specific cell
populations. Thus, despite the relatively low density of PFC terminals
within the VTA (Sesack and Pickel, 1992), the functional influence of
this pathway may be enhanced by selective targeting of specific
neuronal populations.
| |
FOOTNOTES |
Received Dec. 1, 1999; revised Feb. 23, 2000; accepted Feb. 25, 2000.
This work was supported by United States Public Health Service Grant
MH50314 (S.R.S.), a National Alliance for Research on Schizophrenia and
Depression Independent Investigator Award (S.R.S.), and a Scottish Rite
Dissertation Fellowship (D.B.C.). We thank Dr. J. Patrick Card for
sharing his extensive knowledge and technical expertise concerning the
use of pseudorabies virus and also Dr. L.W. Enquist (Princeton
University) for generously supplying PRV and anti-PRV antiserum.
Correspondence should be addressed to Dr. Susan R. Sesack, Department
of Neuroscience, 446 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260. E-mail: Sesack{at}bns.pitt.edu.
| |
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[Abstract]
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M. Gao, C.-L. Liu, S. Yang, G.-Z. Jin, B. S. Bunney, and W.-X. Shi
Functional Coupling between the Prefrontal Cortex and Dopamine Neurons in the Ventral Tegmental Area
J. Neurosci.,
May 16, 2007;
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[Abstract]
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S. B. Floresco and M. T. Tse
Dopaminergic Regulation of Inhibitory and Excitatory Transmission in the Basolateral Amygdala-Prefrontal Cortical Pathway
J. Neurosci.,
February 21, 2007;
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[Abstract]
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E. B. Margolis, H. Lock, G. O. Hjelmstad, and H. L. Fields
The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons?
J. Physiol.,
December 15, 2006;
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[Abstract]
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F. Georges, C. L. Moine, and G. Aston-Jones
No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal
J. Neurosci.,
May 24, 2006;
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[Abstract]
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E. B. Margolis, H. Lock, V. I. Chefer, T. S. Shippenberg, G. O. Hjelmstad, and H. L. Fields
{kappa} opioids selectively control dopaminergic neurons projecting to the prefrontal cortex
PNAS,
February 21, 2006;
103(8):
2938 - 2942.
[Abstract]
[Full Text]
[PDF]
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R. Narendran, W. G. Frankle, R. Keefe, R. Gil, D. Martinez, M. Slifstein, L. S. Kegeles, P. S. Talbot, Y. Huang, D.-R. Hwang, et al.
Altered Prefrontal Dopaminergic Function in Chronic Recreational Ketamine Users
Am J Psychiatry,
December 1, 2005;
162(12):
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[Abstract]
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L. Diaz-Mataix, M. C. Scorza, A. Bortolozzi, M. Toth, P. Celada, and F. Artigas
Involvement of 5-HT1A Receptors in Prefrontal Cortex in the Modulation of Dopaminergic Activity: Role in Atypical Antipsychotic Action
J. Neurosci.,
November 23, 2005;
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[Abstract]
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C. R. Yang and L. Chen
Targeting Prefrontal Cortical Dopamine D1 and N-Methyl-D-Aspartate Receptor Interactions in Schizophrenia Treatment
Neuroscientist,
October 1, 2005;
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452 - 470.
[Abstract]
[PDF]
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H. D. Mansvelder
Yin and Yang of VTA Opioid Signaling. Focus on "Both Kappa and Mu Opioid Agonists Inhibit Glutamatergic Input to Ventral Tegmental Area Neurons"
J Neurophysiol,
June 1, 2005;
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E. B. Margolis, G. O. Hjelmstad, A. Bonci, and H. L. Fields
Both Kappa and Mu Opioid Agonists Inhibit Glutamatergic Input to Ventral Tegmental Area Neurons
J Neurophysiol,
June 1, 2005;
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[Abstract]
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S. Koyama, Y. Kanemitsu, and F. F. Weight
Spontaneous Activity and Properties of Two Types of Principal Neurons From the Ventral Tegmental Area of Rat
J Neurophysiol,
June 1, 2005;
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[Abstract]
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R. J. Kyd and D. K. Bilkey
Hippocampal Place Cells Show Increased Sensitivity to Changes in the Local Environment Following Prefrontal Cortex Lesions
Cereb Cortex,
June 1, 2005;
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[Abstract]
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M. Sarter, C. L Nelson, and J. P Bruno
Cortical Cholinergic Transmission and Cortical Information Processing in Schizophrenia
Schizophr Bull,
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[Abstract]
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N. Santana, A. Bortolozzi, J. Serrats, G. Mengod, and F. Artigas
Expression of Serotonin1A and Serotonin2A Receptors in Pyramidal and GABAergic Neurons of the Rat Prefrontal Cortex
Cereb Cortex,
October 1, 2004;
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[Abstract]
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S. Ikemoto, B. M. Witkin, A. Zangen, and R. A. Wise
Rewarding Effects of AMPA Administration into the Supramammillary or Posterior Hypothalamic Nuclei But Not the Ventral Tegmental Area
J. Neurosci.,
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M. Amargos-Bosch, A. Bortolozzi, M. V. Puig, J. Serrats, A. Adell, P. Celada, M. Toth, G. Mengod, and F. Artigas
Co-expression and In Vivo Interaction of Serotonin1A and Serotonin2A Receptors in Pyramidal Neurons of Prefrontal Cortex
Cereb Cortex,
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[Abstract]
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K. A. Leite-Morris, E. Y. Fukudome, M. H. Shoeb, and G. B. Kaplan
GABAB Receptor Activation in the Ventral Tegmental Area Inhibits the Acquisition and Expression of Opiate-Induced Motor Sensitization
J. Pharmacol. Exp. Ther.,
February 1, 2004;
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A. G. Phillips, S. Ahn, and S. B. Floresco
Magnitude of Dopamine Release in Medial Prefrontal Cortex Predicts Accuracy of Memory on a Delayed Response Task
J. Neurosci.,
January 14, 2004;
24(2):
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A. Diamond, L. Briand, J. Fossella, and L. Gehlbach
Genetic and Neurochemical Modulation of Prefrontal Cognitive Functions in Children
Am J Psychiatry,
January 1, 2004;
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[Abstract]
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R. J. Kyd and D. K. Bilkey
Prefrontal Cortex Lesions Modify the Spatial Properties of Hippocampal Place Cells
Cereb Cortex,
May 1, 2003;
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444 - 451.
