responding for brain stimulation reward (bsr) in the bed nucleus of the stria terminal is (bst) in...
TRANSCRIPT
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 1/13
Responding for Brain Stimulation Reward
in the Bed Nucleus of the Stria Terminalisin Alcohol-Preferring Rats Following Alcohol and Amphetamine Pretreatments
WILLIAM J.A. EILER, II,1 LATHEN HARDY, III,1 JOSUHA GOERGEN,1 REGAT SEYOUM,1
BOIKAI MENSAH-ZOE,1 AND HARRY L. JUNE2,3*1 Psychobiology of Addictions Program, Department of Psychology, Indiana University-Purdue University,
Indianapolis, Indiana 462022 Division of Alcohol and Drug Abuse, Department of Psychiatry, University of Maryland School of Medicine,
Baltimore, Maryland 212013 Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine,
Baltimore, Maryland 21201
KEY WORDS brain stimulation reward (BSR); alcohol preferring (P) and non-pre-ferring (NP) rats; alcohol; amphetamine; SCH 23390
ABSTRACT The bed nucleus of the stria terminalis (BNST) has been reported to
release increased levels of extracellular dopamine (DA) following the systemic admin-
istration of abused drugs in outbred rats. This study examined the BNST as a novel
locus for supporting operant responding for brain stimulation reward (BSR) in rats
bred for alcohol preference while determining any potentiating effects of ethanol
(EtOH) (0.125–1.25 g/kg, i.p.) and amphetamine (0.25–1.60 mg/kg, i.p.) on BSR within
the BNST. Also examined was the capability of D1 receptor blockade to attenuate any
observed potentiation. Following surgical implantation, alcohol-preferring (P) and non-
preferring (NP) rats responded to a range of descending frequencies (300–20 Hz) as
evaluated by a rate-frequency paradigm. The results revealed that the BNST was
capable of supporting BSR in P but not NP rats. Also, amphetamine pretreatment pro-
duced a significant leftward shift in the rate-frequency function in P rats with signifi-cant reductions observed in three other measures of reward threshold, while EtOH
only lowered the minimum frequency needed to produce responding. The effects of sys-
temic amphetamine were successfully attenuated by the unilateral infusion of the D1
receptor antagonist SCH 23390 (5.0 mg) into the contralateral nucleus accumbens. The
results suggest the BNST is capable of supporting BSR performance in P, but not NP
rats, possibly due to increased sensitivity to the electrical stimulation-induced DA
release of BSR in the innately DA ‘‘deficient’’ limbic system of P rats. Synapse
61:912–924, 2007. VVC 2007 Wiley-Liss, Inc.
INTRODUCTION
It is suggested that individuals that self-administer
drugs of abuse may be sensitive not only to a singledrug or reinforcer, but to multiple types of rein-
forcers. Thus, it is believed that individuals that
habitually use drugs of abuse posses an increased
abuse liability, or the increased likelihood to abuse
any drug type. One method used to evaluate the rein-
forcing potential of various drugs is brain stimulation
reward (BSR) (Lewis, 1993). BSR is often referred to,
and now accepted as a model of drug-induced eupho-
ria (Kornetsky and Bain, 1990; Lewis, 1993). While
other neurotransmitter systems are likely involved,
many studies have established that the rewarding
effects of BSR may depend on the ability of the brain
stimulation to activate the mesocorticolimbic dopa-
mine (DA) system (Lewis, 1993; Wise, 1996). BSR canbe used to discreetly activate brain substrates within
Contract grant sponsor: National Institute of Alcohol Abuse and Alcoholism(NIAAA); Contract grant numbers: AA10406, AA11555; Contract grant spon-sor: National Institute of General Medical Science (NIGMS); Contract grantnumbers: AA10422, GM47818; Contract grant sponsor: National Heart, Lung,and Blood Institute, NIH; Contract grant number: T35M.
*Correspondence to: Harry L. June, Division of Alcohol and Drug Abuse,Department of Psychiatry, University of Maryland School of Medicine, 701West Pratt Street, Rm 597, Baltimore, MD 21201, USA.E-mail: [email protected]
Received 17 August 2003; Accepted 29 March 2007
DOI 10.1002/syn.20437
Published online in Wiley InterScience (www.interscience.wiley.com).
VVC 2007 WILEY-LISS, INC.
SYNAPSE 61:912–924 (2007)
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 2/13
the reward circuitry as opposed to a more systemic
activation by other paradigms used to measure the
reinforcing properties of drugs (e.g., conditioned place
preference, drug discrimination, i.v. drug infusion)
(Phillips and Fibiger, 1989; Stellar and Stellar, 1985).
Another positive feature of the BSR paradigm is thatdose-response functions similar to those seen in tradi-
tional pharmacological studies can be obtained by the
use of the curve-shift paradigm in which the stimula-
tion frequency or current intensity can be systemati-
cally varied (Kling-Petersen and Svensson, 1993;
Liebman 1983; Wise and Rompre, 1989; Wise, 1996).
While a number of drugs have been evaluated
using the BSR paradigm, amphetamine has been
reported to be the most reliable drug to facilitate BSR
performance. Amphetamine consistently produces
leftward shifts in the rate frequency function and also
lowers BSR threshold while enhancing lever-press
responding (for review see Schaefer and Michael,
1987; Wise, 1996). Less consistent, however, are the
reports investigating alcohol’s effects on BSR perform-
ance (Bain and Kornetsky, 1989; Lewis and June,
1990; Moolten and Kornetsky, 1990; Schaefer and
Michael, 1987, 1992). While a clear explanation for
the varied effects of alcohol is yet to emerge, Lewis
(1993) has suggested route of administration, time of
testing following administration, and the various
threshold determination methods as likely contribut-
ing factors in these discrepancies. The choice of which
substrate within the mesolimbic DA system to place
the stimulating electrode may also contribute to these
inconsistencies. For this study, we evaluated the bed
nucleus of the stria terminalis (BNST) which repre-sents a novel locus for the BSR paradigm, but has
been shown to function as a neurobiological substrate
for the reinforcing actions of alcohol as well as psy-
chostimulants (Day et al., 2001; Eiler et al., 2003;
Koob, 1999; Leshner and Koob, 1999).
The BNST, a component of the mesolimbic reward
system, receives a number of afferent and efferent
connections from putative drug reward areas as
depicted in Figure 1 (Alheid and Heimer, 1988; Alheid
et al., 1995; Eiler et al., 2003). Of particular interest
is that DA neurons from the ventral tegmental area
(VTA) project directly to the BNST, in a manner anal-
ogous to the nucleus accumbens (NAC) and ventralpallidum both of which have been shown to support
BSR (Mogenson et al., 1979; Panagis et al., 1997).
Figure 1 also illustrates the number of GABAergic
afferents and efferents between the BNST and
numerous limbic structures. The GABA and DA sys-
tems within the BNST have emerged as pivotal neu-
ronal systems in regulating the reinforcing properties
of alcohol and psychostimulants (Carboni et al., 2000;
Eiler et al., 2003; Epping-Jordan et al., 1998; Hyytia
and Koob, 1995) with evidence emerging that GABA
may indirectly regulate DA by modulating the rein-
forcing/activational effects of psychostimulants
(Austin and Kalivas, 1990; Gong et al., 1997) and
alcohol (Harvey et al., 2002; Hodge et al., 1995; June
et al., 2001).
