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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics
JPET 297:316–325, 2001
Vol. 297, No. 1
3380/893790
Printed in U.S.A.
Serotonergic Manipulations Both Potentiate and Reduce Brain
Stimulation Reward in Rats: Involvement of Serotonin-1A
Receptors
AMANDA A. HARRISON1 and ATHINA MARKOU
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California
Received September 27, 2000; accepted January 5, 2001
This paper is available online at http://jpet.aspetjournals.org
Serotonergic neurotransmission is hypothesized to be involved in motivational processes and reward-related behaviors (Miliaressis, 1977; Bendotti and Samanin, 1986; Hillegaart et al., 1991). Nevertheless, the exact role of serotonin
(5-HT) on reward processes remains unclear. That is, increases in serotonin either increase or decrease reward, and
decreases in serotonin also have produced inconsistent results (Poschel et al., 1974; Redgrave 1978; Ahlenius et al.,
1981; McClelland et al., 1989; Hillegaart et al., 1991;
Fletcher et al., 1995). A method used to study reward is the
brain stimulation reward (BSR) procedure (Markou and
Koob, 1992). In this procedure, the reinforcing efficacy of
electrical stimulation of brain sites is indicated by the fact
that subjects perform an operant response to receive the brief
electrical stimuli (Liebman, 1983).
One hypothesis is that serotonin exerts an inhibitory inThis study was supported by National Institute on Drug Abuse Grant
DA11946 and a Novartis Research Grant to A.M. This is publication 13580-NP
from The Scripps Research Institute.
1
Current address: School of Psychology, University of Leeds, Leeds, LS2
9JT, England, UK.
performance, whereas injections of 8-OH-DPAT into the dorsal
raphé nucleus had no effect. A high dose of the selective serotonin
reuptake inhibitor fluoxetine (10 mg/kg) elevated reward thresholds and responses latencies, whereas lower doses (2.5 and 5.0
mg/kg) increased response latencies without affecting thresholds.
Furthermore, the coadministration of a 5-HT1A antagonist,
p-MPPI, and a previously ineffective dose of fluoxetine, a drug
combination that increases serotonin levels, significantly elevated
thresholds. Thus, it is suggested here that the reward-potentiating
effects of systemically administered low doses of 8-OH-DPAT
may be the result of reduced serotonergic neurotransmission,
mediated by activation of 5-HT1A somatodendritic autoreceptors
in the median, but not the dorsal, raphé nucleus. In conclusion, the
present data support the hypothesis that serotonin exerts an
inhibitory influence on reward processes.
fluence on reward processes. This hypothesis is supported by
reports that reductions in serotonergic neurotransmission
induced by either intraventricular 5,6-dihydroxytryptamine
or systemic para-chlorophenylalanine (PCPA) increased BSR
reflected in increased response rates (Poschel and Ninteman,
1971; Poschel et al., 1974). However, the hypothesized serotonergic mediation of BSR remained controversial due to lack
of correlation between the time course of serotonin depletion
and the behavioral effects (Katz and Baldrighi, 1979; Gratton, 1982). Furthermore, (⫾)-8-hydroxy-2-(di-n-propyl-amino)tetralin hydrobromide (8-OH-DPAT), a 5-HT1A receptor agonist (Hall et al., 1985), injected into the median raphé
nucleus lowered BSR thresholds reflecting also increased
reward (Fletcher et al., 1995). This effect is probably due to
activation of 5-HT1A somatodendritic autoreceptors in the
raphé nuclei leading to reduced firing of serotonin neurons
and reduced serotonin release (Aghajanian et al., 1987; Sinton and Fallon, 1988). Consistent with the above-mentioned
effects are the observations that increasing serotonin by systemic administration of d-fenfluramine, 5-hydroxytrytophan,
fluoxetine, or serotonin injections into the nucleus accum-
ABBREVIATIONS: BSR, brain stimulation reward; PCPA, para-chlorophenylalanine; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; 5-HT,
5-hydroxytryptamine; p-MPPI, 4-iodo-N-[2-[4-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide hydrochloride; ITI, intertrial interval.
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ABSTRACT
A discrete-trial current-threshold self-stimulation procedure
was used to assess the effects of increased and decreased
serotonergic neurotransmission, and 5-HT1A receptor activation on brain stimulation reward. Systemic administration of the
5-HT1A receptor agonist 8-OH-DPAT had a biphasic effect on
brain reward thresholds, without affecting the latency to respond, a measure of performance. The low dose of 8-OH-DPAT
(0.03 mg/kg) lowered reward thresholds, whereas higher doses
(0.1 and 0.3 mg/kg) elevated thresholds. The 5-HT1A receptor
antagonist p-MPPI had no effect on brain stimulation behavior,
but reversed both the 8-OH-DPAT-induced lowering and elevation of thresholds, indicating that both of these effects of
8-OH-DPAT are mediated through the 5-HT1A receptor. Injections of 8-OH-DPAT into the median raphé nucleus also lowered brain reward thresholds, without affecting measures of
Serotonin-1A and Brain Stimulation Reward
Materials and Methods
Subjects
Male Wistar rats (Charles River, Hollister, CA) were housed in
pairs in a temperature- and humidity-controlled environment with a
12-h light/dark cycle (lights on 6:00 AM). The subjects were tested
during the light phase of their light/dark cycle. Food and water were
available ad libitum in the home cages. All subjects were treated in
accordance with the National Institutes of Health Guide for the Care
and Use of Laboratory Animals, and the animal facilities and experimental protocols were in accordance with the Association for the
Assessment and Accreditation of Laboratory Animal Care.
