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Stimulation of In Vivo Dopamine Transmission in the Bed Nucleus
of Stria Terminalis by Reinforcing Drugs
Ezio Carboni, Alessandra Silvagni, Maria T. P. Rolando, and Gaetano Di Chiara
Department of Toxicology and Consiglio Nazionale delle Ricerche Center for Neuropharmacology, University of Cagliari,
09126 Cagliari, Italy
Drugs of abuse preferentially increase dopamine transmission
in the shell of the nucleus accumbens. This area is considered
as a transition between the striatum and the extended amyg-
dala a complex neural system that includes the central amyg-
dala and the bed nucleus of stria terminalis, areas that, like the
nucleus accumbens shell, are heavily innervated by mesolimbic
dopamine neurons originating in the ventral tegmental area.
Given the anatomical and neurochemical relationships and sim-
ilarities with the nucleus accumbens shell it was of interest to
investigate whether the dopamine transmission of the bed
nucleus of stria terminalis shares with the accumbens shell the
peculiar responsiveness to drugs of abuse. To this end we
studied by microdialysis with concentric probes, the effect of
drugs of abuse on extracellular dopamine in the bed nucleus of
stria terminalis. We report that morphine, nicotine, cocaine,
ethanol, and the selective dopamine uptake inhibitor GBR
12909 increase effectively and dose dependently extracellular
dopamine in the bed nucleus of stria terminalis. These results
indicate that the bed nucleus of stria terminalis shares with the
nucleus accumbens shell a peculiar sensitivity to the dopamine
stimulant actions of drugs of abuse.
Key words: dopamine; BNST; nicotine; morphine; ethanol;
cocaine
Drugs and substances of abuse like nicotine, morphine, cocaine,
and ethanol share the property of increasing extracellular dopa-
mine (DA) in the nucleus accumbens (NAc) and in particular in
its ventromedial shell subdivision (Imperato and Di Chiara, 1988;
Pontieri et al., 1996; Tanda et al., 1997b). This property is
currently assigned an important role in the addictive liability of
drugs and in the process by which drug addiction is acquired and
maintained. Anatomical and histochemical studies show that the
NAc shell is homologous to a number of interconnected areas as
the bed nucleus of stria terminalis (BNST) and the central amyg-
dala that have been recently assigned to the so called extended
amygdala (Heimer et al., 1993; de Olmos and Heimer, 1999). The
areas and nuclei that participate into this complex share a role in
the acquisition and expression of emotions and of appetitive
behavior (e.g., feeding and sexual behavior) (Hernandez and
Hoebel, 1988; Tetel et al., 1993; Pfaus et al., 1995). Thus, the NAc
shell and the BNST receive a dense innervation from the baso-
lateral amygdala and a dense DA projection from the ventral
tegmentum and both project to the lateral hypothalamus and
periaqueductal gray (de Olmos, 1972, 1990; de Olmos et al., 1985;
Phelix et al., 1992). Strict similarities and connections also exist
between BNST and central nucleus of amygdala in terms of cell
morphology, transmitter content, and efferent connections (Al-
heid et al., 1995). The BNST is innervated by neurons containing
peptides as cholecystokinin (Micevych et al., 1988; Andres et al.,
1993) and corticotropin-releasing factor (CRF) (Cummings et al.,
1983; Phelix et al., 1994). The BNST is thought to be involved in
aversive behavior and in the somatic response to unconditioned
aversive stimuli (Davis and Shi, 1999).
Recently it has been reported that intra BNST infusion of a
DA D
1
receptor antagonist impairs cocaine intravenous self-
administration in rats (Epping-Jordan et al., 1998); moreover,
intra-BNST infusion of a CRF-antagonist impairs stress-induced
reinstatement of cocaine self-administration in rats (Erb and
Stewart, 1999). In view of these observations and of the relation-
ships between the shell of the NAc shell and the BNST we
thought that this area could also be involved in the DA-dependent
mechanism of action of drugs of abuse. We therefore studied by
the microdialysis, the action of various drugs on the extracellular
concentration of DA in the BNST.
MATERIALS AND METHODS
Animals. Male Sprague Dawley rats (Charles River, Calco, Italy) weigh-
ing 230–250 gm were housed under standard conditions of temperature
and humidity under an artificial light (light from 8:00 A.M. to 8:00 P.M.).