[Abstract]
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Y. Dong and F. J. White
Dopamine D1-Class Receptors Selectively Modulate a Slowly Inactivating Potassium Current in Rat Medial Prefrontal Cortex Pyramidal Neurons
J. Neurosci.,
April 1, 2003;
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M. Akil, B. S. Kolachana, D. A. Rothmond, T. M. Hyde, D. R. Weinberger, and J. E. Kleinman
Catechol-O-Methyltransferase Genotype and Dopamine Regulation in the Human Brain
J. Neurosci.,
March 15, 2003;
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[Abstract]
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P. O'Donnell, B. L. Lewis, D. R. Weinberger, and B. K. Lipska
Neonatal Hippocampal Damage Alters Electrophysiological Properties of Prefrontal Cortical Neurons in Adult Rats
Cereb Cortex,
September 1, 2002;
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[Abstract]
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M. E. Wolf
Addiction: Making the Connection Between Behavioral Changes and Neuronal Plasticity in Specific Pathways
Mol. Interv.,
June 1, 2002;
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[Abstract]
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B. J. Everitt and M. E. Wolf
Psychomotor Stimulant Addiction: A Neural Systems Perspective
J. Neurosci.,
May 1, 2002;
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C. Drouin, L. Darracq, F. Trovero, G. Blanc, J. Glowinski, S. Cotecchia, and J.-P. Tassin
alpha 1b-Adrenergic Receptors Control Locomotor and Rewarding Effects of Psychostimulants and Opiates
J. Neurosci.,
April 1, 2002;
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[Abstract]
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H. Neuhoff, A. Neu, B. Liss, and J. Roeper
Ih Channels Contribute to the Different Functional Properties of Identified Dopaminergic Subpopulations in the Midbrain
J. Neurosci.,
February 15, 2002;
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[Abstract]
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J. A. Rosenkranz and A. A. Grace
Cellular Mechanisms of Infralimbic and Prelimbic Prefrontal Cortical Inhibition and Dopaminergic Modulation of Basolateral Amygdala Neurons In Vivo
J. Neurosci.,
January 1, 2002;
22(1):
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[Abstract]
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I. Zironi, P. Iacovelli, G. Aicardi, P. Liu, and D.K. Bilkey
Prefrontal Cortex Lesions Augment the Location-related Firing Properties of Area TE/Perirhinal Cortex Neurons in a Working Memory Task
Cereb Cortex,
November 1, 2001;
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[Abstract]
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M. Giorgetti, G. Hotsenpiller, P. Ward, T. Teppen, and M. E. Wolf
Amphetamine-Induced Plasticity of AMPA Receptors in the Ventral Tegmental Area: Effects on Extracellular Levels of Dopamine and Glutamate in Freely Moving Rats
J. Neurosci.,
August 15, 2001;
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[Abstract]
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J. L. Cornish, M. Nakamura, and P. W. Kalivas
Dopamine-Independent Locomotion Following Blockade of N-Methyl-D-aspartate Receptors in the Ventral Tegmental Area
J. Pharmacol. Exp. Ther.,
July 1, 2001;
298(1):
226 - 233.
[Abstract]
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S. B. Floresco, C. L. Todd, and A. A. Grace
Glutamatergic Afferents from the Hippocampus to the Nucleus Accumbens Regulate Activity of Ventral Tegmental Area Dopamine Neurons
J. Neurosci.,
July 1, 2001;
21(13):
4915 - 4922.
[Abstract]
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[PDF]
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B. A. Sorg, N. Li, and W.-R. Wu
Dopamine D1 Receptor Activation in the Medial Prefrontal Cortex Prevents the Expression of Cocaine Sensitization
J. Pharmacol. Exp. Ther.,
April 12, 2001;
297(2):
501 - 508.
[Abstract]
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M. E. Jackson and B. Moghaddam
Amygdala Regulation of Nucleus Accumbens Dopamine Output is Governed by the Prefrontal Cortex
J. Neurosci.,
January 15, 2001;
21(2):
676 - 681.
[Abstract]
[Full Text]
[PDF]
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TOP
ABSTRACT
INTRODUCTION
Compound via MeSH