Apparatus
The experimental apparatus consisted of 16 Plexiglas chambers
(30.5 ⫻ 30 ⫻ 17 cm) encased in sound-attenuating boxes. Each
operant chamber consisted of a stainless steel grid floor and a metal
wheel manipulandum located on the front wall, which required a
0.2-N force to rotate it a quarter turn. Gold-contact swivel commutators and bipolar leads (Plastics One, Roanoke, VA) connected the
animals to constant current stimulators (Stimtek 1200; San Diego
Instruments, San Diego, CA). The stimulation parameters, data
collection, and all programming functions were controlled by a microcomputer.
Surgical Procedure
When the rats reached 320 g in body weight they underwent
surgical implantation of stainless steel bipolar intracranial self-stimulation electrodes (diameter ⫽ 0.25 mm, length ⫽ 11 mm; Plastics
One). The subjects were anesthetized with a halothane/oxygen vapor
mixture (1.0 –1.5%), placed in a Kopf stereotaxic frame (David Kopf
Instruments, Tujunga, CA) with the incisor bar set at ⫺3.3 mm
below the interaural line (i.e., flat skull; Paxinos and Watson, 1998).
An electrode was implanted into the posterior lateral hypothalamus
according to the coordinates AP, ⫺2.8 mm from bregma; L, ⫾1.7 mm;
DV, ⫺8.8 mm from skull surface. The electrode was implanted in the
right brain hemisphere in half of the subjects and the left hemisphere for the others. In experiments 5 and 6, subjects were prepared
with both electrodes in the lateral hypothalamus and guide cannulae
(23-gauge stainless steel tubing) 2 mm away from either the median
raphé (22o from vertical; AP, ⫺7.8 mm from bregma; L, ⫹3.39 mm;
DV, ⫺7.06 mm from skull surface, guide cannulae were 13 mm in
length) or the dorsal raphé (32o from vertical; AP, ⫺7.8 mm from
bregma; L, ⫹40.0 mm; DV, ⫺5.55 mm from skull surface, guide
cannulae were 11 mm in length). The cannulae were implanted in
the right hemisphere and the electrodes in the left hemisphere in all
subjects. The subjects were given a 7-day postoperative recovery
period before behavioral training.
Drugs
8-OH-DPAT (Sigma, St. Louis, MO) was dissolved in 0.9% saline
and administered subcutaneously in a volume of 1 ml/kg of body weight.
4-Iodo-N-[2-[4-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide hydrochloride (p-MPPI) (Research Biochemicals International,
Natick, MA) was dissolved in sterile water and sonicated for 10 to 20
min, and then brought to a pH of approximately 5.2 with 0.1 M NaOH.
p-MPPI was administered subcutaneously in a volume of 4 ml/kg of
body weight. Infusions of 8-OH-DPAT into either the median or the
dorsal raphé nucleus were administered in a volume of 0.5 ␮l over 1
min, with the injection needle left in place for 1 min after the infusion
to minimize efflux. (⫹)-N-Methyl-␥-[4-(trifluoromethyl)phenoxy]-benzenepropanamine hydrochloride (fluoxetine) (Research Biochemicals International) was dissolved in saline and administered intraperitoneally
in a volume of 1 ml/kg of body weight.
Intracranial Self-Stimulation Behavioral Procedure
The intracranial self-stimulation discrete-trial current-threshold
procedure is a modified version (Markou and Koob, 1992) of a procedure initially developed by Kornetsky and coworkers (Lee and
Kornetsky, 1998). The subjects were initially trained to turn the wheel
manipulandum on a fixed ratio 1 schedule of reinforcement during
which each quarter turn of the wheel resulted in the delivery of a
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bens or the caudate-putamen decreased BSR (Bose et al.,
1974; Redgrave, 1978; McClelland et al., 1989; Lee and Kornetsky, 1998).
The above-mentioned studies used rats with stimulating
electrodes in the medial forebrain bundle, including the area
of the lateral hypothalamus. However, studies in subjects
with electrodes in the raphé nuclei demonstrated a facilitatory role of serotonin on BSR. Electrodes in either the median
(Miliaressis, 1977; van der Kooy et al., 1978) or the dorsal
raphé (Simon et al. 1976; van der Kooy et al., 1978) maintained self-stimulation behavior that was reduced by PCPA,
suggesting that self-stimulation of the raphé nuclei is serotonergically mediated. Response rates for self-stimulation of
the hippocampus also were decreased by PCPA administration (van der Kooy et al., 1977). Taken together, these findings indicate that the role of serotonin in BSR may depend on
the stimulation site.
