Download Opposing roles for dopamine and serotonin in the modulation of

Opposing Roles for Dopamine and
Serotonin in the Modulation of Human
Spatial Working Memory Functions
Neurocognitive research has focused on monoaminergic influences
over broad behavior patterns. For example, dopamine (DA) generally
facilitates informational transfer within limbic and cortical networks
to promote reward-seeking behavior. Specifically, DA activity in
prefrontal cortex modulates the ability for nonhuman primates and
humans to perform spatial working memory tasks. Serotonin (5HT)
constrains the activity of DA, resulting in an opposing relationship
between DA and 5HT with respect to emotional and motor
behaviors. A role for 5HT in constraining prefrontally guided spatial
working memory (WM) processes in humans has not been
empirically demonstrated but is a logical avenue for study if these
principles of neurotransmitter activity hold within cortical networks.
In this study, normal humans completed a visuospatial WM task
under pharmacological challenge with (i) bromocriptine, a DA
agonist and (ii) fenfluramine, a serotonin agonist, in a double-blind,
repeated-measures, placebo-controlled design. Findings indicate
that bromocriptine facilitated spatial delayed, but not immediate,
memory performance. Fenfluramine resulted in impaired delayed
spatial memory. These effects were not due to nonspecific arousal,
attentional, sensorimotor or perceptual changes. These findings
suggest that monoaminergic neurotransmitters (DA and 5HT) may
interact within cortical networks to modulate the expression of
specific cognitive behaviors, particularly effortful processes
associated with goal-directed activity.
Introduction
In this report, we examine the modulatory roles of two monoaminergic neurotransmitters, dopamine (DA) and serotonin
(5HT), with respect to working memory (WM) functions
orchestrated by human prefrontal cortex (PFC). Centrally active
neurochemicals have been investigated in terms of their
inhibitory or excitatory effects on postsynaptic cells and/or their
inhibitory or excitatory effects on specific behaviors (Spoont,
1992). For example, DA appears generally to inhibit the activity
of postsynaptic target cells but to facilitate the behavioral
processes mediated by brain structures that are DA-innervated.
Examples of behaviors facilitated by functional increases in
DA activity include incentive-reward motivation, locomotor
initiation and emotional response facilitation (Collins and
Depue, 1992; P.F. Collins, unpublished), all mediated through
DA activity in the basolateral limbic forebrain. A role for DA in
facilitating cognitive functions, particularly those guided by PFC,
is also apparent (Beninger, 1983; Oades, 1985; Goldman-Rakic,
1987; Luciana et al., 1992). Oades (1985) suggests a mechanism
of DA facilitation, one whereby DA promotes the likelihood of
switching between alternative sources of information both
within and between neural circuits, allowing for modifications
in the temporal characteristics of an ongoing informationprocessing sequence. This function has been defined with
respect to cognitive functions as one of signal-to-noise
enhancement (Sawaguchi et al., 1988, 1990a,b; Cohen and
Servan-Schreiber, 1992, 1993). DA enhances the incoming
Monica Luciana, Paul F. Collins1, Richard A. Depue2
Department of Psychology, 75 East River Road, Minneapolis,
MN 55455, 1Department of Psychology, University of Oregon,
Eugene, OR and 2Department of Human Development at
Cornell University, Ithaca, NY, USA
neural signal relative to background ‘noise’ or interference, thus
creating a neural environment in which heightened DA activity
promotes the firing frequency of innervated neurons.
The threshhold of DA’s behavioral facilitation appears to
depend not only upon ‘trait’ factors related to dopaminergic
transmission, such as the number of midbrain DA cell bodies or
receptors in target structures (Fink and Reis, 1981) but also upon
other neuromodulators that provide regulatory inf luences over
DA activity. One example of a neuromodulator that regulates DA
activity is 5HT. Like DA, 5HT innervates widespread cortical and
subcortical brain regions including the limbic forebrain, basal
ganglia, frontal cortices and hypothalamic nuclei (Dahlstrom and
Fuxe, 1964). 5HT afferents are particularly prominent in the
thalamus and sensory cortices, consistent with a prominent role
for 5HT in modulating the f low of sensory information from the
peripher y to neocortex (Morrison et al., 1984; Azmitia and
Gannon, 1986). Behavioral studies have demonstrated that 5HT
provides tonic inhibition of DA’s facilitatory effects with
respect to a host of behaviors (Depue and Spoont, 1986;
Soubrie, 1986; Spoont, 1992). For example, hyperlocomotion
(mediated through DA activity in the nucleus accumbens) is
observed in rats following either increased DA transmission or
decreased 5HT transmission, and reaches extreme levels when
both neurochemical manipulations are employed (Grabowska,
1974; Gerson and Baldessarini, 1980; Jenner et al., 1983; Howell
et al., 1997). The same is true for other behavioral processes
including DA-enhanced exploratory behavior (Gately et al.,
1985), intracranial self-stimulation (Leccese and Lyness, 1984;
Nakahara et al., 1989) and responses to conditioned incentive
cues (Leone et al., 1983; Hodges and Green, 1984). Neurophysiologically, these findings are supported by evidence that
receptors for DA and 5HT are present and overlapping in both
limbic and cortical brain regions (Goldman-Rakic et al., 1990).
Moreover, specific interactions between prefrontal and limbic
serotonergic receptor systems in modulating the ascending A10
DA pathways have been demonstrated (Hagan et al., 1993; Wang
et al., 1995).
Whether this opposing modulatory relation between DA and
5HT holds with respect to cognitive, as well as limbic and
striatal, functions has not been studied extensively to date, but is
important in understanding neuromodulatory inf luences within
large-scale neurocognitive networks (Goldman-Rakic, 1988;
Mesulam, 1993). For example, the experimental manipulation of
DA transmission in the dorsolateral prefrontal cortex (DLPFC) of
nonhuman primates affects performance on prefrontally guided
spatial WM processes (Goldman-Rakic, 1987; Sawaguchi and
Goldman-Rakic, 1991).
Working memory refers to processes that allow responserelevant information to be maintained or held ‘on-line’ for brief
intervals and later used to guide behavioral actions (Baddeley,
1992; Goldman-Rakic, 1987, 1997). In spatial WM paradigms,
Cerebral Cortex Apr/May 1998;8:218–226; 1047–3211/98/$4.00
this information consists of parameters that define an object’s
location in extrapersonal space. Single-unit recordings from
the DLPFC have identified several subtypes of task-related
neurons during spatial WM performance which differentially
increase in firing rate during the initial presentation of a stimulus
cue, during the delay period, and spanning the interval between
the temporal delay and the response initiation periods (Fuster
and A lexander, 1971; Kojima and Goldman-Rakic, 1982;
Funahashi et al., 1989). Neurotoxic (6-hydroxydopamine)
lesions of the PFC’s dorsolateral convexity have produced
impaired spatial delayed alternation performance in rhesus
monkeys that was reversed by DA agonists (Brozoski et al.,
1979). Additionally, DA enhances PFC neuronal activity associated with the sequence of WM processes, including cellular
responses to the spatial cue, the delay, and/or memory-guided
response initiation (Sawaguchi et al., 1988, 1990a,b). Pharmacological blockade of DA receptors in monkeys results in
reversible decrements in accuracy and latency of an oculomotor
DR task (Sawaguchi and Goldman-Rakic, 1991). Furthermore,
Williams and Goldman-Rakic (1995) have demonstrated through
the use of iontophoretic injections of D1 and D2 receptor
antagonists into the nonhuman primate PFC that dopamine’s
facilitatory effects on the cellular processes that support WM are
dose dependent. The D1 receptor system appears to specifically
generate delay-related cellular activity, but only when stimulated
at an optimal level. The role of the D2 system appears to be more
complex, involving nonspecific regulation of task-relevant
cellular activity. A lterations in the D2 receptor system also
appear to contribute to the cognitive decline associated with
normal aging (Arnsten et al., 1995).
