Neuropsychopharmacology (2009) 34, 2323–2328
& 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00
www.neuropsychopharmacology.org
Dopamine Modulates Cholinergic Cortical Excitability in
Alzheimer’s Disease Patients
Alessandro Martorana*,1,2, Francesco Mori1, Zaira Esposito1, Hajime Kusayanagi1, Fabrizia Monteleone1,
Claudia Codecà1, Giuseppe Sancesario1,2, Giorgio Bernardi2 and Giacomo Koch1,2
1
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, Roma, Italy and 2IRCCS S. Lucia, Ospedale di
Neuroriabilitazione, Via Ardeatina, Roma, Italy
In Alzheimer’s disease (AD) patients dysfunction of cholinergic neurons is considered a typical hallmark, leading to a rationale for the
pharmacological treatment in use based on drugs that enhance acetylcholine neurotransmission. However, besides altered acetylcholine
transmission, other neurotransmitter systems are involved in cognitive dysfunction leading to dementia. Among others, dopamine seems
to be particularly involved in the regulation of cognitive processes, also having functional relationship with acetylcholine. To test whether
cholinergic dysfunction can be modified by dopamine, we used short latency afferent inhibition (SLAI) as a neurophysiological tool. First,
we tested the function of the cholinergic system in AD patients and in healthy subjects. Then, we tested whether a single L-dopa
challenge was able to interfere with this system in both groups. We observed that SLAI was reduced in AD patients, and preserved in
normal subjects. L-dopa administration was able to restore SLAI modification only in AD, having no effect in healthy subjects. We
conclude that dopamine can modify SLAI in AD, thus confirming the relationship between acetylcholine and dopamine systems.
Moreover, it is suggested that together with cholinergic, dopaminergic system alteration is likely to occur in AD, also. These alterations
might be responsible, at least in part, for the progressive cognitive decline observed in AD patients.
Neuropsychopharmacology (2009) 34, 2323–2328; doi:10.1038/npp.2009.60; published online 10 June 2009
Keywords: transcranial magnetic stimulation; short latency afferent inhibition; L-dopa; acetylcholine; Alzheimer’s disease
INTRODUCTION
The marked dysfunction of cholinergic neurons is considered a typical disease hallmark in Alzheimer’s disease
(AD), supporting the rationale for current pharmacological
treatment based on drugs that enhance acetylcholine
neurotransmission. However, besides altered acetylcholine
transmission, recent advances evidenced that other neurotransmitter systems might be involved in cognitive dysfunction occurring in AD. Among the others, dopaminergic
system may play a relevant role in the mechanisms involved
in learning and memory processes, showing strong synaptic
interaction with acetylcholine in different brain areas
(Blokland, 1995; Brooks, 2006; Cao et al, 2005; Di Cara
et al, 2007; Millan et al, 2007). Extrapyramidal signs are
sometimes observed in patients suffering from AD, and are
related to faster cognitive decline and higher mortality
(Rosen and Zubenko, 1991). Impaired dopamine transport
in several brain areas has been reported in even in absence
*Correspondence: Dr A Martorana, Clinica Neurologica, Dipartimento
di Neuroscienze, Università di Roma ‘Tor Vergata’, via Montpellier,
1- 00133, Rome, Italy. Tel.: + 0039 06 72596020; Fax: + 0039 06
72596022, E-mail: martorana@med.uniroma2.it
Received 17 February 2009; revised 5 May 2009; accepted 8 May 2009
of extrapyramidal signs (Murray et al, 1995; Pizzolato et al,
1996). Furthermore, dopamine D2 receptors correlation
with memory dysfunction was described in AD (Kemppainen
et al, 2003). Within these perspectives, we recently
showed that in AD patients the administration of L-dopa
determined consistent modifications of cortical activity
(Martorana et al, 2008), inducing an increase of short
intracortical inhibition (SICI). In that work, we supposed
that dopamine could exert its modulatory function influencing, among others, the cortical cholinergic release as well.