A limitation of many of the above-mentioned studies is that
changes in reward were measured as increases or decreases
in response rates. Response rates are more affected by
changes in behavioral activation induced by manipulations
than threshold measures of reward (Liebman, 1983), which is
relevant because serotonin manipulations affect both response inhibition and locomotor behavior (Soubrié, 1986).
The 5-HT1A receptor has received considerable research
interest due to its hypothesized link to disorders such as
depression and anxiety (Maes and Meltzer, 1995; File et al.,
2000). High densities of 5-HT1A recognition sites are found in
the hippocampus, amygdala, raphé nuclei, lateral septum,
entorhinal cortex, and certain hypothalamic nuclei (Pazos
and Palacios, 1985). The 5-HT1A receptor exists in two forms
in the brain, as somatodendritic autoreceptors and postsynaptic receptors in terminal regions. 5-HT1A receptor-mediated serotonin neurotransmission is involved in the control of
various motivated behaviors, including locomotor activity,
feeding, sexual behavior, and BSR (Ahlenius et al., 1981;
Bendotti and Samanin, 1986; Hutson et al., 1986; Hillegaart
et al., 1989, 1991; Hillegaart, 1990; Montgomery et al., 1991;
Fletcher et al., 1995).
The purpose of the present experiments was to systematically assess the role of serotonin, and more specifically of
5-HT1A receptors, in BSR. A response-rate-independent discrete-trial procedure that provides current intensity thresholds as a measure of reward and response latencies as a
measure of performance was used. The effects of systemically
administered 8-OH-DPAT, a 5-HT1A receptor agonist, were
first examined. The selectivity of the 8-OH-DPAT systemic
effects was then assessed using the 5-HT1A receptor antagonist p-MPPI (Kung et al., 1994). Discrete median and dorsal
raphé nucleus infusions of 8-OH-DPAT assessed 1) the effects of reduced serotonin induced by activation of 5HT1A
autoreceptors, and 2) the differential involvement of the two
raphé nuclei on BSR behavior. Finally, the effects of enhancing serotonin neurotransmission by the coadministration of
fluoxetine, a selective serotonin reuptake inhibitor, and a
5-HT1A receptor antagonist on BSR also were examined.
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Harrison and Markou
subjects Latin square design, with a minimum of 4 days between
consecutive drug treatments.
Experiment 3: Effects of p-MPPI, a 5-HT1A Antagonist, on
the 8-OH-DPAT-Induced Lowering of Brain Reward Thresholds. Eight combination treatments of p-MPPI and 8-OH-DPAT
were administered according to a within-subjects Latin square design, with a minimum of 3 days between consecutive combination
drug treatments (n ⫽ 10). The treatments involved one of four doses
of p-MPPI (0, 0.03, 0.3, 1 mg/kg s.c., 135-min pretreatment) followed
by one of two doses of 8-OH-DPAT (0, 0.03 mg/kg s.c., 30-min pretreatment).
Experiment 4: Effects of p-MPPI on the 8-OH-DPAT-Induced Elevation of Brain Reward Thresholds. Six combination
treatments of p-MPPI and 8-OH-DPAT were administered according
to a within-subjects Latin square design, with a minimum of 3 days
between consecutive combination drug treatments (n ⫽ 10). The
treatments involved one of three doses of p-MPPI (0, 0.3, 1 mg/kg s.c.,
135-min pretreatment) followed by one of two doses of 8-OH-DPAT
(0, 0.3 mg/kg s.c., 30-min pretreatment).
Experiment 5: Effects of 8-OH-DPAT Infusions into the Median Raphé Nucleus on Brain Stimulation Reward. 8-OHDPAT (0, 1.0, 2.5, 5.0 ␮g/0.5 ␮l/1 min, 5-min pretreatment, n ⫽ 11)
was infused directly into the median raphé nucleus through 15-mm
30-gauge stainless steel tubing injectors using a Harvard pump
(Harvard Apparatus Inc., Holliston, MA) according to a within-subjects Latin square design. Each microinfusion was followed by a
1-min period in which the infusion needle was left in place to minimize efflux.
Experiment 6: Effects of 8-OH-DPAT Infusions into the Dorsal Raphé Nucleus on Brain Stimulation Reward. 8-OH-DPAT
(0, 1.0, 2.5, 5.0 ␮g/0.5 ␮l/1 min, 5-min pretreatment, n ⫽ 11) was
infused directly into the dorsal raphé nucleus in a similar manner to
that described above in the median raphé experiment (experiment
5), using 13-mm, 30-gauge stainless steel tubing injectors.
Experiment 7: Effects of Fluoxetine, a Selective Serotonin
Reuptake Inhibitor, on Brain Stimulation Reward. Fluoxetine
(0, 2.5, 5, 10 mg/kg i.p., 120-min pretreatment, n ⫽ 10) was administered according to a within-subjects Latin square design, with a
minimum of 4 days between consecutive drug treatments. Eight of
the subjects in this experiment were also subjects in experiment 2,
half completed experiment 2 first, while the other half completed
experiment 7 first (i.e., crossover design). Stable baseline thresholds
were established between drug treatments and between experiments.