Human studies are consistent with these findings. Deficient
spatial WM performance has been reported in humans with
schizophrenia, an illness in which abnormalities of prefrontal
DA activity have been proposed (Park and Holtzmann, 1994;
Wong et al., 1986), and connectionist modeling that includes a
parameter to represent DA activity in cortical circuits accurately
accounts for the types of cognitive deficits displayed by
schizophrenics as they perfom WM tasks (Cohen and
Ser van-Schreiber, 1992, 1993). Relative to normal controls,
individuals with Parkinson’s disease demonstrate cognitive
deficits on prefrontal tasks as well as decreased activation of
prefrontal circuits during self-generated motor movements in a
WM task (Gotham et al., 1988; Levin et al., 1989; Jahanshahi et
al., 1995). Finally, pharmacological activation of D2 DA
receptors in normal humans has been demonstrated to facilitate
WM in a visuomotor spatial WM task (Luciana et al., 1992). The
current study was designed to replicate this latter finding in a
larger sample of normal subjects (Luciana and Collins, 1997) and
to expand the research beyond a single-transmitter hypothesis.
In particular, we were interested in delineating distinct
functional principles of activity for DA and 5HT in cognition by
examining their roles in spatial WM performance.
Serotonin’s role in learning and memory is among the least
understood of the monoaminergic neurotransmitters (Gold and
Zornetzer, 1983; Ogren, 1985; Wolkowitz et al., 1985), largely
because empirical findings vary depending upon the method by
which 5HT is manipulated, the extent of 5HT depletion or
enhancement, and the nature of the behavioral task employed
(Cole et al., 1994; Lalonde and Vikis-Freibergs, 1985). Consistent
with a proposed role for 5HT in inhibitory processes (Gray,
1982), Fibiger et al. (1978) were among the first to report that
electrical stimulation of the midbrain dorsal raphe (the source of
serotonergic projections to the cortex and striatum) disrupted
animals’ acquisition of a passive avoidance task. It has since been
demonstrated that intracerebral injections of 5HT impair
post-training retention of avoidance learning (Lalonde and
Vikis-Freibergs, 1985) and that administration of selective 5HT
receptor agonists impairs a range of cognitive abilitites,
including passive avoidance (Carli et al., 1992), memory of fear
conditioning (Quartermaine et al., 1993), spatial learning (Carli
and Samanin, 1992), operant learning in a delayed-matchto-sample task (Cole et al., 1994) and, most relevant to the
current study, WM on a radial arm maze task (Winter and
Petti, 1987). Furthermore, intrahippocampal implantation of
serotonergic ner ve grafts impaired rats’ performance on a
spatial learning task (Ramirez et al., 1989). Administration of
5-HT receptor antagonists, such as ondansetron, has been noted
to improve rats’ cognitive performance in a water maze (Fontana
et al., 1995) and to improve other abilities such as avoidance,
spatial and visual learning (McEntee and Mair, 1980; Altman and
Normile, 1986, 1988; Barnes et al., 1990; Domeney et al., 1991;
Carey et al., 1992; McEntee and Crook, 1991).
Whether these findings can be applied to humans has not
been extensively studied, although cognitive deficits have been
noted in human volunteers after receiving acute doses of 5-HT
agonists (Grasby et al., 1992; see Robbins, 1997, for a brief
review) and in psychiatric patients receiving selective serotonergic reuptake inhibitors (Bartfai et al., 1991; Sofuoglu and
DeBattista, 1996). Accordingly, we examined neuromodulatory
inf luences on spatial WM in normal humans using systemic
administration of fenf luramine (Pondimin), a 5HT agonist, and
bromocriptine (Parlodel), a DA agonist. We have previously
reported on the specific agonistic–antagonistic effects of
bromocriptine and haloperidol on spatial memory task
performance (Luciana and Collins, 1997). A subsample of the
participants who contributed data to our earlier report (n = 38 of
50 subjects) were also administered fenf luramine, and they are
the subjects of the current study.
Materials and Methods
Subjects
Twenty- four males and 14 females, aged 19–35 years (mean ± SD = 25.33
± 4.38) gave informed consent after the nature and possible consequences
of participation were explained. Subjects were psychiatrically normal, as
determined by structured interviews (Spitzer et al., 1990) administered
by the first two authors. Exclusions for pregnancy, oral contraceptive use
during the previous 4 months, prescribed medication during the previous
6 months, substance abuse, menstrual irregularities, endocrinopathies,
neurological disease or other relevant clinical conditions were applied.
All participants were examined by a physician prior to participation.
Psychopharmacological Manipulations
Subjects were studied in a double-blind crossover repeated-measures
design. All subjects received placebo (2.5 mg lactose), a 1.25 mg dose of
bromocriptine and a 60 mg dose of fenf luramine, a serotonin agonist,
during separate experimental sessions. Manipulation of the D2 DA system
was primarily selected because of the role that these receptors are
thought to play in a variety of motivational behaviors (Snyder and
Peroutka, 1984; Oades, 1985; Depue and Iacono, 1989; Luciana et al.,
1992). (See Luciana et al., 1992; Depue et al., 1994; Luciana and Collins,
1997, for complete rationales on the use of bromocriptine.)
Fenf luramine’s major clinical use is as an anorectic agent, similar in
structure to amphetamine but without amphetamine’s psychostimulant
properties (Murphy et al., 1986). The major 5HT agonistic properties of
fenf luramine are due to its ability to promote a rapid release of 5HT from
presynaptic terminals (Schwartz et al., 1989; Sabol et al., 1992) although
it can also potentiate serotonergic function by inhibiting the reuptake of
serotonin (Garratini et al., 1975). Because fenf luramine is receptor
nonspecific, it induces a generalized increase in 5HT neurotransmission
Cerebral Cortex Apr/May 1998, V 8 N 3 219
throughout the central nervous system. The specificity of fenf luramine’s
activation of 5HT (but not catecholaminergic) systems has been
supported by neurochemical and behavioral studies (Wood and
Emmett-Oglesby, 1988; Maura et al., 1992; Brauer et al., 1996; Shoabib et
al., 1997).
In this study, validation of each drug’s effects was ascertained by its
inf luence on the secretion of the neurohormone prolactin (PRL),
externally measured in blood serum. In humans, PRL secretion is reliably
and markedly inhibited by bromocriptine in a dose-dependent fashion,
with strong correlations between inhibition of PRL secretion and
bromocriptine dose and serum concentration (Lieberman et al., 1989).
Conversely, acute doses of fenf luramine lead to dose-dependent
increases in serum PRL secretion in healthy human controls (Coccaro et
al., 1990; Park et al., 1995) and in nonhuman primates (Shively et al.,
1995). Moreover, these effects are most significant when the oral dosage
exceeds 60 mg. Fenf luramine-dependent increases in serum PRL are
blocked by the 5HT angatonist metergoline and by the 5HT2 antagonist
ritanserin, suggesting that fenf luramine’s effects on PRL secretion are
mediated through the 5HT2 receptor system. The 5HT2 receptor system
receives projections from the dorsal raphe, which is also the source of
serotonergic projections to frontal cortex (Spoont, 1994).