Here, we aimed to verify this hypothesis by studying the
effects of dopamine on the cholinergic cerebral transmission in normal and in AD patients. To do this, we used a
technique that is based on the coupling of TMS with
peripheral nerve stimulation. Motor-evoked potentials
recorded after TMS of the motor cortex can be suppressed
by electrical stimulation of the median nerve if the time
between stimulation of the median nerve and that of the
motor cortex is 2–8 ms longer than the time needed by the
peripheral nerve afferent input to reach the cortex. This
effect is termed as short latency afferent inhibition (SLAI) of
the motor cortex, and in general it is considered a measure
of inhibitory interactions between afferent input and motor
output. It is suggested that cholinergic system modulates
these inhibitory interactions. Therefore, SLAI is currently
Dopamine and Acetylcholine in Alzheimer’s Disease
A Martorana et al
2324
considered a non-invasive way to test cholinergic activity in
the cerebral cortex in the healthy subjects (Tokimura et al,
2000). On the other hand, other authors suggested that SLAI
may depend on the integrity of circuits linking sensory
input and motor output rather than on cholinergic function,
and thus its modifications may reflect impaired transmission of the sensory afferents (Sailer et al, 2003). Although
apparently distant, these two hypotheses might be reasonably reconciled. The fact that cholinergic drugs can modify
SLAI values did not necessarily indicate that a cholinergic
dysfunction or deficit underlies its modification. Other
neurotransmitters, in particular dopamine, are supposed to
play a modulatory role on the cholinergic transmission.
However, as both the transmitters can serve as neuromodulators, it is conceivable that the functional cholinergic
dysfunction may be the consequence of abnormal neuromodulation of dopamine (Orth et al, 2005). Thus, in
conditions in which dopamine or acetylcholine system are
impaired, SLAI modifications might occur as seen in
Parkinson’s disease (Sailer et al, 2003, 2007), Tourette’s
syndrome (Orth et al, 2005), and AD (Di Lazzaro et al, 2002,
2004). Even pharmacological manipulation may unexpectedly induce imbalance in the transmitters release, modifying the electrophysiological findings in course of such
pathologies. In fact, as clarified later in the Discussion, the
pharmacological manipulation of the dopaminergic system
might induce modifications of cortical acetylcholine release
acting on nuclei of the non-motor regions of the brain,
resulting in the modification of SLAI not observed before
(Sailer et al, 2003).
With these premises, here, we tested whether a single dose
of orally administered L-dopa can interfere with SLAI test in
AD patients compared with healthy controls. We hypothesized that if L-dopa administration could modulate cholinergic activity, in AD patients, changes in the level of SLAI
should also be observed more easily.
Subjects
We examined 10 patients with a diagnosis of probable AD
according to the NINCDS-ADRDA criteria (Varma et al,
1999) and 10 neurologically healthy age-matched control
subjects. The mean (SD) age of the patients was 72.5 (6.1)
years, whereas that of controls was 71.7 (4.9) years. All
patients underwent a complete clinical investigation,
including medical history, neurological examination, minimental state examination (MMSE), a complete blood
screening (including, routine exams, thyroid hormones,
and level of B12), neuropsychological examination
(Pierantozzi et al, 2004), a complete neuropsychiatric
evaluation, and neuroimaging consisting of magnetic
resonance imaging (1.5 T MRI). Exclusion criteria were
the following: patients with isolated deficits and/or unmodified MMSE (X25/30) on revisit (6, 12, 18 months
follow-up), patients with clinically manifest acute stroke in
the last 6 months showing an Hachinsky scale 44, and a
radiological evidence of sub-cortical lesions. None of
patients showed pyramidal and/or extrapyramidal signs at
the neurological examination. At the time of enrolment, in
the 30 days before participating in this study, none of the
patients had been treated with drugs that might have
modulated cerebral cortex excitability, such as antidepresNeuropsychopharmacology
sants, or any other neuroactive drugs (ie, benzodiazepines,
anti-epileptic drugs, or neuroleptics), even patients
assuming drugs like a- or b-blockers were excluded from
that work, as possible interactions with SLAI are not
excluded. However, none of the patients has been treated
before with cholinesterase inhibitors. The study was
performed according to the Declaration of Helsinki and
approved by the ethics committee of the Tor Vergata
University in Rome. All AD patients showed a cognitive
profile consistent with moderate dementia, as assessed by a
neuropsychological evaluation, including the MMSE and a
standardized neuropsychological battery (Carlesimo et al,
1996). On the MMSE, AD patients scored a mean of 18.23
(±3.2) and Clinical Dementia Rating (CDR) was 1.75
(±1.6). All participants or their legal guardian gave the
written informed consent after receiving an extensive
disclosure of study. The local ethic committee approved
the study procedures.