Experiment 8: Effects of p-MPPI and Fluoxetine on Brain
Stimulation Reward. Four combination treatments of p-MPPI and
fluoxetine were administered according to a within-subjects Latin
square design, with a minimum of 7 days between consecutive combination drug treatments (n ⫽ 10). The treatments involved one of
four doses of p-MPPI (0, 1, 3, 10 mg/kg s.c., 135-min pretreatment)
followed by fluoxetine (5 mg/kg s.c., 120-min pretreatment).
Histology
After completion of behavioral testing in experiments 5 and 6 all
subjects were sacrificed with an overdose of sodium pentobarbital
(Abbott Laboratories, Abbott Park, IL) and perfused intracardially
with phosphate-buffered saline and then 4% formaldehyde solution
(Fisons, Rochester, NY). The brains were removed from the skull,
fixed, frozen, and sliced into 50-␮m sections. Mounted sections were
examined under a light microscope to determine the accuracy of
cannula placement.
Data Analyses
All reward threshold and response latency data were expressed as
a percentage of the previous baseline day’s data. The percentage
scores then were analyzed using the one-way repeated-measures
ANOVA. The data from experiments 3 and 4 were treated in an
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contingent electrical reinforcer. The electrical reinforcer had a train
duration of 500 ms and consisted of 0.1-ms rectangular cathodal
pulses that were delivered with 100-Hz frequency. The current intensity delivered was adjusted for each animal and typically ranged
from 100 to 250 ␮A. After successful familiarization with this procedure (two sessions of 100 reinforcers in less than 20 min), the rats
were gradually trained on the discrete-trial, current-threshold procedure.
At the start of each trial, rats received a noncontingent electrical
stimulus. During the following 7.5 s, the limited hold, if the subjects
responded by turning the wheel manipulandum a quarter turn (positive response) they received a second contingent stimulus identical
to the previous noncontingent stimulus. During a 2-s period immediately after a positive response, further responses had no reinforcement or task consequences. If no response occurred during the 7.5-s
limited hold period, a negative response was recorded. The intertrial
interval (ITI), which followed the limited hold period, had an average
duration of 10 s (range 7.5–12.5 s). Responses that occurred during
the ITI resulted in a further 12.5-s delay of the onset of the next trial.
During training, the duration of the ITI and delay periods imposed
by inappropriate ITI responding were gradually increased until the
standard task parameters were reached. Stimulation intensities
were varied according to the classical psychophysical method of
limits. Thus, the subjects received four alternating series of ascending and descending current intensities starting with a descending
series. Within each series the stimulus intensity was altered by 5-␮A
steps between each set of trials (three trials per set). The initial
stimulus intensity was set at 40 ␮A above the baseline current
threshold for each animal. A series was terminated after either 15
stimulus increments (or decrements) had occurred, or after the determination of the threshold for the series (see below). Each test
session typically lasted 30 min and provided two dependent variables.
Thresholds. The current threshold for each descending series
was defined as the stimulus intensity between the successful completion of a set of trials (positive responses during two or more of the
three trials) and the stimulus intensity for the first set of trials, of
two consecutive sets, during which the animal failed to respond
positively on two or more of the three trials. During the ascending
series, the threshold was defined as the stimulus intensity between
the unsuccessful completion of a set of trials (negative responses
during two or more of the three trials) and the stimulus intensity for
the first set of trials, of two consecutive sets, during which the
animal responded positively on two or more of the trials. Thus,
during each test session, four thresholds were determined and the
mean of these values was taken as the threshold for each subject.
Response Latency. The latency between the onset of the noncontingent stimulus at the start of each trial and a positive response
was recorded as the response latency. The response latency for each
test session was defined as the mean response latency of all trials
during which a positive response occurred.
After training in the above-mentioned brain stimulation reward
procedure, rats were tested until stable baseline thresholds had been
achieved (⫾10% over a 5-day period). Drug testing was initiated only
after performance had stabilized, which typically occurred after 2 to
3 weeks of baseline testing. Return to baseline threshold levels was
required between drug injections. Unless otherwise stated (experiments 2 and 7) experimentally naive subjects were used in each
experiment.
Experiment 1: Effects of Systemically Administered 8-OHDPAT, a 5-HT1A Agonist, on Brain Stimulation Reward. After
establishment of stable baseline thresholds, 8-OH-DPAT (0, 0.03,
0.1, 0.3 mg/kg s.c., n ⫽ 11) was administered (30-min pretreatment)
according to a within-subjects Latin square design, with a minimum
of 3 days between consecutive drug treatments.
Experiment 2: Effects of p-MPPI, a 5-HT1A Antagonist, on
Brain Stimulation Reward. p-MPPI (0, 1, 3, 10 mg/kg s.c., 135min pretreatment, n ⫽ 8) was administered according to a within-
Serotonin-1A and Brain Stimulation Reward
identical manner to those of the other experiments except that the
data were analyzed using two-way repeated-measures ANOVAs with
agonist and antagonist doses being the two factors. Statistically
significant results were followed by post hoc comparisons of group
means using the Newman-Keuls analysis. All statistical analyses
were performed using the SuperAnova statistical package (Abacus
Concepts Inc., Berkeley, CA). The level of significance reported is p ⬍
0.05.