Probe preparation. Concentric dialysis probes were prepared with a 7
mm piece of AN 69 (sodium methallyl sulfate copolymer) dialysis fiber
(outer diameter, 310
m; inner diameter, 220
m; Hospal, Dasco, Italy),
sealed at one end with a drop of epoxy glue. Two 5-cm-long pieces of
fused silica (Composite Metal Services) tubing were introduced in the
dialysis fiber taking care to have the inlet reaching the lower end and
the outlet reaching the higher end of the dialyzing portion (2.0 mm) of
the fiber. The inlet and the outlet were then sealed to the fiber and to a
20 mm piece of stainless steel (obtained from a 24 gauge needle) that
were then inserted into a piece of 200
l micropipette tip 7-mm-long and
glued to it. The fiber was covered with a thin layer of epoxy glue except
for the dialyzing part. The probe was left to dry for 24 hr (Di Chiara
1990).
Surgery and e xperiments. Rats were anesthetized with ketamine (Keta-
lar; Parke-Davis, Milan, Italy), placed in a stereotaxic apparatus. The
skull was exposed, and a small hole was drilled on one side. The probe
Received Dec. 6, 1999; revised Aug. 1, 2000; accepted Aug. 2, 2000.
This work has been supported by the Ministero dell’Universita´ e della Ricerca
Scientifica e Tecnologica 60 and 40%.
Correspondence should be addressed to Dr. Ezio Carboni, Department of Tox-
icology, Viale Diaz 182, 09126 Cagliari, Italy. E-mail: ecarboni@unica.it.
Copyright © 2000 Society for Neuroscience 0270-6474/00/200001-05$15.00/0
This article is published in T he Journal of Neuroscience, Rapid
Communications Section, which publishes brief, peer-
reviewed papers online, not in print. Rapid Communications
are posted online approximately one month earlier than they
would appear if printed. They are listed in the Table of
Contents of the next open issue of JNeurosci. Cite this article
as: JNeurosci, 2000, 20:RC102 (1–5). The publication date is
the date of posting online at www.jneurosci.org.
http://www.jneurosci.org/cgi/content/full/4614
The Journal of Neuroscience, 2000, Vol. 20 RC102 1of5
was implanted vertically in the BNST [anterior (A), ⫺0.5; lateral (L), 1.3;
vertical (V), ⫺8.0, from the dura], according to the atlas of Paxinos and
Watson (1987), and then fixed on the skull with dental cement. Some rats
were implanted 1 mm lateral or 1.2 mm anterior to the BNST site. Rats
were housed in a transparent plastic (Plexiglas) hemisphere, closed with
a top hemisphere, with food and water available ad libitum.
Experiments were performed on freely moving rats 24 hr after probe
implant. Ringer’s solution (147 mM, NaCl; 2.2 mM CaCl
2
;4mM KCl) was
pumped through the dialysis probe at constant rate of 1
l/min. Samples
were taken every 20 min and analyzed.
Figure 1 shows the position of the dialyzing part of the fiber in a
schematic representation of a frontal section of the rat brain at the level
of BNST (A, ⫺0.3 mm) redrawn from Paxinos and Watson (1987).
Probes implanted 1 mm lateral to the BNST had fibers located in the
globus pallidus, whereas probes implanted 1.2 mm anterior to the BNST
had fibers located in the caudal NAc shell. All animal experimentation
has been conducted in accordance with the guidelines for care and use of
experimental animals of the European Economic Community (86/809;
DL 27.01.92 number 116).
Analytical procedure. Dialysate samples (20
l) were injected without
any purification into an HPLC apparatus equipped with reverse-phase
column (LC-18 DB; Supelco) and a coulometric detector (ESA Coulo-
chem II, Bedford, MA) to quantitate DA. The first electrode was set at
⫹130 mV and the second electrode at ⫺125 mV). The composition of the
mobile phase was: 50 m
M Na H
2
PO
4
/5 mM Na
2
HPO
4
, 0.1 mM Na
2
EDTA,
0.5 mM octyl sodium sulfate, and 15% (v/v) methanol, pH 5.5. The mobil
phase was pumped with an LKB-Wallac (Gaithersburg, MD) 2150 pump
at a flow rate of 1.0 ml/min. The sensitivity of the assay allowed to detect
5 fmol of DA.