TMS Procedure
Magnetic stimulation was performed using a high-power
Magstim 200 magnetic stimulator (Magstim Co., Whitland,
Dyfed, UK). The magnetic stimuli had a nearly monophasic
pulse configuration, with a rise time of 100 ms, decaying
back to zero over 0.8 ms. A figure of eight coils with external
loop diameters of 9 cm was held over the left motor cortex
at the optimum scalp position to elicit motor responses in
the contralateral first dorsal interosseous (FDI) muscle. The
optimal position was marked on the scalp with a felt pen to
ensure identical placement of the coil throughout the
experiment. The handle of the coil pointed backward and
was perpendicular to the presumed direction of the central
sulcus, about 451 to the midsagittal line. The direction of the
induced current was from posterior to anterior and was
optimal to activate the motor cortex trans-synaptically.
Surface muscle responses were obtained through two 9 mm
diameter Ag-AgCl electrodes with the active electrode over
the motor point of the muscle and the reference on the
metacarpophalangeal joint of the index finger. Muscle
responses were amplified and filtered (bandwidth 3–
3000 Hz) by D150 amplifiers (Digitimer, Welwyn Garden
City, Hertfordshire, UK). Data were collected on a computer
with a sampling rate of 10 kHz per channel and stored for
later analysis using a CED 1401 A-D converter (Cambridge
Electronic Design, Cambridge, UK). All the AD patients
selected were able to understand and carry out the simple
task required for this electrophysiological studyFthat is, to
keep fully relaxed. The resting motor threshold (RMT) was
defined as the lowest intensity that produced MEPs of
450 mV in at least five out of 10 trials with the muscles
relaxed (Rossini et al, 1994). Determination of RMT was
done in step width of 1% of maximal stimulator output
(MSO). Short latency inhibition was studied using the
technique that has been recently described (Di Lazzaro et al,
2002; Sailer et al, 2003). Conditioning stimuli were single
pulses (200 ms) of electrical stimulation applied through
bipolar electrodes to the right median nerve at the wrist
(cathode proximal). The intensity of the conditioning
stimulus was set at just over motor threshold for evoking
a visible twitch of the thenar muscles. The intensity of the
test cortical magnetic stimulus was adjusted to evoke a
Dopamine and Acetylcholine in Alzheimer’s Disease
A Martorana et al
2325
muscle response in relaxed right FDI with an amplitude of
B1 mV peak-to-peak. The conditioning stimulus to the
peripheral nerve preceded the magnetic test stimulus by
different interstimulus intervals (ISIs). ISIs were determined
relative to the latency of the N20 component of the
somatosensory evoked potential induced by stimulation of
the right median nerve. The active electrode for recording
the N20 potential was attached 3 cm posterior to C3 (10–20
system) and the reference was 3 cm posterior to C4. A total
of 500 responses were averaged to identify the latency of the
N20 peak. ISIs from the latency of the N20 plus 2 ms to the
latency of the N20 plus 8 ms were investigated in steps of
2 ms. A total of 10 stimuli were delivered at each ISI. The
subject was given audiovisual feedback at high gain to assist
in maintaining complete relaxation. The inter-trial interval
was set at 5 s (±10%), for a total duration of B 5 min.