Study Protocol
The protocol ran from 11.00 to 19.00 h, beginning with the insertion of
an i.v. catheter into the participant’s nondominant forearm. Identical
drug capsules were orally ingested at 12.00 h. In order to provide an
adequate washout period, experimental sessions were separated by at
least 3 days (Gruen et al., 1978.; McClelland et al., 1990). Subjects
remained awake and recumbent throughout the protocol. They fasted
from midnight the previous night until noon, with the exception of
several glasses of 2% milk to prevent hunger and nausea. Subjects
abstained from caffeine, nonprescription medications and alcohol for at
least 24 h before testing and were asked to observe a low monoamine diet
for 48 h prior to each visit. From 15.30 to 17.00 h during each
experimental session, participants completed several computerized
cognitive measures. These included a spatial WM task, a nonmnemonic
spatial location task and a biletter cancellation vigilance task. These are
each described in detail below.
Spatial Working Memory Task
Subjects were seated with sound-damping headphones and an adjustable
chin-forehead rest with eyes 27 cm from a monochrome computer
monitor. During each trial, subjects observed a central fixation point (a
black ‘+’, 0.63° × 0.63°) on the monitor for 3 s. Next, a visual cue (a black
circle, 0.21° diameter) appeared in peripheral vision within a 360°
circumference for 200 ms. After the occurrence of this visual cue, the cue
and fixation point disappeared, and the screen blackened for delay
intervals of 500, 4000 or 8000 ms. After the delay interval, the screen
instantly lit, and the subject indicated the screen location of the cue with
a fine-pointed lightpen, an input device which activates the monitor to be
touch-sensitive to it (FTG Data Systems, Inc.). Forty-eight trials (16 500, 16
4000 and 16 8000 ms delays), with a 2.0 s intertrial inter val, were
completed with delays randomly interspersed and cue locations
randomized over trials. Visual cues were presented at four different
locations in each of four quadrants for the three delay conditions. Visual
cue eccentricities were 10°, in order to minimize the use of edge or
center cues and to ensure that cues did not fall within each subject’s blind
spot. Locations of 0°, 90°, 180° and 270° were not included because of
the possibility of spatial referencing to exact vertical and horizontal
positions. Cue location was randomized over trials so that the subject
could not predict where the cue would appear on any given trial. This
design was identical to that used in a preliminary study of this research
(Luciana et al., 1992) and to that described in an additional report
(Luciana and Collins, 1997).
That this task is a reliable measure of WM is demonstrated by the
finding of significantly decreased accuracy of subjects’ performance on
500 ms delay versus no-delay trials under placebo conditions and by
continuous decrements in performance accuracy as the delay interval is
increased from 500 ms to 8 s (Luciana et al., 1992; Luciana and Collins,
1997).
220 Dopamine and Serotonin in Human Spatial Working Memory • Luciana et al
Nonmnemonic Spatial Location Control Task
A second visuospatial response task was added to this first measure in
order to determine more precisely that observed effects were not due to
drug effects on basic perceptual and/or sensorimotor processes. Prior to
completing the delayed response task described above, each subject
completed a nonmnemonic spatial location task during which (s)he
completed 16 stimulus trials (one at each stimulus location described
above), where the initial stimulus ( a black ‘*’) remained on screen after
its initial appearance. Subjects were instructed simply to touch the
stimulus dot with the lightpen. Accuracy and latency to respond were
recorded.
Scoring Method
Subjects’ errors in locating the visual cue in both the visuospatial WM and
nonmnemonic spatial location control task were scored as a composite
function of the horizontal and vertical distance (in mm) from actual cue
location. For each trial, composite error scores was computed by
Pythagorean theorem [(horizontal error distance)2 + (vertical error
distance)2 = (composite error distance score)2]. Composite error scores
were summed across each of the 16 trials within the four (no delay, 500,
4000 and 8000 ms) delay intervals and averaged to yield four scores for
each subject for each drug condition (placebo, bromocriptine and
fenf luramine,). Subjects were not given feedback as to the accuracy of
their performance.
Biletter Cancellation Task
To assess each drug’s effect on the maintenance of nonspecific
attentional, arousal and motor processes involved in a targeted visual
search, a biletter cancellation task (Lezak, 1983) was administered. This
task is a paper-and-pencil measure in which the subject views lined arrays
of letters on an 8.5 × 11 inch sheet of paper. The letters are presented in
upper case and organized in six horizontal rows of 52 letters each. The
subject is instructed to draw a line through all occurrences of two target
letters (Es and Cs) as quickly, but as accurately as possible. Time to
completion is recorded but is not experimentally restricted. Number of
omission and commision errors (unmarked target letters and incorrectly
marked nontarget letters respectively) and the time to completion were
tabulated for each drug condition.
The order of cognitive task administration was identical for each
subject on each study day. The nonmnemonic spatial location task was
administered first, followed by the spatial WM and biletter cancellation
tasks.
Assessment of Prolactin Secretion
Assessment Procedures
Pre-drug samples for baseline serum PRL were obtained at 11.45 and
11.55 h and averaged; 13 post-drug samples were obtained every 30 min
from 13.00 to 19.00 h. PRL assessment was limited to days 2–10 (early to
middle follicular phase) of females’ menstrual cycles. Blood samples were
spun down immediately, and serum samples were assayed in duplicate
within 2 days at the University of Minnesota Hospital Laboratory by use of
double-antibody radioimmunoassay.
Blood Pressure Assessment
Standing blood pressure was recorded at the start and end of each study
day. To record global changes in arousal levels, recumbent systolic and
diastolic blood pressures and pulse rates were measured by a registered
nurse hourly throughout each day.
Results
Statistical Analyses
Data were analyzed by univariate repeated-measures analyses of
variance (BMDP version 7.0, modules 2V and 4V) and paired
t-tests (BMDP module 3D). Alpha levels below 0.05 were viewed
as statistically significant.
Figure 1. Mean levels of serum PRL, expressed in micrograms/milliliter, for subjects
within each drug condition. Pre-drug levels were measured at 12.00 h. Post-drug levels
were recorded half-hourly from 12.30 until 19.00 h. Relative to placebo values,
bromocriptine administration resulted in decreased PRL levels over time, while
fenfluramine resulted in increased levels.
Exclusions
Medical records detailing the sequence of events during each
experimental session were blindly reviewed prior to data
analysis by the first two authors (M.L. and P.C.), who reached
consensus as to the validity of cognitive data collected within
each experimental session. Circumstances potentially affecting
the quality of collected data were noted. Subjects who experienced significant adverse reactions under any drug condition
were excluded from data analyses within that drug condition.
Adverse effects were typically related to bromocriptine administration (n = 10 subjects), and most often included sedation,
nausea, dizziness, light-headedness due to a fall in systolic or
diastolic blood pressure and/or vomiting during the time of
cognitive task administration. The 38 subjects (24 males and 14
females) who contributed data to this report completed both the
bromocriptine and fenf luramine protocols without adverse
reactions.
Drug Effects on Prolactin Secretion (Figure 1)
Drug effect values for individual subjects within each placebo–
drug comparison were computed. The average baseline PRL
value on each day of study was first computed by averaging the
11.45 and 11.55 h pre-drug specimen values for each
experimental session. To control for variations in baseline, each
PRL value in a subject’s placebo, bromocriptine and fenf luramine series was expressed as a change from its respective
average baseline value. Thus, each series was represented by 13
PRL baseline-corrected values. Five of these values (15.30, 16.00,
16.30, 17.00 and 17.30 h) were summed to represent, for each
experimental session, the total PRL effect during the time of
cognitive task administration. Comparison of these values on
placebo versus bromocriptine indicated a marked inhibition of
PRL by bromocriptine relative to placebo during the task
administration interval [t(37) = –5.52, P = 0.000]. Conversely,
comparisons of placebo and fenf luramine values indicate an
increase in PRL secretion during the task administration interval
[t(37) = 8.06, P = 0.000], indicating that fenf luramine was
physiologically active during the time of cognitive task
administration. Furthermore, the mean time of the maximum
effects on PRL secretion by each drug (∼17.00–17.30 h)
occurred during the task administration interval with no return
toward baseline values observed within this time period.