Histology. At the end of the experiment, rats were anesthetized and
transcardially perfused with 100 ml of saline (0.9% NaCl) and 100 ml of
formaldehyde (10%). The probes were removed, and brains were cut on
a Vibratome in serial coronal slices oriented according the atlas of
Paxinos and Watson (1987). The lateral margin of the anterior commis-
sure and the internal capsule were taken as reference structures to
identify the BNST. Results from rats implanted outside the BNST were
discarded.
Drugs. Nicotine tartrate, morphine HCl, and cocaine HCl were ob-
tained from Sigma (Milano, Italy), ethanol by Carlo Erba, and GBR
12909 was a gift from by Novo A/S (Bagsveerd, Denmark).
Statistics. Statistical analysis was performed by Statistica (Statsoft).
Two-way ANOVA for repeated measures was applied to the data ex-
pressed as percentage of basal DA concentration obtained from the serial
assays of DA after each treatment. Results from treatments showing
significant overall changes were subjected to post hoc Tukey test with
significance for p ⬍ 0.05. Basal values were the means of three consec-
utive samples differing ⬍10%. Each implanted rat was challenged with a
single dose of the test drug only once.
RESULTS
Basal values of DA in the BNST were 15.8 ⫾ 0.9 fmol/20
l
sample (mean ⫾ SEM; n ⫽ 71). As shown in Figure 1 probes were
localized mostly in the lateral part of the BNST.
A significant increase of dialysate DA (expressed as percentage
above basal values) was elicited by the following drugs of abuse:
cocaine (Fig. 2A) [2.5 mg/kg, i.p. (max ⫹ 62%) and 5.0 mg/kg,
i.p. (max ⫹ 129%)], morphine (Fig. 3A) [0.5 mg/kg, s.c. (max ⫹
76%) and 1.0 mg/kg, s.c. (max ⫹ 141%)]; nicotine (Fig. 3B) [0.1
mg/kg, s.c. (max ⫹ 85%) and 0.4 mg/kg, s.c. (max ⫹ 190%)];
ethanol (Fig. 3C) [0.25 gm/kg, i.p. (max ⫹ 58%) and 0.5 gm/kg,
i.p. (max ⫹ 111%)]. The specific DA reuptake inhibitor GBR
12909 (Fig. 2B) elicited an increase of DA dialysate [5.0 mg/kg,
Figure 1. Schematic representation of a frontal section (top drawing) and
horizontal section (bottom drawing) of rat brain at A, ⫺0.3 mm and V, 6.6
from bregma, respectively, according to the atlas of Paxinos and Watson
(1982). In the frontal section the position of the dialyzing part of the fiber
is illustrated approximately as observed in one frontal section at the level
of the central part of the BNST. ac, Anterior commissure; Acb, accum-
bens nucleus; BSTL, bed nucleus stria terminalis lateralis; BSTM, bed
nucleus stria terminalis medialis; Cpu, caudate putamen; DpMe, deep
mesencephalic nucleus; FrPaM, frontoparietal cortex, motor area; FrPaSS,
frontoparietal area, somatosensory area; GP, globus pallidus; HDB, nu-
cleus horizontal limb diagonal band; LPO, lateral preoptic area; VP,
ventral pallidum; V PL, ventroposterior thalamic nucleus lateralis; VPM,
ventroposterior thalamic nucleus medialis.
Figure 2. Effect of cocaine at 2.5 and 5 mg/kg (as HCl salt), intraperi-
toneally ( A) and of GBR 12909 at 5 and 10 mg/kg, intraperitoneally (B)
on dopamine concentration in dialysate obtained by in vivo microdialysis
from the BNST. Each point is the mean (⫾ SEM) of at least four
determinations. Filled symbols: p ⬍ 0.05 from basal values concentration;
*p ⬍ 0.05 from the correspondent time point of vehicle group.