Measurements were made on each individual trial. The
mean peak-to-peak amplitude of the conditioned MEP at
each ISI was expressed as a percentage of the mean peak-topeak amplitude size of the unconditioned test pulse in that
block. To test whether short latency inhibition was sensitive
to the changes in L-dopa activity, we examined the motor
threshold and the SLAI in 10 patients before and after the
administration of a single dose (125 mg) of L-dopa.
Measurements were made before and 1 h after the administration, when L-dopa presented its maximal effects
(Martorana et al, 2008).
Figure 1 Short latency afferent inhibition at different interstimulus
intervals in AD patients (black diamonds) and control (open squares)
subjects. The interval between median nerve stimulation and cortical stimuli
was corrected for the latency of the N20 component of the
somatosensory evoked potential in each subject (see text). The size of
MEPs is expressed as a percentage of the MEP evoked by magnetic
stimulation alone. Short latency afferent inhibition was reduced in AD
patients at all explored intervals. Error bars indicate standard deviations.
(*Po0.05).
Statistical Analysis
The electrophysiological parameters of AD patients were
compared with those of controls by means of repeated
measures ANOVA with GROUP (AD vs healthy subjects) as
between subjects factor and ISI ( + 2, 4, 6 and 8 ms plus the
latency of the N20) and TREATMENT (pre- vs postL-DOPA) as within-subject factors. When a significant main
effect was reached, t-tests with Bonferroni’s correction were
employed to characterize the different effects of the specific
ISIs. For all statistical analyses, a p-value of o0.05 was
considered to be significant. Mauchley’s test examined for
sphericity. The Greenhouse–Geisser correction was used for
non-spherical data.
RESULTS
None of patients suffered from side effects following
assumption of the single dose of L-dopa.
The N20 latency and amplitude were within normal limits
in all AD patients and control subjects and did not differ
between the two groups (20.5±3.2 vs 20.8±2.9). The mean
(SD) RMT to TMS was significantly lower in AD patients
than in controls (45.9% vs 49.9%) of MSO; t ¼ 3.14; po0.05)
(Figure 1). RMT was not significantly modified by the
administration of L-dopa (p ¼ 0.48 at paired t-test analysis).
For unconditioned TS MEPs amplitude pre-and post-L-dopa
did not differ being 1.08±0.33 mV and 1.04±0.31 mV in
AD and 1.13±0.25 mV and 1.14±0.34 mV in controls,
respectively. Repeated measures ANOVA performed on
SLAI measures showed significant main effects of GROUP
(F ¼ 4.26; po0.05; Z2 ¼ 0.36) and ISI (F ¼ 7.78; po0.001; Z2
¼ 0.61), as well-significant GROUP TREATMENT
Figure 2 In AD patients, administration of L-dopa was effective in
modulating SLAI. (a) SLAI in AD patients was increased after L-dopa
administration at + 2 ms and + 4 ms ISIs. (b) No significant change was
observed in healthy subjects. Error bars indicate standard deviations
(*po0.05).
(F ¼ 3.96; po0.05; Z2 ¼ 0.31) and ISI TREATMENT
(F ¼ 8.23; po0.001; Z2 ¼ 0.40) interactions. The triple
interaction GROUP ISI TREATMENT was not significant. In fact, post hoc analysis showed that before
administration of L-dopa the amount of inhibition was
significantly smaller in AD patients than in normal controls
for all the ISIs tested (all po0.05) (Figure 2). The amount of
Neuropsychopharmacology
Dopamine and Acetylcholine in Alzheimer’s Disease
A Martorana et al
2326
Table 1
ISI
t
p-values
(a) Comparison of SLAI mean values in AD and HS before L-dopa administration
at different ISIs.