Results
Experiment 4: Effects of p-MPPI on the 8-OH-DPATInduced Elevation of Brain Reward Thresholds. Main
effects of both 8-OH-DPAT [F(1,9) ⫽ 27.948, p ⬍ 0.001] and
p-MPPI [F(2,27) ⫽ 9.4, p ⬍ 0.01] were observed. Post hoc
Newman-Keuls analysis of an 8-OH-DPAT ⫻ p-MPPI interaction [F(2,18) ⫽ 12.286, p ⬍ 0.001] demonstrated that, as
seen in experiment 1, the administration of vehicle ⫹ 0.3
mg/kg 8-OH-DPAT significantly elevated reward thresholds
compared with thresholds after vehicle ⫹ vehicle treatment.
p-MPPI (0.3 or 1.0 mg/kg ⫹ vehicle) had no effect on reward
thresholds compared with thresholds after vehicle ⫹ vehicle
treatment, but dose dependently reversed the threshold elevations induced by 0.3 mg/kg 8-OH-DPAT (Fig. 4A). The drug
combinations had no effect on response latencies [F(2,18) ⫽
0.792, p ⬎ 0.1] (Fig. 4B).
Experiment 5: Effects of 8-OH-DPAT Infusions into
the Median Raphé Nucleus on Brain Stimulation Reward. Histological analysis of brain tissue indicated that
cannula placements in all subjects were accurate (Fig. 5A).
Central infusions of 8-OH-DPAT (1.0 and 2.5 ␮g/0.5 ␮l) into
the median raphé nucleus significantly lowered brain reward
thresholds compared with thresholds after vehicle administration [F(3,30) ⫽ 7.674, p ⬍ 0.001] (Fig. 5B), without affecting response latencies [F(3,30) ⫽ 0.307, p ⬎ 0.1] (Fig. 5C).
Experiment 6: Effects of 8-OH-DPAT Infusions into
the Dorsal Raphé Nucleus on Brain Stimulation Reward. Histological analysis of brain tissue indicated that the
cannula placements in four subjects were inaccurate (Fig.
6A). Thus, the behavioral data of these subjects were eliminated from all analyses. Central infusions of 8-OH-DPAT
into the dorsal raphé nucleus (in the remaining subjects, n ⫽
7) had no statistically significant effect on either brain stimulation reward thresholds [F(3,18) ⫽ 0.578, p ⬎ 0.1] (Fig. 6B)
or response latencies [F(3,18) ⫽ 0.52, p ⬎ 0.1] (Fig. 6C).
Experiment 7: Effects of Fluoxetine, a Selective Serotonin Reuptake Inhibitor, on Brain Stimulation Reward. Fluoxetine (10 mg/kg) significantly elevated reward
thresholds compared to thresholds after vehicle treatment,
and 2.5 or 5.0 mg/kg fluoxetine [F(3,30) ⫽ 6.489, p ⬍ 0.01]
(Fig. 7A). All doses of fluoxetine administered increased the
latency to respond [F(3,30) ⫽ 3.988, p ⬍ 0.05] compared with
the response latency after vehicle treatment (Fig. 7B).
Experiment 8: Effects of Combined p-MPPI and Fluoxetine Treatment on Brain Stimulation Reward. The
coadministration of 10 mg/kg p-MPPI and a previously ineffective dose of fluoxetine (5 mg/kg) significantly elevated
reward thresholds compared with thresholds after vehicle ⫹
5 mg/kg fluoxetine treatment [F(3,27) ⫽ 3.349, p ⬍ 0.05] (Fig.
8A). Neither 10 mg/kg p-MPPI (under Results of experiment
2) nor 5 mg/kg fluoxetine (present experiment) had an effect
TABLE 1
Range of mean baseline thresholds and response latencies for all experiments
Experiment
1:
2:
3:
4:
5:
6:
7:
8:
Systemic 8-OH-DPAT
p-MPPI
0.03 (mg/kg) 8-OH-DPAT ⫹ p-MPPI
0.3 (mg/kg) 8-OH-DPAT ⫹ p-MPPI
Median raphé 8-OH-DPAT
Dorsal raphé 8-OH-DPAT
Fluoxetine
Fluoxetine ⫹ p-MPPI
Baseline Thresholds (␮A)
Baseline Response Latencies (s)
158.56–160.80
151.46–161.72
173.33–184.12
138.04–141.54
146.51–157.76
159.46–164.76
128.52–136.40
119.88–127.21
3.25–3.35
3.27–3.47
3.41–3.53
3.16–3.31
3.30–3.43
3.27–3.54
3.06–3.25
2.94–3.20
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Baseline Thresholds and Response Latencies. Baseline data were analyzed using one-way ANOVAs to assess
potential drifts of baseline performance. No significant differences in thresholds or response latencies were found in
any of the experiments (see Table 1 for ranges of thresholds
and responses latencies for each experiment).
