European Journal of Neurology 2010, 17: 364–376 doi:10.1111/j.1468-1331.2009.02900.

REVIEW ARTICLE

Neurotransmission in ParkinsonÕs disease: beyond dopamine

P. Barone
Dipartimento di Scienze Neurologiche and IDC-Hermitage-Capodimonte, Naples, Italy

Keywords:
neurotransmitter,
non-motor symptoms,
ParkinsonÕs disease
Received 29 May 2009
Accepted 3 November 2009
ParkinsonÕs disease (PD) is most frequently associated with characteristic motor
symptoms that are known to arise with degeneration of dopaminergic neurons.
However, patients with this disease also experience a multitude of non-motor symp-
toms, such as sleep disturbances, fatigue, apathy, anxiety, depression, cognitive
impairment, dementia, olfactory dysfunction, pain, sweating and constipation, some
of which can be at least as debilitating as the movement disorders and have a major
impact on patientsÕ quality of life. Many of these non-motor symptoms may be evident
prior to the onset of motor dysfunction. The neuropathology of PD has shown that
complex, interconnected neuronal systems, regulated by a number of different neu-
rotransmitters in addition to dopamine, are involved in the aetiology of motor and
non-motor symptoms. This review focuses on the non-dopaminergic neurotransmis-
sion systems associated with PD with particular reference to the effect that their
modulation and interaction with dopamine has on the non-motor symptoms of the
disease. PD treatments that focus on the dopaminergic system alone are unable to
alleviate both motor and non-motor symptoms, particularly those that develop at
early stages of the disease. The development of agents that interact with several of the
affected neurotransmission systems could prove invaluable for the treatment of this
disease.

gastrointestinal (GI) symptoms (e.g. constipation,

Introduction
ParkinsonÕs disease – general background
ParkinsonÕs disease (PD) is the second most common
neurodegenerative disorder after AlzheimerÕs disease [1].
It is a chronic and progressive disorder that is estimated
to affect over 4 million people worldwide [2], although it
is likely that this number is underestimated [3].
Although there is no definitive diagnostic test for PD,
the disease is generally defined by the presence of at least
two of the following motor symptoms: resting tremor,
rigidity, bradykinesia and postural instability [4]. Al-
though these motor symptoms are most frequently
associated with the disease, patients also experience a
multitude of non-motor symptoms which are often just as
debilitating, and sometimes more so, than the movement
disorders. These include fatigue, neuropsychiatric
symptoms (e.g. depression, apathy, anxiety, cognitive
impairment, dementia, hallucinations, attention defi-
cits), autonomic dysfunction (e.g. bladder disturbances,
sweating, orthostatic hypotension, erectile impotence),
Correspondence: Prof. Paolo Barone, Dipartimento di Scienze Neu-
rologiche, Università Federico II, Via Pansini 5, Naples 80131, Italy
(tel.: +39 081 7462670; fax: +39 081 546 6596; e-mail: barone@
unina.it).
nausea, dysphagia, sialorrhea), sensory symptoms (e.g.
olfactory disturbances, pain) and sleep problems
including rapid eye movement (REM) sleep behavioural
disorder (RBD) [4,5], many of which may be evident
prior to the onset of motor disorders [6,7].
Generally, research in PD has focused mainly on
neurodegeneration of dopaminergic nigrostriatal cells as
the key cause of motor dysfunction. On the other hand,
non-motor symptoms in PD are not fully associated
with specific neurotransmitter dysfunctions. Conceiv-
ably, the smooth operation of routine motor and
non-motor functions requires a structurally complex
neuronal circuitry with a high degree of interconnec-
tivity that utilizes a number of different neurotransmit-
ters including dopamine, glutamate, acetylcholine and
c-aminobutyric acid (GABA).
This review focuses on neurotransmission systems
beyond dopamine that are involved in the neuronal
circuits of the brain closely associated with PD with
particular reference to the effect that their modulation
and interaction with dopaminergic circuits has on the
clinical manifestation of non-motor symptoms. This
review is complementary to a recent review focusing on
the dopaminergic basis of non-motor symptoms [8].
For an extensive clinical description of non-motor
symptoms, see Chaudhuri et al. 2006 [5].