Drug Effects on Accuracy of Visuospatial Delayed
Response Performance (Figure 2)
Means and standard deviations for accuracy and latency of spatial
delayed response performance within each drug and delay (500,
Figure 2. Average error scores for performance on the spatial delayed response task
as a function of delay interval and drug condition. For each of 16 trials within each delay
condition, error score was tabluated for the subject’s response as a function of its
horizontal and vertical distance away from the actual target. These error scores,
expressed in millimeters, were summed and averaged within each delay condition. A
high score reflects increased error.
4000, 8000 ms) condition are represented in Table 1. A
repeated-measures ANOVA on averaged error scores over trials
on three delays (500, 4000, 8000 ms) and three drug conditions
(placebo versus bromocriptine versus fenf luramine) indicated a
main effect of drug [F(2,74) = 4.54, P < 0.05], a main effect of
delay [F(2,74) = 95.73, P < 0.000], and a significant drug × delay
interaction [F(4,148) = 5.20, P < 0.001]. A priori linear
contrasts were done to assess the effects of bromocriptine
versus fenf luramine on performance accuracy. As compared to
placebo, there was a marginal main effect of bromocriptine
[F(1,37) = 2.81, P = 0.10] as well as a significant drug × delay
interaction [F(2,74) = 3,31, P < 0.05]. For the fenf luramine
versus placebo comparison, there was no significant main effect
of drug, but there was also a significant drug × delay interaction
[F(2,74) = 3.45, P < 0.05].
Similar contrasts were performed to compare performance
on short delay (4000 ms) and long delay (8000 ms) drug trials
relative to the 500 ms delay under each drug condition. For
short-delay trials (4000 versus 500 ms), there was no significant
drug × delay interaction for bromocriptine/placebo comparisons
[F(1,37) = 2.79, NS] or for fenf luramine/placebo comparisons
[F(1,37) = 0.09, NS]. For long delay trials (8000 versus 500 ms),
there were significant drug × delay interactions relative to
placebo for both bromocriptine [F(1,37) = 6.04, P < 0.05] and
fenf luramine [F(1,37) = 6.30, P < 0.05]. These drug effects,
represented in Figure 2, indicate that accuracy of performance
on 4000 ms trials was not manipulated by either bromocriptine
or fenf luramine administration. The finding of a significant drug
× delay interaction in the long delay condition (8000 versus
500 ms) indicated inhibition of 8000 ms delayed memory
performance by fenf luramine and facilitation of 8000 ms
delayed memory performance by bromocriptine.
Drug Effects on Latency of Visuospatial Delayed
Response Performance (Figure 3)
Response latencies were similarly examined, yielding no
significant main effect of drug [F(2,70) = 0.19, NS], a main effect
of delay [F(2,70) = 4.54, P = 0.01] and no significant drug × delay
Cerebral Cortex Apr/May 1998, V 8 N 3 221
Table 1
Spatial delayed response performance
Drug condition
Delay Interval
No delay
Placebo
Bromocriptine
Fenfluramine
500 ms
4000 ms
8000 ms
Accuracy
Latency
Accuracy
Latency
Accuracy
Latency
Accuracy
Latency
3.67 ± 2.48
3.59 ± 1.96
3.86 ± 2.13
1167.9 ± 348.7
1194.3 ± 372.1
1247.5 ± 412.2
6.68 ± 3.29
6.46 ± 2.60
6.81 ± 2.39
2052.44 ± 551.1
2023.4 ± 474.1
2076.7 ± 478.9
9.20 ± 3.88
8.26 ± 2.88
9.46 ± 4.05
2078.00 ± 488.1
2095.2 ± 509.9
2080.2 ± 516.7
10.66 ± 4.05
9.39 ± 2.95
11.91 ± 4.35
2106.0 ± 536.1
2107.5 ± 522.4
2155.3 ± 565.7
Values represent means and SDs. Accuracy scores are average error scores, in millimeters, across 16 trials within each delay condition. Latency scores are expressed in milliseconds and are averaged
across 16 trials within each delay condition.
Figure 3. Average response latencies in milliseconds as a function of delay interval
and drug condition for the spatial delayed response task. Latencies represent averages
across each of sixteen trials within each delay condition.
interaction [F(4,140) = 1.06, NS]. A priori linear contrasts
comparing the effects of bromocriptine and fenf luramine,
relative to placebo, yielded no main effect of bromocriptine nor
a bromocriptine × delay interaction [F(1,35) = 1.98, NS]. There
was also no main effect of fenf luramine administration nor was
there a fenf luramine × delay interaction [F(2,70) = 1.36, NS].
Linear contrasts compariing the 4000 and 500 ms delays yielded
neither a main effect of delay [F(1,35) = 1.98, NS] nor a
significant drug × delay interaction [F(2,70) = 1.36, NS].
Comparisons of the 8000 and 500 ms delay conditions yielded a
main effect of delay [F(1,35) = 5.83, P < 0.05] but no significant
drug × delay interaction [F(2,70) = 0.32, NS]. The main effects of
delay inter val were due to longer response latencies at
increasing delay intervals. Drug effects on response latencies are
presented in Figure 3.
Figure 4. Drug effects on peripheral indices of autonomic arousal from baseline (12.00
h) until the end of the cognitive task administration interval (18.00 h). The upper graph
represents changes in systolic blood pressure. Middle figure represents changes in
diastolic blood pressure. Blood pressure was recorded under resting conditions. Bottom
graph represents changes over time in one-minute resting pulse rate. All values
represent mean levels for each time point recorded.
Drug Effects on Basic Sensorimotor and Attentional
Processes
or response latency [F(2,62) = 0.84, NS] for this group of
subjects.
Nonmnemonic Spatial Location Performance (see Table 1)
Drug effects on basic sensorimotor and perceptual abilities were
examined. Subjects’ errors in touching a stimulus dot with the
lightpen device when the dot remained on screen were
examined. Means and standard deviations for accuracy scores
and response latencies are represented in Table 1. There was no
effect of drug condition (bromocriptine or fenf luramine, relative
to placebo) on average performance acuracy [F(1,31) = 0.31, NS]
Biletter cancellation task (Table 2)
A repeated-measures ANOVA comparing the total error score
across drug conditions yielded no main effect of drug [F(2,72) =
0.01, NS]. A similar analysis on the times to completion across
drug conditions yielded no effect of drug [F(2,72) = 0.30, NS].
Means and standard deviations representing task performance
within each drug condition are presented in Table 2.
222 Dopamine and Serotonin in Human Spatial Working Memory • Luciana et al
Table 2
Letter cancellation task performance by drug condition
Drug
Number of errors
Time to completion
Placebo
Bromocriptine
Fenfluramine
1.16 ± 1.80
1.19 ± 1.63
1.14 ± 1.27
93.37 ± 24.02
93.19 ± 16.21
90.79 ± 21.35
Number of omission and commission errors were summed to yield the total number of errors.
Times to completion were recorded in seconds. Values listed represent means ± 1 SD.
Moderators of Cognitive Performance
Error scores and response latencies under placebo conditions
were not significantly associated with age (rs = 0.01–0.21).