Experiment 1: Effects of Systemically Administered
8-OH-DPAT, a 5-HT1A Agonist, on Brain Stimulation
Reward. The 5-HT1A receptor agonist 8-OH-DPAT had a
biphasic effect on brain stimulation reward thresholds
[F(3,30) ⫽ 16.028, p ⬍ 0.001]. The lowest dose administered,
0.03 mg/kg, significantly lowered thresholds compared with
thresholds after saline treatment, whereas the two highest
doses, 0.1 and 0.3 mg/kg, significantly elevated thresholds
compared with thresholds observed after administration of
either saline or 0.03 mg/kg 8-OH-DPAT (Fig. 1A). 8-OHDPAT had no effect on response latencies, a measure of
general motoric performance [F(3,30) ⫽ 1.725, p ⬎ 0.1] (Fig.
1B).
Experiment 2: Effects of p-MPPI, a 5-HT1A Antagonist, on Brain Stimulation Reward. Systemic administration of p-MPPI, had no statistically significant effect on either reward thresholds [F(3,21) ⫽ 1.783, p ⬎ 0.1] (Fig. 2A), or
the latency to respond [F(3,21) ⫽ 1.688, p ⬎ 0.1] (Fig. 2B).
Experiment 3: Effects of p-MPPI, a 5-HT1A Antagonist, on the 8-OH-DPAT-Induced Lowering of Brain
Reward Thresholds. Main effects of both 8-OH-DPAT
[F(1,9) ⫽ 38.553, p ⬍ 0.001] and p-MPPI [F(3,27) ⫽ 19.282,
p ⬍ 0.001] were observed. Post hoc Newman-Keuls analysis
of an 8-OH-DPAT ⫻ p-MPPI interaction [F(3,27) ⫽ 16.076,
p ⬍ 0.001] demonstrated that, as seen in experiment 1, the
administration of vehicle ⫹ 0.03 mg/kg 8-OH-DPAT significantly lowered reward thresholds compared with thresholds
after vehicle ⫹ vehicle treatment. p-MPPI (0.03, 0.3, or 1.0
mg/kg ⫹ vehicle) had no effect on reward thresholds compared with thresholds after vehicle ⫹ vehicle treatment, but
did reverse the 8-OH-DPAT-induced lowering of thresholds
in a dose-dependent manner (Fig. 3A). None of the drug
combinations had any effect on response latencies [F(3,27) ⫽
1.538, p ⬎ 0.1] (Fig. 3B).
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Harrison and Markou
on brain reward thresholds when administered alone. None
of the drug combination treatments had an effect on response
latencies [F(3,27) ⫽ 1.939, p ⬎ 0.1] (Fig. 8B).
Discussion
Systemic administration of the 5-HT1A receptor agonist
8-OH-DPAT, depending on the dose, increased or decreased
BSR reflected in changes in reward thresholds. 8-OH-DPAT
did not affect response latencies, an independent measure
assessing performance effects. These results indicate that
the effects of 8-OH-DPAT on reward thresholds were not
confounded by performance effects and are consistent with
previous reports of biphasic effects of 8-OH-DPAT on BSR
(Montgomery et al., 1991).
Although the systemic administration of the 5-HT1A antagonist p-MPPI had no effect on BSR behavior, p-MPPI
blocked both the reward potentiating and the reward reducing effects of systemically administered 8-OH-DPAT, without
Fig. 2. Effects of p-MPPI, a 5-HT1A antagonist, on brain reward thresholds (A) and response latencies (B) (mean ⫾ S.E.M.). p-MPPI had no effect
on brain stimulation reward thresholds or response latencies.
affecting response latencies. p-MPPI has high affinity and
selectivity as a 5-HT1A receptor antagonist with Kd ⫽ 0.36
nM, whereas the Ki values for ␣1, ␣2, ␤, D2, and 5-HT2
receptors were 35, 181, 740, 19, and 270 nM, respectively
(Kung et al., 1994). Taken together, these results suggest
that both the reward-enhancing and the reward-reducing
effects of 8-OH-DPAT are primarily mediated through
5-HT1A receptor activation. The biphasic effects of systemically administered 8-OH-DPAT may be due to a dose-related
selective stimulation of the two types of 5-HT1A receptors, the
somatodendritic autoreceptors and the postsynaptic receptors. 8-OH-DPAT has affinity for both subtypes of 5-HT1A
receptors (Hall et al., 1985). Systemic administration of
8-OH-DPAT reduced serotonin release in the striatum and
ventral hippocampus, effects indicative of autoreceptor activation (Kreiss and Lucki, 1997). Thus, the reward-enhancing
effect may be attributable to decreased serotonin release
resulting from activation of 5-HT1A somatodendritic autoreceptors in the raphé nuclei, whereas the reward-reducing
effect may be attributable to activation of 5-HT1A postsynaptic receptors.
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Fig. 1. Effects of systemically administered 8-OH-DPAT, a 5-HT1A agonist, on brain stimulation reward thresholds (A) and response latencies
(B), (mean ⫾ S.E.M.). Asterisks (ⴱ) denote statistically significant differences from thresholds after vehicle treatment. *p ⬍ 0.05, **p ⬍ 0.01.