To further examine the role of abuse liability, we
chose to use subjects selectively bred for alcohol pref-
erence. While several rat lines have been developed
through selective breeding to produce high and low
alcohol drinking variants with the alcohol perferring/
nonperferring (P/NP) lines most widely used andstudied (Cloninger, 1987; McBride and Li, 1998; Mur-
phy et al., 2002). The P rat is particularly useful as
an animal model as it fulfills all criteria (for review
see Cicero, 1979; Lester and Freed, 1973) to accept-
ably model human alcoholism to the satisfaction of
the alcohol research community (McBride and Li,
1998; Murphy et al., 2002). While its utility in study-
ing alcoholism is clear, the P rat may also be useful
in making inferences to the reinforcing potential (i.e.,
abuse liability) of drugs other than alcohol, specifi-
cally the psychostimulant amphetamine.
The purpose of the present study was to determine
if the BNST could be used in a manner analogous toother putative reward loci, as a novel locus to support
lever-press responding contingent on direct electrical
stimulation in rats selectively bred to consume alco-
hol (Phillips and Fibiger, 1989; Stellar and Stellar,
1985) To accomplish this, we employed a BSR para-
digm utilizing the curve-shift model coupled with an
array of parameters to assess BSR performance. Sec-
ondly we attempted to determine if reward potentiat-
ing effects of alcohol and amphetamine could be
observed on BSR within the BNST of P and NP rats.
The final purpose was to determine if the D1 DA
Fig. 1. Schematic illustration of the interrelationship of dopami-nergic and GABAergic inputs and outputs and their connectivitybetween the VTA via the medial forebrain bundle (MFB)/lateral
hypothalamus (LH) to the bed nucleus of the stria terminalis(BNST) and other extended amygdala loci.
913BSR IN BNST OF P RATS FOLLOWING EtOH AND A mp
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 3/13
receptor played a role in regulating the BSR potenti-
ating effects of amphetamine.
MATERIALS AND METHODS
Subjects
Male P rats (n ¼ 10) and NP rats (n ¼ 9) of the S50generation (Indiana University, Indianapolis, IN)
weighing between 410 and 546 g at the time of test-
ing were used as subjects. The animals were individu-
ally housed in shoebox cages in a temperature and
humidity controlled room with food and water avail-
able ad libitum. Behavioral training took place
between 9 a.m. and 3 p.m. All experimental proce-
dures were conducted in strict compliance with the
NIH Guide for the Care and Use of Laboratory Ani-
mals.
Stereotaxic surgery
Rats were anesthetized with sodium pentobarbital
(45 mg/kg, i.p.) and placed in a stereotaxic apparatus.
The animals were then implanted with platinum elec-
trodes with a diameter of 0.3 mm (Plastics One, Roa-
noke, VA) into the bed nucleus of the stria terminalis
(BNST) of the left hemisphere. The Teflon insulated
electrode was fixed to the skull with stainless steel
screws and dental acrylic. Animals were also concur-
rently implanted with a contralateral 22-gauge guide
cannula in the NAC within the right hemisphere. In
relation to bregma, the coordinates for the BNST
were as follows: AP À0.5, ML 62.5, DV À7.6, with an
8.78 lateral angle from the skull. The coordinates for
the NAC were as follows: AP +1.4; ML 61.0; DV –6.0
from the skull. The cannulas were aimed 1 mm above
the intended brain loci. A stylet which protruded
1 mm beyond the tip of the guide cannulae was
inserted when the injector was not in place. All coor-
dinates were made using the rat brain atlas of Paxi-
nos and Watson (1998).
Histology
After the completion of all experimental procedures,
the rats were sacrificed via CO2 inhalation. The loca-
tion of the electrode was immediately lesioned by an
isolated physiological stimulator [Model A13-65](Coulbourn Instruments, Allentown, PA) using three-
3 s, 4 milliamphere bursts with a 1 s separation
between bursts. Next, to identify the guide cannulae
location within the NAC, cresyl violet acetate (0.50
ml) was injected into the infusion site, and the brains
were removed and frozen. Subsequently, histological
evaluations were performed to determine the place-
ment of the electrodes. Once the brains were sec-
tioned on a microtone at 50 mm and placed on slides
they were stained with cresyl violet acetate. The sec-
tions were examined under a light microscope with
lesions and cannula placements indicated on draw-
ings adapted from the rat brain atlas of Paxinos and
Watson (1998).
Behavioral apparatus
Behavioral training and testing were conducted in
10 standard operant chambers (Coulbourn Instru-
ments, Allentown, PA) equipped with a removable
lever enclosed in a sound attenuating cubicle. Each
lever press triggered an electrical pulse of a given
current intensity supplied by an isolated physiological
stimulator [Model A13-65] (Coulbourn Instruments,
Allentown, PA). The stimulation was a 0.2 s train of
100 Hz biphasic rectangular pulses of 1.0 ms duration
similar to our previous research (Lewis and June,
1990). Responses and reinforcements were controlled
and recorded during a 20 min operant session by PC
computers using the Jay-Shake-Li ICSS operant soft-
ware program (Shake-Li and Huston, 2002).
Behavioral training
After surgical implantation, the BSR group was
trained to respond to electrical stimulation under an
FR1 schedule of reinforcement. This was accom-
plished through shaping via successive approxima-
tion. During this training phase the current of the
electrical stimulus was varied to determine the cur-
rent for each rat that evoked optimal responding. The
rats continued to respond for electrical stimulation at
their optimal current, or the current level that main-
tained the highest level of responding (50–350 m A)until their responding stabilized. For this study, stabi-
lization is defined as daily responses within 620% of
the average responses for 5 consecutive days.
BSR parameters
The BSR model and calculation of BSR parameters
used in the present study are based on the earlier
work by Kling-Petersen and Svensson (1993) and
emulates the experimental paradigm employed by
Shake-Li and Huston (2002). Four dependent varia-
bles were collected for the present study: (1) the
frequency that corresponds with 50% of responding,often referred to as EF50 or half maximal frequency/
responding, (2) the minimum/lowest frequency capa-
ble of maintaining BSR, (3) the maximum frequency
producing the highest rate of lever pressing through-
out the BSR session, and (4) total number of lever
presses (i.e., responses) produced during the 20 min
session. The first three variables are used to deter-
mine the BSR threshold (Kling-Petersen and Svens-
son 1993; Shake-Li and Huston, 2002). It is these
variables that produce the curve shift that is indica-
tive of a change in threshold (Lewis, 1993; Stellar
914 W.J.A. EILER ET AL.
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 4/13
and Stellar 1985; Wise, 1989). The final two variables
are important in the formation of the asymptote of
the rate/frequency curve. The asymptote is an essen-
tial component of BSR analysis, as it indicates
whether or not an experimental manipulation pro-
duces a motoric effect (Lewis 1993; Miliaressis et al.1986; Stellar and Stellar, 1985). A motor enhance-
ment due to an experimental manipulation is mani-
fested by an increase in the asymptote relative to con-
trol levels, whereas a decrease in the asymptote indi-
cate a reduction in motor capacity (Stellar and
Stellar, 1985; Wise, 1989) All data were collected
using the ICSS computer program developed by
Shake-Li and Huston (2002).