2of5 J. Neurosci., 2000, Vol. 20 Carboni et al. • Addictive Drugs on Bed Nucleus Dopamine
i.p. (max ⫹ 112%) and 10 mg/kg, i.p. (max ⫹ 161%)]. Two-way
ANOVA of the results obtained by the different doses of the
above listed drugs showed a significant effect of dose and signif-
icant dose ⫻ time interaction for cocaine (main effect: F
(2,12)
⫽
4.11, p ⬍ 0.05; interaction: F
(12,72)
⫽ 4.19, p ⬍ 0.001), nicotine
(main effect: F
(3,17)
⫽ 14.19, p ⬍ 0.001; interaction: F
(18,102)
⫽
4.51, p ⬍ 0.001), morphine (main effect: F
(2,16)
⫽ 5.9, p ⬍ 0.05;
interaction: F
(16,128)
⫽ 1.85, p ⬍ 0.05), ethanol (main effect: F
(2,13)
⫽ 11.17, p ⬍ 0.005; interaction: F
(12,78)
⫽ 3.16, p ⬍ 0.005) and
GBR 12909 (main effect: F
(2,9)
⫽ 8.42, p ⬍ 0.01; interaction:
F
(18,81)
⫽ 7.13, p ⬍ 0.001). When the microdialysis probe was
implanted in the globus pallidus (1 mm lateral to the BNST) basal
values of DA were 90.75 ⫾ 9.35 fmol/20
l sample (mean ⫾ SEM;
n ⫽ 8). Challenge with 0.4 mg/kg of nicotine produced a nonsig-
nificant increase of dialysate DA by 18% above basal (main effect:
F
(1,6)
⫽ 0.86, p ⫽ 0.38; interaction: F
(6,36)
⫽ 1.57, p ⫽ 0.18 (data
not shown). When the microdialysis probe was implanted in the
caudal NAc (1.2 mm rostral to the BNST site), basal values of DA
were 75.63 ⫾ 11.40 fmol/20
l sample (mean ⫾ SEM; n ⫽ 8).
Challenge with 0.4 mg/kg of nicotine maximally increased DA in
dialysate by 78% above basal (main effect: F
(1,6)
⫽ 25.83, p ⬍
0.002; interaction: F
(6,36)
⫽ 11.51, p ⬍ 0.0001) (data not shown).
DISCUSSION
This study shows that reinforcing drugs like nicotine, morphine,
ethanol, and cocaine increase dialysate DA in the BNST. This
effect is shared by the selective DA reuptake inhibitor GBR
12909, which is self-administered by rats (Roberts, 1993; Tella et
al., 1996) and by monkeys (Villemagne et al., 1999).
Topographic specificity of drug effect
The BNST is surrounded by DA-rich areas both laterally (caudate
putamen/globus pallidus) and cranially (NAc shell). In view of
this, one could argue that the changes induced by the drugs do not
arise from the BNST itself but are the result of DA diffusion from
adjacent areas. This possibility however is unlikely for a number
of reasons: first, the time course of drug-induced changes of
dialysate DA in the BNST does not provide any indication (e.g.,
delayed and attenuated changes) of the above mechanism. To the
contrary, drug-induced changes in BNST DA are sharper than in
the NAc shell; second, as shown by the effect of nicotine at sites
located cranially or laterally to the BNST, the changes in dialysate
DA are specific to the implanted area being independent from
basal dialysate DA. Thus, in spite of the similarity in the basal
levels of DA, the laterally located globus pallidus does not re-
spond to nicotine, whereas the cranially located NAc shell re-
sponds, although less than the BNST, to nicotine. Finally, the
diffusion coefficient of DA in brain tissue is such that at a distance
of 0.7 mm from the dialysis membrane the amount of DA recov-
ered by the dialysis probe has been found to be negligible (Rice
et al., 1985; Nicholson and Rice, 1986). In DA-rich areas, such as
the NAc shell the presence of an efficient DA reuptake should
further reduce the already limited diffusion of DA in brain tissue.
This is further demonstrated by the fact that clear-cut differences
in the effect of drugs of abuse can be obtained within the NAc
itself between medial and lateral locations 1 mm apart (Pontieri
et al., 1996; Tanda et al., 1997b). These observations and consid-
erations exclude that the changes recorded in the BNST are the
result of diffusion of DA from the adjacent NAc shell.
Mechanism of drug effects
The mechanism by which reinforcing drugs increased DA in the
BNST is likely to be different depending on the drug class to
which they belong.