2 ms
3.52
0.001
4 ms
3.09
0.009
6 ms
2.87
0.012
8 ms
3.10
0.009
(b) Comparison of SLAI mean values in AD before and after L-dopa administration
at different ISIs
2 ms
2.88
0.009
4 ms
2.81
0.010
6 ms
1.82
0.102
8 ms
0.62
0.554
Figure 3 In AD patients, individual changes in SLAI before and after Ldopa administration (measured as the difference of % SLAI values before
and after L-dopa administration) did correlate with scores obtained at
MMSE.
inhibition was increased only in AD patients after L-dopa
administration at + 2 ms and + 4 ms ISIs (all po0.05)
(Figure 2a). On the other hand, when the same analysis was
performed in a group of healthy controls, no significant
difference emerged (Figure 2b).
Furthermore, in subsequent analysis, we found that in AD
patients the individual amount of increase of SLAI induced
by L-dopa (at ISI ¼ + 4 ms, measured as the difference of %
values pre-and post-L-dopa) did correlate with cognitive
impairment as assessed by MMSE (R ¼ 0.70; p ¼ 0.02)
(Figure 3 and Table 1).
DISCUSSION
In this work, we confirm that SLAI of the motor cortex is
significantly reduced (dis-inhibited) in AD patients compared with age-matched normal subjects (Di Lazzaro et al,
2002). In addition, we observed that SLAI dis-inhibition
could be promptly restored by the acute administration of
L-dopa to these patients. Our results therefore suggest that
dopamine is able to modulate cortical cholinergic function
in AD patients.
In general, SLAI depends on the integrity of corticocortical inhibitory circuits, and is suggested to be modulated at least in part by cholinergic system (Tokimura et al,
2000). In particular, acetylcholine is thought to be involved
in the modulation of intracortical circuits mediated by
groups of GABAergic interneurons, rather than directly
acting on pyramidal cells (Di Lazzaro et al, 2000; 2002,
2004). At this regard, Di Lazzaro et al (Di Lazzaro et al,
2005) showed that different types of benzodiazepines, such
as diazepam and lorazepam, resulted in distinct effects on
both SICI and SLAI. In particular, diazepam increased both
SLAI and SICI, whereas lorazepam reduced SLAI but
increased SICI, suggesting that the interactions between
cholinergic and GABA-ergic circuits may require the
activation of a variety of different receptor subtypes. In
this context, we recently described that L-dopa administraNeuropsychopharmacology
tion was able to change the excitability of GABAergic
intracortical circuits in AD patients (Martorana et al, 2008).
The current findings show that dopamine plays a critical
role in modulating cortical cholinergic activity also,
presumably interacting with such GABAergic intracortical
circuits.
Several anatomical (Beckstead et al, 1979; Gaykema and
Zaborszky, 1996; Smiley et al, 1999) and pharmacological
(Hersi et al, 2000; Millan et al, 2007) studies showed that
dopamine and acetylcholine are tightly interconnected,
being involved in various cognitive functions, such as
memory, attention, and learning (Blokland, 1995; Brooks,
2006, Cao et al, 2005, Di Cara et al, 2007, Millan et al, 2007).
It is still unclear, however, whether dopamine modulation
of acetylcholine release from cortical neurons occurs
through synaptic or non-synaptic (volume transmission)
mechanisms or possibly through a combination of both.
However, on the anatomical ground the dopaminergic
control of cortical acetylcholine release likely occurs at
different levels.