Experiment 1: examination of basal sensitivity
to the reinforcing effect of BSR in P and
NP rats following EtOH or
amphetamine pretreatment
The animals ( P ¼ 10, NP ¼ 9) were initially trained
to bar press under an FR1 schedule of reinforcement
at a current level of 100 l A employing a frequency of
100 Hz. which produced sustained lever pressing at
100 l A. This current level was determined to be the
optimal current for BSR performance. After the ani-
mals had established a consistent level of responding,
the current level was adjusted for each animal to
reach a maximal level of lever press responding. This
current was operationally defined as the optimal cur-
rent (100%) level. For the P rats, this current level
ranged from 250 to 150 l A, while in the NP rats it
ranged from 300 to 200 l A. After animals were stabi-lized on the optimal current under an FR1 schedule,
the current was set to 50% of the animals optimal
current level, since it has been suggested that the
current level that produces the maximal level of
responses may not be the preferred (i.e., efficacious)
for the rats, or most sensitive to the drug treatments
(Stellar and Stellar, 1985; Lewis, 1993). Further, as
noted earlier, submaximal current levels produce sub-
maximal response rates and may be more indicative
of the rewarding efficacy of the stimulation (Liebman,
1983). The rate/frequency function was then gener-
ated by presenting a series of frequencies in a de-
scending manner from 300 to 20 Hz: (i.e., 300, 260,220, 180, 140, 100, 80, 60, 40, and 20 Hz). The rate/
frequency function was generated over session time of
20 min and 30 s. Three, 1 s priming pulses were
presented prior to each tested frequency.
After responding was stabilized animals were given
1 of 4 doses (0.125, 0.35, 0.75, 1.25 g/kg i.p.) of etha-
nol (EtOH) (10% w/v), or 1 of 4 doses (0.25, 0.75, 1.25,
1.60 mg/kg i.p.) of amphetamine 5 min before the
BSR session. A minimum of 3 and a maximum of 4
days of no testing separated each EtOH and ampheta-
mine drug dose administration. Twenty-four hours
post drug administration, we examined the effects of
all drug treatments to determine residual drug
effects. All rats received the same dose of EtOH or
amphetamine on the same day and the doses were
administered in random order using a random num-
ber generator.
Experiment 2: effect of SCH 23390 on the basal
sensitivity to the reinforcing effect of BSR in P
rats following amphetamine pretreatment
SCH 23390 was mixed prior to each infusion. The
drugs were mixed into 0.25 ml of sterile saline. The
SCH 23390 was then unilaterally infused into
the NAC at a rate of 0.1 ml/min for 2.5 min using a
Harvard infusion pump. The injector tip was left in
the cannula for an additional minute to facilitate the
diffusion of all injected drug from the injector tip into
the brain loci. The animals were then either placed
into the operant chamber or given an i.p. injection of 0.75 mg/kg of amphetamine and then placed in the
operant chamber 5 min following the injection. After
the rats received the initial infusion, subsequent infu-
sions were not performed until responding returned
to baseline.
Drug preparation
EtOH (95%) (AAPER Alcohol and Chemical, Shel-
byville, KY) was diluted with saline to produce 10%
(w/v) solution and injected at volumes sufficient to
produce 0.25–1.25 g/kg doses. d-Amphetamine was
dissolved in saline and injected in a volume of 1 ml/
kg. The SCH 23390 was mixed readily with sterile sa-line immediately before the experiments and was
injected unilaterally using a Harvard Pump. The d-
Amphetamine and SCH 23390 were purchased from
Sigma Drug Company (St. Louis, MO).
Data analysis
Separate repeated measures ANOVAs were used on
P and NP responding data, maximum frequency data,
minimum frequency data, and EF50 data separately
to further delineate within subject effects. A t-test
post hoc analysis was conducted on all significant
ANOVA’s.
RESULTS
Figures 2A and 2B show a reconstruction of serial
coronal sections of the rat brain illustrating the loca-
tion of the unilateral electrodes tip in the BNST of
the (A) P and (B) NP rats. The electrode tips were
well localized within the mediolateral to dorsolateral
BNST of both rat lines. Figure 2C illustrates a recon-
struction of serial coronal sections of the rat brain
depicting the location of the unilateral cannula im-
plantation in the NAC; the cannulae were located in
915BSR IN BNST OF P RATS FOLLOWING EtOH AND A mp
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 5/13
both the shell and core. Figure 3 depicts photomicro-
graphs of the actual unilateral placements in the
mediolateral and dorsolateral BNST for 3 P (A–C)
and 2 NP (D–E) rats following electrode lesioning.
Figures 3F and 3G depict the actual placements for 2
P rats in separate photomicrographs illustrating the
extent of the lesion sustained as a result of the uni-
lateral guide cannula in the NAC.
Experiment 1: examination of basal sensitivity
to the reinforcing effect of BSR in P and
NP rats following EtOH or
amphetamine pretreatment
Effects of EtOH on BSR performance
P rats. Figure 4A illustrates the rate of lever
pressing as a function of stimulation frequency in P
rats following EtOH administration (n ¼ 7). The rate-
frequency curves show that relative to placebo, the
amount of stimulation that sustained responding was
not changed at the lower frequencies with any of the
EtOH doses, but beginning at 150 Hz, a leftward shift
in the rate frequency function began to emerge forthe 0.75 and 1.25 g/kg doses. Figure 4B shows that
EtOH produced a dose-dependent reduction in mini-
mum frequency resulting in a significant effect of
dose [ F (4,24) ¼ 4.82, P < 0.01]. Minimum frequencies
ranged from 49 6 11 to 130 6 20 Hz. Post hoc analy-
ses determined that both the 0.75 ( P < 0.01) and 1.25
g/kg ( P < 0.02) doses significantly lowered minimum
frequency compared with placebo. Figure 4C shows
that none of the EtOH treatments altered the EF50
parameter relative to placebo resulting in a non-
significant effect of dose [ F (4,24) ¼ 0.88, P < 0.49].
Fig. 3. Representative histological photomicrographs of theactual unilateral placements in the mediolateral and dosolateralBNST for 3 alcohol-preferring (P) ( A–C) and 2 alcohol-nonpreferring(NP) (D–E) rats following electrode lesioning. Figures (F and G)depict the actual placements for 2 P rats in separate photomicro-graphs illustrating the extent of the lesion sustained as a result of the unilateral guide cannula in the NAC.
Fig. 2. Reconstruction of serial coronal sections of the rat brainsillustrating the location of the unilateral electrode’s tip in the bed
nucleus of the stria terminalis (BNST) of the ( A ) P (n ¼ 7) and (B)NP rats (n ¼ 6). C: Illustrates a reconstruction of serial coronal sec-tions of the P rat brains (n ¼ 7) depicting the location of the unilat-eral cannula implantation in the nucleus accumbens (NAC) (contra-lateral hemisphere). Each rat is represented by one solid black circlein all figures. Coronal sections are adapted from the rat brain atlasof Paxinos and Watson (1998).