Crosses (†) denote statistically significant differences compared with
thresholds after administration of 0.03 mg/kg 8-OH-DPAT, indicating
dose-dependent effects of 8-OH-DPAT, ††p ⬍ 0.01.
Serotonin-1A and Brain Stimulation Reward
To assess the effects of 8-OH-DPAT on the 5-HT1A somatodendritic autoreceptors, 8-OH-DPAT was injected into either the median or the dorsal raphé nucleus. Dissociable
effects on BSR were observed. Injections into the median
raphé nucleus potentiated BSR, an effect consistent with
previous reports (Fletcher et al., 1995), whereas injections
into the dorsal raphé nucleus had no effect. The similarity of
the reward-potentiating effects of 8-OH-DPAT administered
either systemically at low doses or directly into the median
raphé nucleus suggests that reduced serotonergic neurotransmission induced by activation of 5-HT1A autoreceptors
in the median raphé nucleus may be responsible for the
systemic effect. The present results are reminiscent of reports that 8-OH-DPAT injections into the median raphé nucleus increased, whereas injections into the dorsal hippocampus that is rich in 5-HT1A receptors (Pazos and Palacios,
1985) decreased social interactions in rats (File et al., 2000).
Fig. 4. Reversal of 8-OH-DPAT-induced elevations of reward thresholds
by p-MPPI (A) with no treatment effects on response latencies (B),
(mean ⫾ S.E.M.). Asterisks (ⴱ) denote statistically significant differences
from thresholds after the corresponding p-MPPI ⫹ vehicle treatment,
*p ⬍ 0.05, **p ⬍ 0.01. Crosses (†) denote statistically significant differences from thresholds after administration of vehicle ⫹ 0.3 mg/kg 8-OHDPAT, †p ⬍ 0.05, ††p ⬍ 0.01. Hashes (#) denote a statistically significant
difference from thresholds after 0.3 mg/kg p-MPPI ⫹ 0.3 mg/kg 8-OHDPAT treatment, indicating a p-MPPI-induced dose-dependent reversal
of the effects of 8-OH-DPAT, #p ⬍ 0.05, ##p ⬍ 0.01.
Based on the above-mentioned findings, it is predicted that
activation of postsynaptic 5-HT1A receptors through microinjections in terminal serotonergic regions rich in 5-HT1A receptors, such as the hippocampus and the amygdala, would
decrease BSR.
The lack of effect of 8-OH-DPAT injections into the dorsal
raphé nucleus is surprising for two reasons. First, because
the number of 5-HT1A receptors in the dorsal raphé is approximately 5-fold greater than those in the median raphé
(Weissmann-Nanopoulos et al., 1985). Second, because the
serotonin cells of the dorsal raphé respond more sensitively
than those of the median raphé to 8-OH-DPAT in terms of
both decreases in neuronal discharge rates (Sinton and Fallon, 1988), and decreases in forebrain serotonin synthesis
(Invernizzi et al., 1991). Nevertheless, the present results are
consistent with similar behavioral dissociations between the
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 5, 2017
Fig. 3. Reversal of 8-OH-DPAT-induced lowering of reward thresholds by
p-MPPI (A) with no treatment effects on response latencies (B), (mean ⫾
S.E.M.). Asterisks (ⴱ) denote statistically significant differences from
thresholds after the corresponding p-MPPI ⫹ vehicle treatment, **p ⬍
0.01. Crosses (†) denote statistically significant differences from thresholds after administration of vehicle ⫹ 0.03 mg/kg 8-OH-DPAT, ††p ⬍ 0.01.
Hashes (#) denote a statistically significant difference from thresholds
after 0.03 mg/kg p-MPPI ⫹ 0.03 mg/kg 8-OH-DPAT, indicating a p-MPPIinduced dose-dependent reversal of the effects of 8-OH-DPAT, ##p ⬍ 0.01.
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Harrison and Markou
effects of dorsal and median raphé infusions of 8-OH-DPAT.
8-OH-DPAT injections into the dorsal raphé reduced locomotor activity and had no effect on male sexual behavior,
whereas 8-OH-DPAT injections into the median raphé increased both locomotor activity and sexual behavior (Hillegaart, 1990; Hillegaart et al., 1991). These behavioral dissociations are probably related to the different targets of the
ascending projections from the dorsal and median raphé nuclei. The median raphé projects primarily to limbic forebrain
areas such as the septum, amygdala, and hippocampus,
whereas the dorsal raphé projects to striatal areas (Azmitia
and Segal, 1978). Infusions of 8-OH-DPAT into the dorsal
raphé reduce serotonin synthesis in the striatum, nucleus
accumbens, and cortex but not in the hippocampus and hypothalamus, whereas median raphé infusions reduced serotonin synthesis in all of the above-mentioned areas (Invernizzi et al., 1991). Thus, the median raphé effects may be
mediated through reduced serotonergic neurotransmission in
the hypothalamus that was the stimulation site in the
present study. This hypothesis is consistent with data summarized above indicating an inhibitory role for serotonin on
hypothalamic BSR (see the Introduction).