Similarly, the effects of bromocriptine and fenf luramine on task
performance were unrelated to age. There were no main effects
of gender or interactions between drug condition and gender on
task performance. Finally, there were no main effects of visit
number or interactions between drug condition and visit
number for performance on the delayed response task.
Drug Effects on Blood Pressure and Pulse Rate
(Figure 4)
The effects of each drug on systolic and diastolic blood pressures
were evaluated in a manner similar to PRL secretion. Blood
pressure was recorded hourly from 12.00 to 19.00 h while
subjects were in a recumbent position. Drug effect values for
individual subjects within each placebo–drug comparison were
computed. The baseline blood pressure value on each day of
study was assessed at 12.00 h, and consisted of recordings of
both systolic and diastolic blood pressures. To control for variations in baseline across separate study days, each subsequent
blood pressure value in a subject’s placebo, bromocriptine and
fenf luramine series was expressed as a change from its
respective baseline value. Thus, each series was represented by
seven baseline-corrected values. Three of these values (15.00,
16.00, 17.00 h) were summed to represent, for each experimental session, the total blood pressure effect during the time of
cognitive task administration.
From 15.00 to 17.00 h there was a significant difference in
baseline-corrected systolic blood pressure on placebo versus
bromocriptine [t(37) = –4.55, P < 0.001] but not between
placebo and fenf luramine [t(37) = 0.45. NS]. Bromocriptine
resulted in a systematic decrease in systolic blood pressure over
time. Diastolic blood pressure was similarly evaluated, yielding a
significant effects of bromocriptine [t(37) = –1.99, P = 0.05] but
no significant effect of fenf luramine [t(37) = –0.33, NS]. Pulse
rate was not affected by either bromocriptine [F(36) = 1,73, P <
0.10] or fenf luramine [t(36) = –0.03, NS]. These findings are
represented in Figure 4.
Discussion
Spatial WM processes, at delays exceeding 4000 ms, appear
to have been facilitated in the same group of subjects
by bromocriptine and impaired by fenf luramine. Neither
bromocriptine nor fenf luramine affected task components that
were unrelated to the delay manipulation such as attentional,
sensory or psychomotor processes engaged in attending to the
trial sequence and formulating a response as indexed by performance on the biletter cancellation task and by nonmnemonic
spatial location performance. Assessment of autonomic indices
of arousal (blood pressure and pulse rate) indicated that
bromocriptine resulted in a significant decrease in blood
pressure during the task administration inter val. Pulse rate
was not affected. Relative to placebo values, fenf luramine
administration did not result in significant blood pressure or
pulse rate changes.
The pattern of results supports several general conclusions
with respect to potential dopaminergic–serotonergic interactions in the modulation of specific cognitive behaviors.
Although we acknowledge that our effect sizes are small, we
have progressively demonstrated and replicated our finding of
facilitated spatial WM in normal humans by increased DA
transmission and impairment by decreased DA transmission
(Luciana et al., 1992; Luciana and Collins, 1997). These data
parallel findings in nonhuman primates with respect to
modulation of spatial WM functions following manipulations of
DA transmission in DLPFC. The suggestion based on the primate
literature is that DA acts on a neuronal level to enhance the
stimulus signal across the temporal delay inter val relative to
background noise or interference (Sawaguchi et al., 1988,
1990a,b). Our findings are consistent with this hypothesis.
In this study, increased 5HT transmission impaired spatial
WM, consistent with 5HT’s opposing modulatory inf luence
relative to DA on other behaviors. That is, functional increases of
5HT, as achieved by a single acute dose of fenf luramine, appear
to have constrained the general f low of information that
underlies successful peformance on this task. A more direct test
of DA/5HT interactions would be accomplished by administering doses of DA and 5HT agonists simultaneously to the same
group of subjects. However, if DA is endogenously activated
during spatial memory performance, as would be presumed
from the animal literature, which emphasizes the importance of
catecholamines in the modulation of WM (Goldman-Rakic, 1987;
Sawaguchi and Goldman-Rakic, 1991), then 5HT appears to have
countered the effects of task-related DA enhancement, as has
been demonstrated with other forms of behavior, including
5HT’s attenuation of amphetamine-induced hyperlocomotion.
Moreover, the effects of fenf luramine on specific parameters of
WM performance exactly parallel what is seen when DA is
exogenously activated using bromocriptine, despite the fact that
an exact parametric correpondence between the doses of each
drug used for individual subjects was not attempted.
Given the preponderance of 5HT in sensory pathways and the
presence of DA in basal ganglia circuits, it is significant that the
observed changes in cognitive task performance did not appear
to be secondary to changes in basic sensorimotor, attentional or
global arousal processes. Neither bromocriptine nor fenf luramine exerted an inf luence on task response latencies, on the
ability to simply locate a stimulus dot under nonmnemonic
conditions nor on a speeded targeted visual search task.
A lthough our findings suggest that bromocriptine caused a
decrease in autonomic arousal, fenf luramine administration did
not result in a corresponding increase. Moreover, if changes in
arousal are mediating cognitive performance, the effects are not
equivalent across tasks or with respect to performance
parameters within a task. Hence, we conclude that these data
provide support for the interpretation that the observed changes
in spatial WM performance are due, not to basic motor,
mnemonic or sensory alterations, but to each drug’s effects on
processes that are associated with the temporal integration of
the sensory cue with the desired response.
Neither bromocriptine nor fenf luramine exerted inf luences
on WM task performance until the delay interval exceeded 4 s.
While it may be that longer delay intervals are necessary to tax
executive processes that support WM in normal adult humans,
Cerebral Cortex Apr/May 1998, V 8 N 3 223
applications of DA or its antagonists directly into the principal
sulcal region of nonhuman primates results in changes in task
performance when temporal delay intervals are as short as 1 s
(Sawaguchi and Goldman-Rakic, 1991). The fact that performance accuracy was not altered, even subtly, at all delay
intervals raises the question of whether short versus long delay
intervals equivalently engage processes outside of memory that
are important for optimal ‘working with memory’ performance.
Robbins (1996) notes that when normal humans perform a
self-ordered searching task involving spatial WM, they recruit an
organized strategy to minimize the task’s mnemonic demands.
Moreover, although individuals with both frontal and temporal
lobe lesions demonstrate mnemonic errors on the task, strategy
use is significantly impaired in 70% of patients with lesions to the
frontal, but not temporal, lobes of the brain (Owen et al., 1990,
1996) and correlates with the degree of mnemonic error in
this group. Based on these findings, Robbins (1996) provides
empirical support to suggest that deficient performance on
spatial WM tasks involve two components: one that is purely
mnemonic (highly dependent upon temporal lobe structures)
and one that involves strategic use of memory to accomplish
behavioral goals, dependent on an intact PFC. Our data support
the view that monoaminergic neurotransmitters interact to
modulate spatial WM performance through this latter, more
‘effortful’ task component, since neither bromocriptine nor
fenf luramine affected purely mnemonic or psychomotor aspects
of performance.
What types of effortful processes might contribute to accurate spatial WM performance in a delay-dependent manner? It
seems reasonable to speculate that more difficult task items (e.g.
those requiring mnemonic integration through increasingly long
temporal delays) tax not only short-term memory processes,
but also higher-order processes such as focused attention
and inhibitor y control that are important for maintaining
motivational resources over time, allowing for ongoing effort
toward the achievement of specific goals (in this case, accuracy
of manually guided task performance). The importance of
effortful processes as mediators of frontal lobe task performance
has been emphasized in several recent reports (Burgess and
Shallice, 1996; Kapur et al., 1996; Luciana and Nelson, 1997;
Wheeler et al., 1997).