916 W.J.A. EILER ET AL.
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 6/13
Figures 4D and 4E also show that EtOH did not sig-
nificantly alter total responding or maximal frequency
[F(4,24) ¼ 1.67, P < 0.19], [ F (4,24) ¼ 1.43, P < 0.25],
respectively.
NP rats. The rate-frequency curve for NP rats (n
¼ 6) following EtOH administration is illustrated in
Figure 5A. The plot illustrates the erratic perform-
ance of the NP line, clearly demonstrating the inabil-
ity of BSR to act as a sufficient stimulus to elicit sta-
ble behavior in this rat line. Panel B of Figure 5
depicts the failure of EtOH (0.35 or 1.25 g/kg) to al-
ter the minimum frequency needed to produce
responding [ F (2,10) ¼ 2.18, P > 0.05]. EtOH alsofailed to produce any effect on the maximum fre-
quency parameter [ F (2,10) ¼ 2.94, P > 0.05] as illus-
trated in Figure 5C. Figure 5D shows the effect of
the two tested doses of EtOH on the total lever-press
responding in NP rats. Of importance in this figure
is the low level of basal responding for BSR produced
by the NP rat line, a mere 7% of the number of
responses produced in the P line. As with the mini-
mum and maximum frequencies, EtOH failed to al-
ter the total number of responses [ F (2,10) ¼ 0.57, P
> 0.05]. It was impossible to calculate the EF50 in
these animals due to both the low levels of respond-
ing and the inconsistent response to the varying fre-
quencies.
Effects of amphetamine on BSR performance
P rats. Figure 6A illustrates the rate of lever
pressing as a function of stimulation frequency follow-
ing amphetamine treatments. The rate-frequency
curves show that relative to placebo, the amount of
stimulation that sustained responding was reduced
with all doses of amphetamine as indicated by left-
ward shifts in the rate frequency function. Figure 6Bshows that amphetamine produced a reduction in
minimum frequency resulting in a significant effect of
dose, with no further reductions being observed with
the 1.6 mg/kg dose relative to the 1.25 mg/kg dose
[ F (4,24) ¼ 2.85, P < 0.05]. Post hoc analyses con-
firmed that the 0.75–1.60 mg/kg doses significantly
lowered minimum frequency compared with placebo
( P 0.05). Figure 6C shows that amphetamine pro-
duced a reduction on the EF50 parameter relative to
placebo [ F (4,24) ¼ 5.45, P < 0.01]. However, similar
to the minimum frequency, no further reductions
Fig. 4. Rats were tested on a 300–20 Hzdescending frequency schedule, and at asubmaximal current intensity (50% opti-mal current) following i.p. administrationof EtOH (10% v/v) (0.0–1.25 g/kg) across a20 min operant session in P rats ( n ¼ 7).EtOH was administered 5 min prior tothe BSR session. A : BSR rate-frequencycurves. For clarity the standard error of measurements (SEM) are omitted on thisand subsequent rate frequency graphs.B: Minimum frequency. C: Effectivefrequency (EF50) [threshold parameter].D: Total responding. E: Maximal fre-quency. Bars represent the standard errorof measurements (SEM) in this and subse-quent figures. ** P < 0.01, * P < 0.05 fromplacebo control.
917BSR IN BNST OF P RATS FOLLOWING EtOH AND A mp
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 7/13
were observed with the 1.6 mg/kg dose relative to the
1.25 mg/kg dose; however, the 0.25–1.60 mg/kg doses
all significantly lowered the EF50 parameter com-
pared with placebo ( P 0.05). Figure 6D shows mean
total responding following the 4 doses of ampheta-
mine. Mean total responding ranged from 277 6 82 to
652 6 170. Amphetamine elevated responding with
all the tested doses relative to placebo; however, the
overall ANOVA failed to reach statistical significance[ F (4,24) ¼ 1.69, P ! 0.05]. While an analysis of var-
iance did not demonstrate significance, it is clear that
all tested doses of amphetamine trended toward a sig-
nificant increase in responding for BSR. Figure 6E
shows that amphetamine produced reductions on the
maximum frequency measure with all tested doses,
resulting in a significant effect of doses [ F (4,24) ¼
2.89, P < 0.05]. Post hoc analyses confirmed that the
0.25–1.60 mg/kg doses significantly lowered the maxi-
mum frequency compared with placebo condition ( P <
0.05).
NP rats. Figure 7A illustrates the rate of lever
pressing as a function of stimulation frequency follow-ing amphetamine treatments in NP rat line (n ¼ 6)
and as with the EtOH condition this plot also demon-
strates the inability of BSR to act as a sufficient
stimulus to elicit stable behavior in this rat line even
following the administration of a potent psychostimu-
lant. Figure 7B shows that the 0.25 mg/kg dose of
amphetamine was sufficient ( P < 0.05) to alter the
minimum frequency needed to produce responding
[ F (2,10) ¼ 4.81, P < 0.05]. The 0.25 mg/kg dose of am-
phetamine also produced a significant ( P < 0.05)
effect on the maximum frequency parameter [ F (2,10)
¼ 4.54, P < 0.05] as illustrated in Figure 7C. Figure
7D shows the effect of the two tested doses of amphet-
amine on the total lever-press responding in NP rats.
As with EtOH, amphetamine failed to alter the total
number of responses [ F (2,10) ¼ 3.48, P > 0.05].
Again, the low levels of responding and the inconsis-
tent response to the varying frequencies made it
impossible to calculate the EF50 parameter in these
animals.
Experiment 2: effect of SCH 23390 on the basal
sensitivity to the reinforcing effect of BSR in P
rats following amphetamine pretreatment
Effects of SCH 23390 on BSR performance in
P rats with and without amphetamine
Figure 8A illustrates the rate of lever pressing as a
function of stimulation frequency following the con-
tralateral microinjection of SCH 23390 into the NAC.
None of the drug treatments reached statistical sig-
nificance on any of the BSR parameters (data notshown). Figure 8B illustrates the rate of lever press-
ing as a function of stimulation frequency with am-
phetamine and SCH 23390 alone, and the combina-
tion of SCH 23390 (5.0 mg) and amphetamine (0.75
mg/kg, i.p.). The SCH 23390 and the amphetamine
data are redrawn from Figures 6 and 8. The rate-
frequency curves show that when rats were microin-
jected with a 5.0 mg dose of SCH 23390 in the NAC it
attenuated the reinforcing efficacy of amphetamine,
as indicated by a rightward, albeit downward shift in
the rate/frequency function. Figure 8C shows that
Fig. 5. Rats were tested on a 300–20 Hz descending frequency schedule,and at a submaximal current intensity(50% optimal current) following i.p.administration of EtOH (10% v/v)(0.0–1.25 g/kg) across a 20 min oper-ant session in NP rats (n ¼ 6). EtOHwas administered 5 min prior to theBSR session. A : BSR rate-frequencycurves. B: Minimum frequency.C: Effective frequency (EF50) [thresh-
old parameter]. D: Total responding.E: Maximal frequency. ** P < 0.01, * P< 0.05 from placebo control.