Consistent with the present data and previous reports (Lee
and Kornetsky, 1998), enhancing serotonergic neurotransmission by the acute administration of fluoxetine, a selective
serotonin reuptake inhibitor, elevated reward thresholds at
the highest (10-mg/kg) dose administered. Fluoxetine also
increased response latencies at all doses administered. Thus,
the threshold-elevating effect of acute fluoxetine may not be
a reward-related effect but instead may be due to alterations
of motor performance. However, previous reports indicated
elevated BSR thresholds after fluoxetine administration
without effects on response latencies (Lee and Kornetsky,
1998). Thus, the effects of fluoxetine on response latencies
are not consistent, and response latencies, as assessed by the
discrete-trial BSR procedure, may not necessarily be the best
measure of nonspecific effects of manipulations. In conclusion, the fluoxetine data also support the hypothesis that
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Fig. 5. Effects of median raphé infusions (histologies, Paxinos and
Watson 1998) (A) of 8-OH-DPAT on brain stimulation reward thresholds
(B) and response latencies (C) (mean ⫾ S.E.M.). Infusions of 8-OH-DPAT
into the median raphé nucleus lowered brain stimulation reward thresholds without affecting response latencies. Asterisks (ⴱ) denote statistically significant differences from thresholds after vehicle treatment. *p ⬍
0.05, **p ⬍ 0.01.
Fig. 6. Effects of dorsal raphé infusions (histologies, Paxinos and Watson,
1998) (A) of 8-OH-DPAT on brain stimulation reward thresholds (B) and
response latencies (C) (mean ⫾ S.E.M.). Infusions of 8-OH-DPAT into the
dorsal raphé nucleus had no effect on reward thresholds or response
latencies.
Serotonin-1A and Brain Stimulation Reward
enhancement of serotonergic neurotransmission decreases
BSR. Other than the 5-HT1A receptor, other receptors that
also may be involved in serotonin-induced inhibition of reward include the 5-HT1B receptor (Harrison et al., 1999).
The coadministration of p-MPPI, a 5-HT1A antagonist, and
a previously ineffective dose of fluoxetine (5 mg/kg) elevated
reward thresholds without affecting response latencies. Although there was a tendency for dose dependence of the
effects of p-MPPI on augmenting the effects of a previously
ineffective dose of fluoxetine (5 mg/kg) on threshold, this dose
dependence was not statistically reliable in the present
study. Nevertheless, previous work with p-MPPI and fluoxetine demonstrated that 3 mg/kg p-MPPI combined with 5
mg/kg fluoxetine was sufficient to induce threshold elevations in two independent replications (Harrison et al., 2001).
Thus, the p-MPPI-induced potentiation of fluoxetine’s effect
on thresholds is probably mediated by 5-HT1A receptor blockade in the raphé nuclei, presumably by potentiating the
effects of fluoxetine on serotonin levels. The present behav-
Fig. 8.. Effects of p-MPPI ⫹ fluoxetine on brain stimulation reward
thresholds (A) and response latencies (B) (mean ⫾ S.E.M.). p-MPPI (10
mg/kg) ⫹ fluoxetine (5 mg/kg) elevated reward thresholds without affecting response latencies. Asterisks (ⴱ) denote statistically significant differences from thresholds after vehicle treatment and 5 mg/kg fluoxetine.
*p ⬍ 0.05.
ioral data are consistent with neurochemical data indicating
that fluoxetine-induced enhancement of serotonergic neurotransmission is potentiated by pretreatment with a 5-HT1A
antagonist (Hjorth, 1993). These results are again consistent
with the hypothesis that serotonin plays an inhibitory role in
lateral hypothalamic BSR.
Nevertheless, it should be noted that the dose of p-MPPI
required to block the reward-decreasing effects of 8-OHDPAT (0.3 mg/kg p-MPPI) was significantly lower than that
demonstrated to augment the reward-reducing effects of fluoxetine previously (Harrison et al. 2001) and in the present
study (3 and 10 mg/kg, respectively). Thus, the possibility
remains that p-MPPI-induced augmentation of fluoxetine’s
effect on BSR may be mediated by antagonism at other
serotonin, and potentially nonserotonin, receptors for which
p-MPPI may have affinity at high concentrations (Kung et
al., 1994).
As discussed above, fluoxetine reliably decreases BSR (Lee
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Fig. 7. Effects of fluoxetine on brain stimulation reward thresholds (A)
and response latencies (B) (mean ⫾ S.E.M.). Fluoxetine (10 mg/kg) elevated brain stimulation reward thresholds. Fluoxetine (2.5, 5.0, or 10
mg/kg) increased the latency to respond. Asterisks (ⴱ) denote statistically
significant differences from thresholds or latencies after vehicle treatment. *p ⬍ 0.05, **p ⬍ 0.01.
323
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Harrison and Markou
Acknowledgments
We thank Mike Arends for computer and library searches and
editorial assistance, Robert Lintz and Robyn Bianco for technical
support, and Richard Schroeder for help with histologies.
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Send reprint requests to: Athina Markou, Ph.D., Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines
Rd., La Jolla, CA 92037. E-mail: [email protected]
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