Moreover, a specific role for serotonin in modulating
motivational biases during cognitive task performance has been
suggested (Steckler and Saghal, 1995). With respect to DA,
Williams and Goldman-Rakic (1995) suggest a precise role for
the D1 receptor system in modulating the ‘memory fields’ of
locally active neurons. Their research suggests that systemic
administration of D1 receptor agonists, at optimal dose levels,
would enhance mnemonic processes regardless of delay interval.
In constrast, Williams and Goldman-Rakic (1995) found that
iontophoretic administrations of D2 antagonists did not
specifically alter the mnemonic fields of task-related neurons.
This obser vation is consistent with the fact that the cortical
distribution of D2 receptors is prominent in layers III and V,
where information processing occurs through widespread
corticocortical, corticostriatal and corticolimbic networks (see
Luciana et al., 1992, for a more complete discussion). Hence, the
predicted effects of subtle manipulations of the D2 system on
WM would not involve alterations in specific processes, but in
those aspects of task performance that best ref lect the effortful
integration of sensory, motor, mnemonic and motivational
resources. Under pharmacological challenge conditions, it is
likely that increasingly pronounced behavioral changes would
224 Dopamine and Serotonin in Human Spatial Working Memory • Luciana et al
be observable either with increased task demand (e.g. in the
course of longer delay intervals, by increasing informational load
within WM tasks, or under conditions of low motivation) or with
more direct neurochemical manipulations.
Clinical Implications
Although distinct modulatory roles for DA and 5HT have gained
increasing acceptance with respect to limbically mediated
emotional and striatally mediated motor behaviors, the findings
of this study suggest that complex cognitive functions, such as
those organized within prefrontal cortical circuitr y, may fall
under opposing modulatory inf luences of DA and 5HT similar to
those obser ved in studies of simpler forms of behavioral
responding in nonhuman primates. Under the most adaptive set
of endogeneous conditions, the neurochemical balance between
DA and 5HT could be inf luential in determining overall proficiency in similar cognitive tasks. These findings are important
from a clinical perspective, since both DA and 5HT disruptions
have been implicated in psychiatric disorders including
schizophrenic psychosis (Kapur and Remington, 1996), mood
disorders (Depue and Iacono, 1989; Kramer, 1991) and disorders
of impulse control (Coccaro et al., 1989). Although current
psychiatric treatment strategies tend to focus on manipulations
of one transmitter system or the other (Kramer, 1991), leading to
single-transmitter theories of etiology of specific clinical
disorders, it is likely that an understanding of the complex
interactions among modulatory neurotransmitters may contribute to increasingly refined pharmacological treatments.
Whether this finding of impaired spatial WM by fenf luramine
can be generalized to nonspatial forms of WM and replicated
through the use of other psychopharmacological agents is a
matter for continued research. Moreover, it is essential, from a
clinical standpoint, to assess whether similar pharmacological
effects would be evident in the course of chronic versus acute
treatment with other 5HT agonists.
Notes
The assistance of the staff of the Clinical Research Center at the University
of Minnesota Hospital and Jim Mitchell, MD who acted as medical
consultant to this project, is gratefully acknowledged. Thanks are
extended to Kathy McGuire and Muree L. Larson for assistance in data
collection and to Auke Tellegen who provided invaluable support and
mentorship while this data was being collected and analyzed. This work
was supported by NIMH grant MH48114 awarded to R.A.D. and by grant
M01-RR00400 from the National Center for Research Resources, National
Institute of Health.
Address correspondence to Monica Luciana, Department of
Psychology, 75 East River Road, Minneapolis, MN 55455, USA. Email:
[email protected].
References
A ltman HJ, Normile HJ (1986) Enhancement of the memor y of a
previously learned aversive habit following pre-test administration of a
variety of serotonergic antagonists in mice. Psychopharmacology
90:24–27.
A ltman HJ, Normile HJ (1988) What is the nature of the role of the
serotonergic nervous system in learning and memory: prospects for
development of an effective treatment strategy for senile dementia.
Neurobiol Aging 9:627–638.
Arnsten AFT, Cai JX, Steere JC, Goldman-Rakic PS (1995) Dopamine D2
receptor mechanisms contribute to age-related cognitive decline: The
effects of quinpirole on memory and motor performance in monkeys.
J Neurosci 15:3429–3439.
Azmitia EC, Gannon PJ (1986) The primate serotonergic system: a review
of human and animal studies and a report on Macaca fascicularis. In:
Advances in Neurology, Vol. 43, Myoclonus (Fahn S, Marsden CD, Van
Woert M, eds). New York: Raven Press.
Baddeley A D (1992) Working memory. Science 255:556–559.
Bartfai A, Asberg M, Martensson B, Gustavsson P (1991) Memory effects
of clomipramine treatment: relationship to CSF monoamine
metabolites and drug concentrations in plasma. Biol Psychiat
30:1075–1092.
Barnes JM, Costall B, Coughlan J, Domeney AM, Gerrard PA, Kelly ME,
Naylor RJ, Onaivi ES, Tomkins DM, Tyers MB (1990) The effects of
ondansetron, a 5-HT3 receptor antagonist on cognition in rodents and
primates. Pharmacol Biochem Behav 35:955–962.
Beninger RJ (1983) The role of dopamine in locomotor activity and
learning. Brain Res Rev 6:173–196.
Brauer LH, Johanson CE, Schuster CR, Rothman RB, deWit H (1996)
Evaluation of phentermine and fenf luramine alone and in
combination in normal healthy volunteers. Exp Clin Psychopharmacol
(in press).
Brozoski TJ, Brown RM, Rosvold HE, Goldman P (1979) Cognitive deficit
caused by regional depletion of dopamine in prefrontal cortex of
rhesus monkey. Science 205, 929–931.
Burgess PW, Shallice T (1996) Response suppression, initiation and
strategy use following frontal lobe lesions. Neuropsychologia
34:263–272.
Carey GJ, Costall B, Domeney AM., Gerrard PA, Jones DNC, Naylor RJ,
Tyers B (1992) Ondansetron and arecoline prevent scopolamineinduced cognitive deficits in the marmoset. Pharmacol Biochem
Behav 42:75–83.
Carli M, Samanin R (1992) 8-hydroxy-2-(di-n-propylamino) tetralin
impairs spatial learning in a water maze: role of postsynaptic 5HT1A
receptors. Br J Pharmacol105:720–726.
Carli M, Lazarova M, Tatarczynska E, Samanin R (1992) Stimulation of
5-HT1A receptors in the dorsal hippocampus impairs acquisition and
performance of a spatial task in a water maze. Brain Res 595: 50–56.
Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, Cooper TB, Mohs
RC, Davis KL (1989) Serotonergic studies in patients with affective
and personality disorders. Arch Gen Psychiat 46:587–599.
Cohen, J.D., and Ser van-Schreiber D. (1992) Context, cortex, and
dopamine: a connectionist approach to behavior and biology in
schizophrenia. Psychological Reports, 45–75.
Cohen JD, Servan-Schreiber D (1993) A theory of dopamine function and
its role in cognitive deficits in schizophrenia. Schizophr Bull
19:85–104.
Cole BJ, Jones GH, Turner JD (1994) 5-HT1A receptor agonists improve
the performance of normal and scopolamine-impaired rats in an
operant delayed matching to position task. Psychopharmacology
116:135–142.
Collins PF, Depue R A (1992) A neurobehavioral systems approach to
developmental psychopathology: implications for disorders of affect.