918 W.J.A. EILER ET AL.
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 8/13
when the 5.0 mg dose of SCH 23390 was given imme-
diately prior to the 0.75 mg/kg amphetamine dose, it
significantly ( P < 0.05) attenuated the reduction on
the minimum frequency parameter. Given alone, con-
tralateral administration of the D1 antagonist was
without effect. These data profiles resulted in a signif-
icant ANOVA [ F (3,18) ¼ 3.22, P < 0.04]. Figure 8D
shows that when the 5.0 lg dose of SCH 23390 was
given immediately prior to amphetamine, it did
attenuate amphetamine’s reduction of the EF50
parameter, however; this effect was not significant
( P > 0.05). These data profiles resulted in a signifi-cant ANOVA [ F (3,18) ¼ 4.87, P 0.01]. Figure 8E
shows that when the 5.0 lg dose of SCH 23390 was
given immediately prior to the amphetamine it com-
pletely ( P < 0.01) reversed the marked amphetamine-
induced enhancement on lever-press responding.
Given alone, the D1 antagonist produced a reduction
on responding. These data profiles yielded a signifi-
cant main effect of drug treatment [ F (3,18) ¼ 11.77, P
0.01]. No significant effects were observed on the
maximum frequency measurement (Fig. 8F) with the
combination treatment.
DISCUSSION
The primary purpose of this study was to determine
the ability of the BNST to support BSR responding in
animals with a genetic predisposition to alcohol. To
accomplish this we tested an animal model of human
alcoholism, the P rat, and its contrasting counterpart,
the NP, utilizing a rate-frequency BSR paradigm to
evaluate the effects of EtOH and amphetamine on le-
ver-press responding contingent on direct electrical
stimulation of the BNST. We further investigated the
capacity of the D1 receptor antagonist SCH 23390
centrally administered into the contralateral NAC inreversing the potentiating effects of systemically
delivered amphetamine on BSR.
The initial finding of this study was that while the
P rat consistently lever-pressed for direct electrical
stimulation of the BNST, the NP rat line failed to
dependably respond to such stimulation producing
only one response per minute on average in contrast
to the $16 responses made by the P rats under the
same conditions. It is not surprising that the BNST
can support BSR responding as a number of neuro-
anatomical studies have demonstrated that reciprocal
Fig. 6. Rats were tested on a 300–20 Hzdescending frequency schedule, and at asubmaximal current intensity (50% opti-mal current) following i.p. administrationof amphetamine (0.0–1.60 mg/kg) across a20 min operant session in P rats ( n ¼ 7).
Amphetamine was administered 5 minprior to the BSR session. A : BSR rate-fre-quency curves. B: Minimum frequency. C:Effective frequency (EF50). D: Totalresponding. E: Maximal frequency. ** P <
0.01, * P < 0.05 from placebo control.
919BSR IN BNST OF P RATS FOLLOWING EtOH AND A mp
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 9/13
projections exist from the BNST to both the lateral
hypothalamus and the VTA (Eiler et al., 2003; Mac-
Donald, 1991; Sun and Cassell, 1993), two established
DA reward loci that have been demonstrated to regu-
late BSR (Phillips and Fibiger, 1989; Stellar and Stel-
lar, 1985). It is also important to note that the BNST
neurons have been shown to be antidromatically acti-
vated via stimulation of their efferent fibers in thehypothalamus (Dalsass and Siegel, 1987). Such evi-
dence makes the inability of the BNST to support
responding for electrical stimulation in the NP rat
line somewhat difficult to explain. One possible expla-
nation is the inherently deficient DA tone seen in the
P rat line (Murphy et al., 2002). It is conceivable that
this deficiency renders the P rat more sensitive to
increases in DA release in the terminal fields of the
mesolimbic pathway creating a more ‘‘rewarding’’
effect of such a DA release. Therefore, the NP rat line
may not be alone in its ability to support BNST BSR.
Such a hypothesis could be addressed by replicating
this study using outbred Wistar rats, the parentstrain of the P and NP lines, to determine if the
BNST can only support BSR responding in a DA defi-
cient limbic system as seen in the P rat line.
The second objective of this study was to evaluate
what effect, if any, EtOH and amphetamine may have
on the reward threshold of BSR in the BNST of the P
and NP rat lines. To determine the effect of EtOH on
lever-press responding for electrical stimulation of the
BNST, both rat lines were given EtOH systemically
just prior to BSR testing. Not surprisingly, EtOH pre-
treatment had no effect on BSR in NP animals.
EtOH, however, was able to alter one parameter of
reward threshold in the P rat line. Both the 0.75 and
1.25 g/kg doses of EtOH were sufficient to reduce the
minimum frequency needed to elicit responding with
no effects seen in the other threshold parameters. As
discussed in the introduction, many conflicting
reports exist in the literature in relation to facilita-
tion of BSR performance following alcohol administra-tion (Bain and Kornetsky, 1989; Lewis and June,
1990; Moolten and Kornetsky, 1990; Schaefer and Mi-
chael, 1987, 1992). Lewis and June (1990, 1994)
showed that reward threshold was consistently low-
ered with i.p. administration of alcohol in doses of
0.25–0.75 g/kg with stimulating lateral hypothalamic
(LH) electrodes, but not mesencephalic ventral norad-
renergic bundle (VNB) sites. Kornetsky and his
colleagues (Bain and Kornetsky, 1989; Moolten and
Kornetsky, 1990) reported that oral alcohol self-
administration (i.e., subject administered) lowered
reward threshold when the lateral hypothalamic
region of the MFB was stimulated; however, i.p. (ex-perimenter administered) alcohol was ineffective. In
agreement with Kornetsky and his colleagues, Schae-
fer and Michael (1987, 1992) have consistently failed
to observe a threshold lowering effect with i.p. or
intragastrically administered alcohol. The findings of
this study suggest that even within the BNST, alcohol
is a less potent reinforcer when compared with other
drugs of abuse. A recent microdialysis study by Car-
boni et al. (2000) appears to support this hypothesis
by demonstrating that, within the BNST, the
enhancement of extracellular DA release by morphine
Fig. 7. Rats were tested on a300–20 Hz descending frequencyschedule, and at a submaximal cur-rent intensity (50% optimal cur-rent) following i.p. administrationof amphetamine (0.0–1.60 mg/kg)across a 20 min operant session inNP rats (n ¼ 6). Amphetamine wasadministered 5 min prior to theBSR session. A : BSR rate-frequency
curves. B: Minimum frequency.C: Effective frequency (EF50). D: Totalresponding. E: Maximal frequency.** P < 0.01, * P < 0.05 from placebocontrol.
920 W.J.A. EILER ET AL.
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 10/13
and cocaine was far greater than seen with alcohol.
Therefore, it is possible that alcohol’s diminished rein-
forcing profile may be related to its reduced capacityin enhancing DA in the mesolimbic reward circuitry.
Amphetamine was also evaluated in both lines for
its potential effect on the reward threshold of BNST
mediated BSR. Unlike with EtOH, the NP animals
did exhibit a potentiation of BSR on the reward
threshold as seen by a decrease in both the minimum
and maximum frequencies needed to support respond-
ing following a 0.25 mg/kg dose of amphetamine.