Dopamine released from terminals directly in the motor
cortex could have favorable effects either acting on
intracortical cholinergic interneurons bearing receptors
for dopamine (Berlanga et al, 2005), or could act at
subcortical level facilitating the glutamatergic excitatory
drive from thalamo-cortical pathway, on the classic basalganglia-thalamo-cortical loop (DeLong, 1990). In this view,
the thalamo-cortical inputs would in turn excite cortical
cholinergic neurons bearing glutamatergic receptors (Conti
et al, 1999). Alternatively, dopamine could act through the
modulation of the projections originating from the Nucleus
Accumbens (NAcc) to the cholinergic basal forebrain
neurons (Ingham et al, 1998; Sarter et al, 1999). The NAcc
is a subcortical nucleus considered the ventral homolog of
caudate-putamen and the NAcc neurons give rise to a
massive GABAergic projection to the basal forebrain
neurons. Several line of evidence showed that the pharmacological manipulation of accumbal dopamine receptors,
can influence the acetylcholine release in cortex. In
particular, the accumbal dopamine, D2-like receptor
stimulation has a negative effect on the acetylcholine release
Dopamine and Acetylcholine in Alzheimer’s Disease
A Martorana et al
2327
from the basal forebrain cholinergic neurons projecting to
the cortex (Del Arco et al, 2007; Brooks et al, 2007), whereas
the dopamine D1-like receptor activation has opposite
effects (Löffler et al, 2006). The suggested mechanisms, that
may be not mutually exclusive, could in turn influence the
cortical excitability acting on cortical GABA interneurons,
modulating cortical hyperexcitability (Di Lazzaro et al, 2002
and Martorana et al, 2008), therefore, explaining SLAI
changes observed in our recordings.
In this perspective, the finding that L-dopa was able to
restore SLAI in AD patients may reside in the anatomofunctional modifications induced by the degenerative
processes observed in AD. In fact pathological studies
showed that in AD, in addition to b-amyloid and senile
plaques deposits, changes in several neurotransmitter
systems occur. Together with the cholinergic system, the
serotoninergic and noradrenergic systems also seem to be
strongly altered (Langlais et al, 1993; Nazarali and
Reynolds, 1992; Reinikainen et al, 1988; Zaborszky and
Cullinan, 1996). However, the dopaminergic is also
implicated (Allard et al, 1994; McNeill et al, 1984). In
particular, the reduced levels of dopamine transporters
restricted to the NAcc together with altered receptors
expression for dopamine recently described (McNeill et al,
1984; Kumar and Patel, 2007), provide sufficient evidence
that dopamine content deficit also occurs during the
neurodegenerative process of AD. These alterations, in
association with the changes because of the progressive
neurodegenerative processes (aberrant growth of dendritic
trees and amyloid deposit) (Arendt et al, 1995; Preda et al,
2008; Wu et al, 2007) can induce, as a consequence a
perturbation in the balance of the other neurotransmitter
systems, leading to altered cortical excitability and cognitive
decline. In this view, the prompt effect of L-dopa on SLAI
has to be interpreted as the result of a momentarily restored
transmitter deficiency, leading to restored electrophysiological patterns.
In this view, further studies are needed to verify whether
chronic therapy with L-dopa may lead to persistent
modifications of cholinergic activity and in which direction.
Thus, additional studies with larger samples of patients
could determine if the L-dopa effects on cholinergic circuit
may be related to disease duration. Finally, it has to be
noticed that L-dopa had no effect in control patients.
Healthy subjects with a preserved dopaminergic (and
cholinergic) system are probably capable of storing additional external loads of L-dopa or dopamine in their
terminals, so that significant extra-stimulation of dopamine
receptors did not occur.
In conclusion, our results suggest that in AD dopamine
may influence cortical cholinergic activity. Further electrophysiological and pharmacological studies are required to
better understand the role exerted by specific dopamine
receptors on cholinergic circuits. Moreover, the current
findings may imply new strategies of intervention even to
ameliorate cognitive disturbances in AD.
DISCOLSURE/CONFLICT OF INTEREST
The authors declare that, except for income received from
the primary employer, no financial support or compensa-
tion has been received from any individual or corporate
entity over the past 3 years for research or professional
service and there are no personal financial holdings that
could be perceived as constituting a potential conflict of
interest.
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