In: Rochester Symposium on Developmental Psychopathology, Vol. 4,
Developmental perspectives on depression (Cicchetti D, Toth SL,
eds), pp. 29–101. Rochester, NY: University of Rochester Press,
Dahlstrom A, Fuxe K (1964) Evidence for the existence of monoaminecontaining neurons in the central nervous system I: Demonstrations of
monoamines in the cell bodies of brain stem neurons. Acta Physiol
Scand 62(suppl. 232):1–55.
Depue R A, Iacono WG (1989) Neurobehavioral aspects of affective
disorders. Annu Rev Psychol 40:457–492.
Depue R A, Spoont MR (1986) Conceptualizing a serotonin trait: a
behavioral dimension of constraint. Ann NY Acad Sci 487:47–62.
Depue R A, Luciana M, Arbisi P, Collins PF, Leon A (1994) Relation of
agonist-induced dopamine activity to personality. J Personal Soc
Psychol 485–498.
Domeney AM, Costall B, Gerrard PA, Jones DNC, Naylor RJ, Tyers MB
(1991) The effect of endansetron on cognitive performance in the
marmoset. Pharmacol Biochem Behav 38:169–75.
Fibiger HC, Lepiane FG, Philips AG (1978) Disruption of memor y
produced by stimulation of the dorsal raphe nucleus: mediation by
serotonin. Brain Res 155:380–386.
Fink JS, Reis DJ (1981) Genetic variations in midbrain dopamine cell
number: parallel with differences in responses to dopaminergic
agonists and in naturalistic behaviors mediated by dopaminergic
systems. Brain Res 222:335–349.
Fontana DJ, Daniels SE, Henderson C, Eglen RM, Wong EHF (1995)
Ondansetron improves cognitive performance in the Morris water
maze spatial navigation task. Psychopharmacology 120:409–417.
Funahashi S, Bruce CJ, Goldman-Rakic PS (1989) Mnemonic coding of
visual space in the monkey’s dorsolateral prefrontal cortex.
J Neurophysiol 61:331–349.
Fuster JM, Alexander GE (1971) Neuron activity related to short-term
memory. Science 173:652–654.
Garratini S, Jory A, Buczko W, Samanin R (1975) The mechanism of action
of fenf luramine. Postgrad Med J 51(suppl 1):27–35.
Gately PF, Poon SL, Segal DS, Geyer MA (1985) Depletion of brain
serotonin by 5,7-dihydroxytr yptamine alters the response to
amphetamine and the habituation of locomotor activity in rats.
Psychopharmacology 87:400–405.
Gerson SC, Baldessarini RJ (1980) Motor effects of serotonin in the central
nervous system. Life Sci 27:1435–1451.
Gold PE, Zornetzer SF (1983) The mnemon and its juices: neuromodulation of memory processes. Behav Neural Biol 38:151–189.
Goldman-Rakic PS (1987) Circuitr y of primate prefrontal cortex and
regulation of behavior by representational memory. In: Handbook of
physiology: the nervous system. Bethesda, MD: Am. Physiol. Soc., vol.
5, pp. 373–417.
Goldman-Rakic PS (1988) Topography of cognition: parallel distributed
networks in primate association cortex. Annu Rev Neurosci
11:137–156.
Goldman-Rakic PS (1997) Space and time in the mental universe. Nature
386:559–560.
Goldman-Rakic PS, Lidow MS, Gallager DW (1990) Overlap of
dopaminergic, adrenergic, and serotoninergic receptors and
complementarity of their subtypes in primate prefrontal cortex.
J Neurosci 10:2125–2138.
Gotham AM, Brown RG, Marsden CP (1988) Frontal cognitive deficits in
patients with Parkinson’s disease on and off levodopa. Brain
111:299–321.
Grabowska M (1974) Inf luence of midbrain raphe lesions on some
pharmacological and biochemical effects of apomorphine in rats.
Psychopharmacologia 39:315–322.
Grasby PM, Friston KJ, Bench CJ, Frith CD, Paulesu E, Cowen PJ, Liddle
PF, Frakowiak RSJ, Dolan R (1992) The effect of apomorphine and
buspirone on regional cerebral blood f low during the performance of
a cognitive task measuring neuromodulatory effects of psychotropic
drugs in man. Eur J Neurosci 4:1203–1212.
Gray J (1982) The neuropsychology of anxiety. Oxford: Clarendon Press.
Gruen P, Sachar EJ, Langer G, Altman N, Leifer M, Frantz A, Halpern F
(1976) Prolactin responses to neuroleptics in normal and
schizophrenic subjects. Arch Gen Psychiat 35:108–116.
Hagan RM, Kilpatrick GJ, Tyers MB (1993) Interactions between
5-HT-sub-3 receptors and cerebral dopamine function: implications
for the treatment of schizophrenia and psychoactive substance abuse.
Psychopharmacology 112:S68–S75.
Hodges HM, Green S (1984) Evidence of the involvement of brain GABA
and serotonin systems in the anticonf lict effects of chlodiazepoxide in
rats. Behav Neural Biol 40:127–154.
Howell LL, Czoty PW, Byrd LD (1997) Pharmacological interactions
between serotonin and dopamine on behavior in the squirrel monkey.
Psychopharmacology 131:40–48.
Jahanshahi M, Jenkins IH, Brown RG, Marsden CD, Passingham RE,
Brooks DJ (1995) Self-initiated versus externally-triggered movements
I. An investigation using measurement of regional cerebral blood f low
with PET and movement-related potentials in normals and Parkinson’s
disease subjects. Brain 118:913–933.
Jenner P, Sheehy M, Marsden CD (1983) Noradrenaline and 5-hydroxytryptamine modulation of brain dopamine function: implications for
the treatment of Parkinson’s disease. Br J Clin Pharmacol 15:
277s–289s.
Kapur S, Remington G (1996) Serotonin–dopamine interaction and its
relevance to schizophrenia. Am J Psychiat 153:466–476.
Kapur S, Tulving E, Cabeza R, McIntosh AR, Houle S, Craik FIM (1996)
The neural correlates of intentional learning of verbal materials: a PET
study in humans. Cognit Brain Res 4:243–249.
Kojima S, Goldman-Rakic PS (1982) Delay-related activity of prefrontal
neurons in rhesus monkeys performing delayed response. Brain Res
248:43–49.
Kramer PD (1993) Listening to Prozac. New York: Penguin.
Lalonde R, Vikis-Freibergs V (1985) Manipulations of 5-HT activity and
memory in the rat. Pharmacol Biochem Behav 22:377–382.
Leccese AP, Lyness WH (1984) The effects of putative 5-hydroxytryptamine receptor active agents on d-amphetamine self-administration in
Cerebral Cortex Apr/May 1998, V 8 N 3 225
controls and rats with 5,7-dihydroxytryptamine median forebrain
bundle lesions. Brain Res 303:153–162.
Leone CM, DeAguir JC, Graeff FG (1983) Role of 5-hydroxytryptamine in
amphetamine effects on punished and unpunished behavior.
Psychopharmacology 80:78–82.
Levin BE, Labre MM, Weiner WJ (1989) Cognitive impairments associated
with early Parkinson’s disease. Neurology 39:557–561.
Lezak MD (1983) Neuropsychological assessment. New York: Oxford
University Press.
Lieberman JA, Alvir J, Mukherjee S, Kane JM (1989) Treatment of tardive
dyskinesia with bromocriptine: a test of the receptor modification
strategy. Arch Gen Psychiat 46:908–913.