However, it must be stated that these data are highly
suspect and probably contribute little to scientific
understanding due to the low levels and erratic
responding seen in the NP line for BSR. Response
profiles like these make interpreting these data diffi-cult; however, they do serve to clearly demonstrate
the NP line’s reduced sensitivity to BNST mediated
BSR reward when compared to the P rat line. The P
rats, with their robust, consistent rates of responding
also show a potentiation of the BSR reward threshold
with significant reductions in the EF50, as well as,
the minimum and maximum frequency parameters in
nearly all tested doses (except the 0.25 mg/kg dose on
minimum frequency). Of the tested doses the 1.25
mg/kg dose appears to be the most effectual. These
effects are consistent with a well established litera-
ture on outbred rats with electrodes in the MFB or
VTA (Esposito et al., 1980; Schafer and Michael,
1992; Wise, 1996). Amphetamine is reputed to be themost optimal drug to study leftward shifts in the rate
frequency function in BSR studies (Gallistel and Kar-
ras, 1984; Kling-Petersen and Svensson, 1993; Wise
and Munn, 1993) since it produces an impulse-inde-
pendent release of DA from nerve terminals (Carboni
et al., 1989; Hurd and Ungerstedt, 1989), and blocks
DA inactivation by blocking its reuptake (Heikkila
et al., 1975; Wise, 1996). The data of the present
study are also in agreement with recent findings from
this laboratory using amphetamine in P and NP rats
with electrodes in the MFB (Eiler et al., 2005). These
data demonstrated that amphetamine facilitated BSR
threshold measures to a greater degree in P rat whencompared with NP rats. Unlike the present study,
however, NP rats readily initiated BSR responding
following electrode inplantation in the MFB. Together,
these data suggest that alcohol preferring rats are
more sensitive to the rewarding effects of ampheta-
mine relative to their nonpreferring (NP) counter-
parts.
While it is possible that amphetamine, a potent
psychostimulant, may merely increase the perform-
ance capacity, locomotor activity, of the P rats to a
greater level than seen in NP rats, explaining the dif-
Fig. 8. Rats were tested on a 300–20Hz descending frequency schedule, and at asubmaximal current intensity (50% optimalcurrent) following central infusion of SCH23390 (5.0 mg) into the NAC and/or i.p.administration of amphetamine (0.75 mg/ kg) across a 20 min operant session in Prats (n ¼ 7). A : BSR rate-frequency curves
following contralateral microinjections of SCH 23390 (2.5 and 5.0 lg) in the NAC. B:Illustrates the rate of lever pressing as afunction of stimulation frequency with am-phetamine (0.75 mg/kg, i.p.) (redrawn fromFig. 6A) and SCH 23390 (5.0 lg) alone, andthe combination of the two (5.0 lg SCH23390 + 0.75 mg/kg amphetamine, i.p.). C:Minimum frequencies (D) Effective fre-quency (EF50) (E) Total responding (F)Maximal frequency. ** P < 0.01 from pla-cebo control, * P < 0.05 from placebo con-trol, { P < 0.05 from amphetamine.
921BSR IN BNST OF P RATS FOLLOWING EtOH AND A mp
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 11/13
ferential responding, we do not believe this is the
case. While the asymptotic function of the rate-
response curve was elevated relative to placebo by
the higher doses of amphetamine tested, other
research groups have suggested that increases in
response rates may occur independently of changes inBSR threshold (Markou and Koob, 1991) and strong
evidence supports the notion that performance altera-
tions do not significantly change reward threshold
values (Edmonds and Gallistel, 1974; Miliaressis and
Rompre, 1987). Wise (1996) further contends that
drugs of abuse generally increase simple response
rate when optimal stimulation parameters are cho-
sen. More importantly, simple increases in activity
would be thought to increase responding throughout
the 20 min testing session; however, reductions in the
EF50 /half-maximal responding parameter, one of the
most highly accepted measures of BSR reward thresh-
old (Miliaressis et al., 1986; Stellar and Stellar, 1985;
Wise and Rompre 1989), provide evidence that the
increased responding levels are sensitive to frequency
and not simply increased locomotor activity.
Lastly, this study attempted to determine the capa-
bility of the D1 DA receptor antagonist SCH 23390
centrally administered into the NAC to attenuate the
potentiation of the BSR reward threshold produced
by the moderate 0.75 mg/kg dose of amphetamine.
Because of the lack of consistent data in the NP line,
this portion of the study was conducted only on in P
rats. It was found that SCH 23390 alone (2.5 and 5.0
mg) was unable to affect any of the tested BSR pa-
rameters; however, the 5.0 mg dose was sufficient to
significantly reverse the reductions observed on totalresponding and minimum frequency with a 0.75 mg/
kg dose of amphetamine. Also, while not statistically
significant, the 5.0 mg dose of SCH 23390 did mildly
reverse the reduction in EF50 seen with amphetamine
alone. Recent work from our laboratory shows similar
effect of SCH 23390 on amphetamine potentiated
BSR reward in the MFB (Eiler et al., 2006). These
data are consistent with a recent study single-unit
recording study by Cheer et al. (2005) that demon-
strates that SCH 23390 attenuates neural activity in
the NAC during intracranial self-stimulation in the
MFB. They suggest that NAC neurons are preferen-
tially inhibited by GABA A receptors following MFBstimulation. This data suggests that D1 blockade by
SCH 23390 in this study may attenuate the effects of
amphetamine by the inhibition of GABA interneurons
projecting directly to the BNST and other limbic
structures and/or longer relays back to the VTA.
While the mechanism is still unclear, the potentiation
of the BSR reward threshold produced by ampheta-
mine appears to be at least partially regulated by the
DA D1 receptor system within the NAC.
It is important to note that this study did not inves-
tigate the potential effects other neurotransmitter
systems may have on BSR and its regulation in the
BNST. Substantial neuroanatomical and neurochemi-
cal studies have shown that the BNST is uniquely
positioned such that GABA, norepinephrine, and
opioid neurotransmission could independently or
through interactions with the DA systems, regulatereward related behaviors of the BNST. For example,
the BNST receives one of the densest NE fiber inputs
in the CNS, receiving axonal projections from the
ventral [A1, A2] and dorsal [A6] noradrenergic cell
body groupings (Phelix et al., 1992; Swanson and
Hartman, 1975). These noradrenergic fibers travel
through the MFB in close conjunction with the DA
fibers projecting from the VTA (Swanson and Hart-
man, 1975; Ungerstedt, 1971). The BNST also has a
fair density of opioid receptors (Mansour et al., 1987,
1995; Uhl et al., 1978) and receives direct enkepha-
lin-containing fibers originating from the central nu-
cleus of the amygdala via the stria terminalis (Uhl
et al., 1978). Finally, as depicted in Figure 1,
GABAergic afferents originating from several limbic
loci project to the BNST. The BNST also sends
GABAergic fibers to the VTA. This nexus of converg-
ing neurotransmitter systems renders the BNST a
focal point where DA, NE, GABA, and opioids, may
converge to regulate the reinforcing properties of
drugs of abuse and subsequently BSR (cf. Koob, 1999;
Koob and LeMoal, 2001).