Cocaine and GBR 12909
Cocaine-induced increase of dialysate DA in the BNST is most
likely because of blockade of DA carrier. Consistent with this
mechanism is the observation that the specific DA reuptake
inhibitor GBR 12909 also increased DA in this area. We have
previously reported (Carboni et al., 1990; Tanda et al., 1997a)
that, in contrast with cocaine, GBR 12909 does not increase DA
output in the prefrontal cortex (PfCx); on the contrary, the
norepinephrine (NE) reuptake inhibitor desipramine (DMI) is
highly effective in raising the dialysate DA in the PfCx but not in
the NAc. These data suggest that in an area in which NE trans-
mission is strongly represented DA could be taken up NE termi-
nals. In the BNST NE terminals are located in the medial rather
than in the lateral part (Moore, 1978; Phelix et al., 1992). There-
fore in the lateral part of BNST, where probes were mostly
Figure 3. Effect of morphine (A) at 0.5 and 1 mg/kg (as HCl salt) subcutaneously, nicotine (B) at 0.05, 0.1, and 0.4 mg/kg (as free base) subcutaneously,
and ethanol (C) at 0.25 and 0.5 gm/kg (injected as 10% v/v solution) intraperitoneally on dopamine concentration in dialysate obtained by in vivo
microdialysis from the BNST. Each point is the mean (⫾ SEM) of at least four determinations. Filled symbols: p ⬍ 0.05 from basal values concentration;
*p ⬍ 0.05 from the correspondent time point of vehicle group.
Carboni et al. • Addictive Drugs on Bed Nucleus Dopamine J. Neurosci., 2000, Vol. 20 3of5
located, the extent of DA uptake by NE terminals should be
minimal. This explains the effectiveness of GBR 12909 and the
failure of DMI (data not shown) in raising DA in the BNST. An
increase of DA in the BNST might play a role in the reinforcing
properties of cocaine. This view is supported by the observation
that bilateral intracranial injections of the D
1
receptor antagonist
SCH 23390 into the lateral BNST partially attenuates the rein-
forcing effects of cocaine under a fixed-ratio schedule (Epping-
Jordan et al., 1998). This observation is in turn consistent with the
high level of DARP 32 in BNST (Shalling et al., 1990), a protein
associated with neurons expressing D
1
receptors.
Morphine
The present observation that morphine potently and dose-
dependently increased DA output in the BNST further supports
the strict relationship between DA and the reinforcing properties
of opioids (Johnson and North, 1992; Di Chiara, 1995). An
involvement of BNST in the mechanism of action of opioids is
suggested by the observation that naltrexone precipitated opiate
withdrawal is associated with an increase in the early gene FOS in
the ventral and dorsolateral region of BNST where DA innerva-
tion is more dense (Aston-Jones et al., 1999).
Nicotine
The systemic administration of nicotine effectively and dose de-
pendently increased dialysate DA in the BNST. This effect is
likely to be because of stimulation of DA neurons that from the
VTA project to both the NAc shell and the BNST (Mereu et al.,
1987; Pidoplicko et al., 1997) and through presynaptic nicotine
receptors on DA terminals (Marshall et al., 1997; Wonnacott,
1997).
Ethanol
Ethanol increased in a dose-dependent manner DA output in the
BNST. By analogy with the ethanol-induced increase of DA in the
NAc (Imperato and Di Chiara, 1988) also the effect in the BNST
is likely to be the result of stimulation of the firing of VTA
neurons (Gessa et al., 1985). On the other hand a possible
involvement of GABAergic transmission of the BNST has been
suggested by Hyytia and Koob (1995) on the basis of the obser-
vation that injection of the competitive GABA
A
receptor antag-
onist SR 95531 into the BNST as well as into the NAc shell and
in the central amygdala reduced ethanol responding in a two-
lever free choice operant task. Recently Davis and Shi (1999)
showed that local injection of the glutamate antagonist NBQX
into the BNST significantly decreased light-enhanced startle re-
flex, suggesting that BNST plays a role in anxiety. As ethanol is
known to have antianxiety effects one might speculate that DA in
the BNST may play a role in this effect; in fact, the BNST is rich
of D2 receptors, which might be located in glutamate terminals
where they could inhibit glutamate release by analogy with their
action in the caudate putamen (Morari et al., 1998).
Conclusions
The results presented here indicate that cocaine, morphine, nic-
otine, and ethanol share the property of increasing DA transmis-
sion in the BNST. This effect may be related to an action at the
level of neuronal circuits activated by natural reinforcers like food
and sexual activity where DA might play an active role (Du et al.,
1998; Meredith et al., 1998).
The present observation together with the results of local
infusion studies (Epping-Jordan et al., 1998) suggest that DA
transmission of the BNST plays a role in the mechanism of drug
abuse and addiction. From a more general point of view, the
observation that an area such as the BNST that has been included
in the extended amygdala shares with the NAc shell, which is
considered a transition area between the extended amygdala and
the striatum, the sensitivity to drugs of abuse, is consistent with
the notion of the existence of strict homologies between the shell
of the NAc and the extended amygdala as far as concerns their
role in emotional and motivational functions.
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