Luciana M, Collins PF (1997) Dopamine modulates working memory for
spatial but not object cues in normal humans. J Cognit Neurosci
9:330–347
Luciana M, Depue R A, Arbisi P, Leon A (1992) Facilitation of working
memor y in humans by a D2 dopamine receptor agonist. J Cognit
Neurosci 4:58–68.
Luciana M, Nelson CA (1997) The functional emergence of prefrontallyguided working memory systems in four-to-eight year-old children.
Neuropsychologia (in press).
Maura G, Gemignani A, Versace P, Martire M, Raiteri M (1982)
Carrier-mediated and carrier-independent release of serotonin from
isolated central nerve endings. Neurochem Int 4:219–224.
McClelland GR, Cooper SM, Pilgrim J (1990) A comparison of the central
nervous system effects of haloperidol, chlorpromazine, and sulpiride
in normal volunteers. Br J Clin Pharmacol 30: 795–803.
McEntee WJ, Mair RG (1980) Memor y enhancement in Korsakoff’s
psychosis by clonidine: further evidence for a noradrenergic deficit.
Ann Neurol 7:466–470.
McEntee WJ, Crook TH (1991) Serotonin, memory and the aging brain.
Psychopharmacology 103:143–149.
Mesulam MM (1990) Large-scale neurocognitive networks and distributed
processing for attention, language, and memor y. Ann Neurol
28:597–613.
Morrison JH, Foote SL, Bloom, FE (1984) Regional, laminar,
developmental and functional characteristics of noradrenaline and
serotonin innervation patterns in monkey cortex. In: Monoaminergic
innervation of cerebral cortex (Descarries L, Reader TR, Jaspers HH,
eds). New York: Alan R. Liss.
Murphy DL, Mueller EA, Garrick NA, Aulakh CS (1986) Use of
serontonergic agents in the clinical assessment of central serotonin
function. J Clin Psychiat 47:9–15.
Nakahara D, Ozaki N, Miura H, Nagatsu T (1989) Increased dopamine and
serotonin metabolism in rat nucleus accumbens produced by
intracranial self-stimulation of medial forebrain bundle as measured
by in vivo microdialysis. Brain Res 495:178–181.
Oades RD (1985) The role of noradrenaline in tuning and dopamine in
switching between signals in the CNS. Neurosci Biobehav Rev
9:261–282.
Ogren SQ (1985) Evidence for a role of brain serotonergic transmission in
avoidance learning. Acta Psychiatr Scand 125(suppl 544).
Owen A M, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW (1990)
Planning and spatial working memory following frontal lobe lesions in
man. Neuropsychologia 28:1021–1034.
Owen A M, Morris RG, Sahakian BJ, Polkey CE, Robbins TW (1996)
Double dissociations of memor y and executive functions in a
self-ordered working memor y task following frontal lobe excision,
temporal lobe excision or amygdala-hippocampectomy in man. Brain
(in press).
Park SBG, Williamson DJ, Cowen PJ (1995) Do the endocrine and
subjective effects of d-fenf luramine predict response to selective
serotonin reuptake inhibitors? Int Clin Pharmacol 10: 215–220.
Park S, Holtzmann PS (1992) Schizophrenics show spatial working
memory deficits. Arch Gen Psychiat 49:975–982.
Quartermaine D, Clemente J, Shemer A (1993) 5-HT1A agonists disrupt
memory of fear conditioning in rats. Biol Psychiat 33:247–254.
226 Dopamine and Serotonin in Human Spatial Working Memory • Luciana et al
Ramirez TM, Altman HJ, Normile HJ, Kuhn DM, Azmitia EC (1989) The
effects of serotonergic intrahippocampal neonatal grafts on learning
and memory in the Stone 14-unit T-maze. Soc Neurosci Abstr 15:465.
Robbins TW (1996) Dissociating executive functions of the prefrontal
cortex. Phil Trans R Soc B (in press).
Robbins TW (1997) Arousal systems and attentional processes. Biol
Psychol 45:57–71.
Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in
prefrontal cortex: involvement in working memor y. Science
251:947–950.
Sawaguchi T, Matsumura M, Kubota K (1988) Dopamine enhances the
neuronal activity of spatial short-term memory task in the primate
prefrontal cortex. Neurosci Res 5:465–473.
Sawaguchi T, Matsumura M, Kubota K (1990a) Catecholamine effects on
neuronal activity related to a delayed response task in monkey
prefrontal cortex. J Neurophysiol 63:1385–1400.
Sawaguchi T, Matsumura M, Kubota K (1990b) Effects of dopamine
antagonists on neuronal activity related to a delayed response task in
monkey prefrontal cortex. J Neurophysiol 63:1401–1412.
Shively CA, Fontenot MB, Kaplan JR (1995) Social status, behavior, and
central serotonergic responsivity in female cynomolgus monkeys. Am
J Primatol 37:333–339.
Shoabib M, Baumann MH, Rothman RB, Goldberg SR, Schindler CW
(1997) Behavioral and neurochemical characteristics of phentermine
and fenf luramine administered separately and as a mixture in rats.
Psychopharmacology 131, 296–306.
Snyder SH, Peroutka SJ (1984) Antidepressants and neurotransmitter
receptors. In: Neurobiology of mood disorders (Post RM, Ballenger CJ,
eds), pp. 686–697. Baltimore: Williams and Wilkins.
Sofuoglu M, DeBattista C (1996) Development of obsessive symptoms
during nefazodone treatment. Am J Psychiat 153:577–578.
Soubrie P (1986) Reconciling the role of central serotonin neurons in
human and animal behavior. Behav Brain Sci 9:319–364.
Spitzer RL, Williams JB, Gibbon M, First MB (1990) Structured clinical
interview for DSM-IIIR — non-patient edition (SCID-NP, Version 1.0).
Washington, DC: American Psychiatric Press.
Spoont MR (1992) The modulator y role of serotonin in neural information processing: implications for human psychopathology. Psychol
Bull 112:330–350.
Steck ler R, Sahgal A (1995) The role of serotonergic-cholinergic
interactions in the mediation of cognitive behavior. Behav Brain Res
67:165–199.
Wang RY, Ashby CR, Zhang JY (1995) Modulation of the A10 dopamine
system: electrophysiological studies of the role of 5-HT-sub-3-like
receptors. Behav Brain Res 73:7–10.
Wheeler MA, Stuss DT, Tulving E (1997) Toward a theory of episodic
memory: the frontal lobes and autonoetic consciousness. Psychol Bull
121:331–354.
Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by
dopamine D1 receptors in prefrontal cortex. Nature 376:572–575.
Winter JC, Petti DT (1987) The effects of 8-hydroxy2-(di-n-propy-lamino)
tetralin and other serotonergic agonists on performance in a radial
maze: a possible role for 5-HT1A receptors in memory. Pharmacol
Biochem Behav 27:625–628.
Wolkowitz OM, Tinglenberg JR, Weingartner H (1985) A psychopharmacological perspective on cognitive functions II. Specific
pharmacologic agents. Neuropsychobiology 14:133–156.
Wood DM, Emmett-Oglesby MW (1988) Substitution and cross-tolerance
profiles of anorectic drugs in rats trained to detect the discriminative
stimulus properties of cocaine. Psychopharmacology 95:364–368.
Wong DF, Wagner HN, Tune LF, Dannals RF, Pearson GD, Links JM,
Tamminga CA, Broussolle EP, Ravert HT, Wilson A A, Toung JK, Malay
J, Williams JA, O’Tuama LA, Snyder SH, Kuhar MJ, Gjedde A (1986)
Positron emission tomography reveals elevated D2 dopamine
receptors in drug-naive schizophrenics. Science 234:1558–1563.