In conclusion, the present study demonstrated that
the BNST is a novel BSR reward locus capable of sup-
porting BSR performance in P, but not NP rats. We
hypothesize that the ‘‘innately’’ deficient DA system
within P rats may increase their sensitivity to ele-vated concentrations of DA in the terminal fields of
the BNST and other reward areas such as the NAC.
Amphetamine was also found to markedly lower BSR
threshold measures and enhanced response rates
while alcohol was without effect on all but the mini-
mum frequency parameter. Thus, the reinforcing
potency of alcohol on BSR performance was markedly
less compared with amphetamine. This undoubtedly
reflects the relative amount of extracelluar DA
released within terminals of the BNST, NAC and
other DA sensitive loci. It was also found that unlia-
teral infusion of the D1 antagonist SCH 23390 was
capable of attenuating the effects of amphetamine onBSR. In short, the BNST appears to be a viable neu-
ral substrate capable of assessing the reinforcing, and
hence, abuse liablity of drugs of abuse, particularly in
rats with a predisposition to alcoholism.
ACKNOWLEDGMENTS
The authors thank Drs. T.-K. Li, currently at
NIAAA, and Larry Lumeng and the Alcohol Research
Center, Indiana University School of Medicine for pro-
viding the P and NP rats.
922 W.J.A. EILER ET AL.
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 12/13
REFERENCES
Alheid GF, Heimer L. 1988. New perspectives in basal forebrain or-ganization of special relevance for neuopsychiatric disorders: Thestriatopallidal, amygdaloid, and corticopetal components of sub-stantia inominata. Neuroscience 27:1–39.
Alheid GF, DeOlmos JS, Beltramino CA. 1995. Amygdala andextended amygdala. In: Paxinos G, editor. The rat nervous sys-
tem. Paxinos G editor. New York: Academic. pp 495–578. Austin MC, Kalivas PW. 1990. Enkephallinergic and GABAergic
modulation of motor activity in the ventral pallidum. J PharmacolExp Ther 252:1370–1377.
Bain G, Kornetsky C. 1989. Ethanol self-administration and reward-ing brain stimulation. Alcohol 6:499–503.
Carboni E, Imperato A, Perzzani L, Di Chara G. 1989. Ampheta-mine, cocaine, phencyclidine and nomifensine increase extra-cellular dopamine concentrations preferentially in the nucleusaccumbens of freely moving rats. Neuroscience 28:653–661.
Carboni E, Silvangi A, Rloando MTP, Di Chiara G. 2000. Stimula-tion of in vivo dopamine transmission in the bed nucleus of thestria terminalis by reinforcing drugs. J Neurosci 20:RC102.
Cheer JF, Heien ML, Garris PA, Carelli RM, Wightman RM. 2005.Simultaneous dopamine and single-unit recordings reveal accum-bens GABAergic responses: Implications for intracranial self-stim-ulation. Proc Natl Acad Sci USA 27; 102:19150–19155.
Cicero TJ. 1979. A critique of animal model analogs of alcoholism. In: Majchrowich E, Nobel EP, editors. Biochemistry
and pharmacology of ethanol, Vol. 2. New York: Plenum Press.p 533–560.
Cloninger CR. 1987. Neurogenetic adaptive mechanisms in alcohol-ism. Science 236:410–416.
Dalsass M, Siegel A. 1987. The bed nucleus of the stria terminalis:Electrophysiological properties and responses to amygdaloid andhypothalamic stimulation. Brain Res 425:346–350.
Day HEW, Badiani A, Uslander JM, Oates MW, Vittoz NM, Robin-son TE, Watson SJ, Akil H. 2001. Environmental novelty differen-tially affects c-fos mRNA expression induced by amphetamine orcocaine in subregions of the bed nucleus of the stria terminalisand amygdala. J Neurol 21:732–740.
Edmonds DE, Gallistel CR. 1974. Parametric analysis of brain stim-ulation reward in the rat. III. Effect of performance variables onthe reward summation function. J comp Physiol Psychol 87:876–883.
Eiler WJA II, Seyoum R, Foster KL, Mailey C, June HL. 2003. TheD1 dopamine receptor regulates alcohol-motivated behaviors inthe bed nucleus of the stria terminalis in Alcohol-Preferring (P)
rats. Synapse 48:45–56.Eiler WJA II, Woods JE II, Masters J, Hardy L III, Cook J, GoergenJ, Mensah-Zoe B, McKay PF, Seyoum R, June HL. 2005. Brainstimulation reward performance and sucrose maintained behav-iors in alcohol preferring (P) and non-preferring (NP) rats. AlcoholClin Exp Res 29:571–583.
Eiler WJA II, Masters J, McKay PF, Hardy L III, Goergen J, Men-sah-Zoe B, Seyoum R, Cook J, Johnson N, Neal-Beliveau B, JuneHL. 2006. Amphetamine lowers brain stimulation reward (BSR)threshold in alcohol preferring (P) and non-preferring (NP) rats:regulation by D1 and D2 receptors in the nucleus accumbens. ExpClin Psychopharmacol 14:361–376.
Epping-Jordan MP, Markou A, Koob GF. 1998. The dopamine D-1receptor antagonist SCH 23390 injected into the dorsolateral bednucleus of the stria terminalis decreased cocaine reinforcement inthe rat. Brain Res 784:105–115.
Esposito RU, Perry W, Kornetsky C. 1980. Effects of d-amphetmaineand naloxone on brain stimulation reward. Psychopharmacology69:187–191.
Gallistel CR, Karras D. 1984. Pimozide and amphetamine haveopposing effects on the reward summation function. PharmacolBiochem Behav 20:73–77.
Gong JH, Li X-W, Lai ZN, Froehlich JC, Yu L. 1997. Quantitativecomparison of mu opioid receptor mRNA in selected CNS regionsof alcohol naıve rats selectively bred for high and low alcoholdrinking. Neurosci Lett 227:9–12.
Harvey SC, Foster KL, McKay PF, Carroll MR, Seyoum R, WoodsJE, Grey C, Jones CM, McCane S, Cummings R, Mason D, Ma C,Cook JM, June HL. 2002. The GABA A receptor a1 subtype in theventral pallidum regulates alcohol seeking behaviors. J Neurosci22:3765–3775.
Heikkila RE, Orlansky H, Mytilineou C, Cohen G. 1975. Ampheta-mine: Evaluation of d- and l-isomers as releasing agents anduptake inhibitors for 3H-dopamine and 3H-norepinephrine in sli-ces of rat neostriatum and cerebral cortex. J Pharmacol Exp Ther194:47–56.
Hodge CW, Chappelle AN, Samson HH. 1995. GABAergic transmis-sion in the nucleus accumbens is involved in the termination of ethanol self-administration in rats. Alcohol Clin Exp Res 19:1486–1493.
Hurd YL, Ungerstedt U. 1989. Cocaine an in vivo microdialysisevaluation of its acute action on dopamine transmission in ratstriatum. Synapse 3:48–54.
Hyytia P, Koob GF. 1995. GABA A receptor antagonism in the
extended amygdala decreases ethanol self-administration in rats.Eur J Pharmacol 283:151–159.
June HL, Harvey SC, Foster KL, McKay PF, Cummings R, GarciaM, Mason D, Grey C, McCane S, Williams L, Johnson TB, He X,Rock S, Cook J. 2001. GABA A receptors containing a5 subunits inthe CA1 and CA3 hippocampal fields regulate ethanol-motivatedbehaviors: An extended ethanol reward cirtutry. J Neurosci21:2166–2177.
Kling-Peterson T, Svensson K. 1993. A simple computer-basedmethod for performing and analyzing intracranial self-stimulationexperiments in rats. J Neurosci 47:215–225.
Koob GF. 1999. The role of the striatopallidal and extended amyg-dala systems in drug addiction. Ann NY Acad Sci 877:445–460.
Koob GF, LeMoal M. 2001. Drug addiction, dysregulation of reward,and allostasis. Neuropsychopharm 24:97–129.
Kornetsky C, Bain G. 1990. Brain Stimulation Reward: A model fordrug-induced euphoria. Mod Methods Pharmacol 6:211–231.
Leshner AI, Koob GF. 1999. Drugs of abuse and the brain. Proc Assoc Am Physicians 111:99–108.
Lester D, Freed EX. 1973. Criteria for an animal model of alcohol-ism. Pharmacol Biochem Behav 1:103–107.
Lewis MJ. 1993. Electrical brain stimulation reward: A model of drug reward and euphoria. In: van Harren F, editor. Methods inbehavioral pharmacology. Oxford, UK: Elsiever.
Lewis MJ, June HL. 1990. Neurobehavioral studies of ethanolreward and activation. Alcohol 7:213–219.
Lewis MJ, June HL. 1994. Synergistic effects of ethanol and cocaineon brain stimulation reward. J Exp Anal Behav 61:223–229.
Liebman JM. 1983. Discriminating between reward and perform-ance: A critical review of intracrainial self-stimulation methodol-ogy. Neurosci Biobehav Rev 7:45–72.
MacDonald AJ. 1991. Topographical organization of amygdaloid pro- jections to the caudatoputamen, nucleus accumbens, and relatedstriatal-like areas of the rat brain. Neuroscience 44:15–33.
Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ. 1987. Autoradiographic differenation of mu, delta, and kappa opioidreceptors in the rat forebrain and midbrain. J Neurosci 7:2445–2464.
Mansour A, Fox CA, Akil H, Watson SJ. 1995. Opoid-recptor mRNA expression in the rat CNSL anatomical and functional implica-tions. Trends in Neurosci 18:22–29.
Markou A, Koob GF. 1991. Construct validity of a self-stimulationthreshold paradigm: Effects of reward and performance manipula-tions. Physiol Behav 51:111–119.
McBride WJ, Li TK. 1998. Animal models of alcoholism: Neurobiol-ogy of high alcohol-drinking behavior in rodents. Crit Rev Neuro-biol 12:339–369.
Miliaressis E, Rompre PP. 1987. Effects of concomitant motor reac-tions on the measurement of rewarding efficacy of brain stimula-tion. Behav Neurosci 101:827–831.
Miliaressis E, Rompre P-P, Laviolette LP, Philippe L, Coulombe D.1986. The curve-shift paradigm in self-stimulation. Physiol Behav37:85–91.
Moolten M, Kornetsky C. 1990. Oral self-administration of ethanoland not experimenter-administered ethanol facilitates rewardingbrain stimulation. Alcohol 7:221–225.
Mogenson G, Takigawa M, Robertson A, Wu M. 1979. Self-stimula-
tion of the nucleus accumbens and ventral tegmental area of theTsai attenuated by microinjections of spiroperidol in to the nu-cleus accumbens. Brain Res 171:247–259.
Murphy JM, Stewart RB, Bell RL, Badia-Elder NE, Carr LG,McBride WJ, Lumeng L, Li TK. 2002. Phenotypic and genotypiccharacterization of the Indiana University rat lines selectivelybred for high and low alcohol preference. Behav Genet 32:5:363–388.
Panagis G, Nomikas GG, Miliaressis E, Chergui K, Kastellakis A,Svensson TH, Spyrak C. 1997. Ventral pallidum self-stimulationinduces stimulus dependent increases in c-fos expression inreward related brain regions. Neuroscience 77:175–186.
Paxinos G, Watson C. 1998. The rat brain in stereotaxic coordinates.Sydney: Academic Press.
Phelix CF, Liposits Z, Paull WK. 1992. Monoamine innervation of bed nucleus of stria terminalis: An electron microscope investiga-tion. Brain Res Bull 28:949–965.
923BSR IN BNST OF P RATS FOLLOWING EtOH AND A mp
Synapse DOI 10.1002/syn
8/3/2019 Responding for Brain Stimulation Reward (BSR) in the Bed Nucleus of the Stria Terminal Is (BST) in Alcohol Preferring (P) Rats Following EtOH and Amphetamin…
http://slidepdf.com/reader/full/responding-for-brain-stimulation-reward-bsr-in-the-bed-nucleus-of-the-stria 13/13
Phillips AG, Fibiger HC. 1989. Neuroanatomical bases of intracra-nial self-stimulation: Untangling the Gordian knot. In: LiebmanJM, Cooper SJ, editors. The neuropharmacological basis of reward. New York: Oxford Press. pp 66–105.
Schaefer GJ, Michael RP. 1987. Ethanol and current thresholds forbrain self- stimulation in the lateral hypothalamus of the rat.
Alcohol 4:209–213.Schaefer GJ, Michael RP. 1992. Schedule-controlled brain stimula-
tion: Has it utility for behavioral pharmacology? Neurosci BehavRev 16:569–583.
Shake-Li J, Huston JP. 2002. Non-linear dynamics of operant behav-ior: A new approach via the extended return map. Rev Neurosci13:37–57.
Stellar JR, Stellar E. 1985. Chapter 6: The neuroanatomy of brain-stimulation reward. In: The neurobiology of motivation andreward. Springer-Verlag, New York. pp 121–156.
Sun N, Cassell MD. 1993. Intrinsic GABAergic neurons inthe rat central extended amygdala. J Comp Neurol 330:381–404.
Swanson LW, Hartman BK. 1975. The central adrenergic system. An immunoflurescence study of the location of cell bodies andtheir efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J Comp Neurol 163:467–505.
Uhl GR, Kuhar MJ, Snyder SH. 1978. Enkephalin-containing path-way: Amygdaloid efferents in the stria terminalis. Brain Res149:223–228.
Ungerstedt U. 1971. Sterotaxic mapping of monoamine pathways in
the rat brain. Acta Physiol Scand Suppl 367:1–48.Wise RA. 1989. The brain and reward. In: Liebam JM, Cooper SJ,
editors. The Neurphormacological Basis of Reward. Oxford:Oxford University Press. p 337–424.
Wise RA. 1996. Addictive drugs and brain stimulation reward. Annu Rev Neurosci 19:319–340.
Wise RA, Munn E. 1993. Effects of repeated amphetamine injectionson lateral hypothalamic brain stimulation reward and subsequentlocomotion. Behav Brain Res 55:195–201.
Wise RA, Rompre P-P. 1989. Brain Dopamine and Reward. AnnuRev Psychol 40:191–225.
924 W.J.A. EILER ET AL.
Synapse DOI 10.1002/syn