 2009 The Author(s)

364 Journal compilation  2009 EFNS

Basal ganglia
The basal ganglia not only are a group of functionally
related and strongly interconnected nuclei which form
the key components of the complicated circuitry that
mediates motor function, but are also intricately in-
volved in cognitive function and emotional behaviour
[9]. The components within the basal ganglia connect
with different parts of the cerebral cortex and the
thalamus as well as with various structures leading to
the red nucleus, brainstem reticular formation and
spinal cord [10]. The role of the basal ganglia in motor
function has been extensively investigated and the
pathological changes to these structures in PD are well
known [11,12]. However, their role in non-motor
functions is not so widely understood.
Neuronal networks between the cortex and the basal
ganglia, in particular the striatum, have been found to be
involved in the modulation of appetitive behaviours such
as drug addiction [13]. Other studies have shown that the
striatum has a role in cognitive information processing in
non-motor tasks [14] and specifically with learning and
memory [15]. The basal ganglia are associated with
reinforcement learning [16] and Pavlovian behavioural
responses [17] with specific structures linked to set
functions. For instance, the encoding and the mainte-
nance of working memory are coupled with neuronal
activity in the left anterior caudate, anterior putamen
and globus pallidus with the right anterior caudate
showing activity only in the maintenance phase [18].
Each of these structures appears to have more specific
Thalamus
i. Medialis dorsalis
ii. Medialis dorsalis parsmagnocellularis
iii. Medialis dorsalis parvocellularis
iv. Ventralis lateralis pars medialis
Planning of motor action, bimanual control, learned movements
Global pallidus internal /
Substantia nigra pars reticulata
i. Rostrolateral, ventral pallidum/rostrodorsal
ii. Medial dorsomedial/rostromedial
iii. Lateral dorsalmedial/rostrolateral
iv. Ventrolateral/caudolateral
Figure 1 Functional neurotransmitter
circuits between the basal ganglia and
the cortex.
 2009 The Author(s)
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
Neurotransmission in ParkinsonÕs disease 365
functions: the caudate being involved with sequence
learning [19,20], drive, executive control and attention
[21]; the putamen having less influence on cognitive
functions [21] but associated with habit learning [20];
and specific areas of the external globus pallidus linked
with emotional aspects of behaviour [22,23].
The wide and varied interactions of neurotransmitter
systems that can be affected in PD make it evident that
patients experience extensive disruptions in both motor
and non-motor systems. Figure 1 shows a schematic
representation of four neuronal circuits within the basal
ganglia and the autonomic, motor and cognitive func-
tions they are involved with. As each of these circuits is
reliant on structurally complex neuronal circuitry, it is
apparent that a better understanding of interactions
between different neurotransmitters and the role they
play in non-motor symptoms of PD is urgently
required.
Neurotransmitter interactions
Disruption of the interactions between the various
neurotransmitter systems all have consequences in the
symptomatology of PD. The motor function of the
striatum is dependent on the equilibrium reached
between dopamine and acetylcholine [24] whilst dopa-
minergic activity within the substantia nigra pars
compacta is itself modulated by glutamatergic and
GABAergic innervations [25]. Serotonergic neurons
can also impair release of striatal dopamine in PD [26],
and serotonin–dopamine interactions are strongly
Cortex
i. Anterior cingulated area
ii. Lateral orbitofrontal cortex
iii. Dorsdolateral prefrontal cortex
iv. Supplementary motor area
i. Anterior cingulate circuit
Autonomic functions, rational cognitive functions,
reward anticipation, decision making, empathy and emotion
ii. Lateral orbitofrontal circuit
Association cortex, decision making, emotion and reward
iii. Dorsolateral prefrontal circuit
Planning, organisation, regulation, sensory and
menemonic information, working memory, intellectual
function and action
iv. Motor circuit
Striatum
i. Ventral striatum
ii. Ventralmedial caudate
iii. Dorsolateral caudate
iv. Putamen
366 P. Barone
implicated in reward-related behaviour, such as addic-
tion, and in neuropsychiatric disorders such as depres-
sion [27]. It has even been suggested that there is a
complex relationship between dopamine, serotonin and
noradrenaline, with imbalances in these neurotrans-
mitters being related to specific symptoms of major
depressive disorder [28].
Mood and anxiety disorders have been reported to
exist as comorbid conditions in approximately 20% of
patients with PD [29], although anxiety is frequently
reported prior to the onset of motor symptoms [30].
This suggests that the anxiety may be symptomatic of
PD as opposed to a consequence of diagnosis. Distur-
bances in central noradrenergic systems may be causa-
tive in the onset of the anxiety although interactions
with other neurotransmitters, such as serotonin and
dopamine, may also be involved [30]. The observation
that selective serotonin reuptake inhibitors (SSRIs),
administered to treat the depressive symptoms associ-
ated with PD, can affect the motor symptoms suggests
that there may be an interaction between serotonin and
dopamine in PD [31]. Although some studies have re-
ported a worsening of motor symptoms, a recent large
study with sertraline reported an improvement in Uni-
fied Parkinson’s Disease Rating Scale motor scores,
with an exacerbation of tremor in some patients [32].
Noradrenaline and dopamine are also thought to
play an important role in learning, particularly in
associative tasks [33]. It is thought that during the
learning task, extracellular dopamine concentration in
the medial pre-frontal cortex is regulated by dopamine
transporters present on noradrenaline neurons [33].
Dopaminergic and cholinergic neurotransmitters also
have a major influence on REM and non-REM sleep.
Indeed, RBD is often an early non-motor symptom of
PD [34] and is predictive of cognitive impairment in
non-demented patients with PD [35,36]. REM sleep is
associated with increased cholinergic receptor activity
and a corresponding decrease in dopaminergic activity.
Accordingly, reducing REM sleep in patients with PD
by suppressing cholinergic receptor activity can help
improve motor symptoms [37]. Pre-clinical studies have
also suggested that there could be GABAergic–gluta-
matergic involvement in REM sleep [38] and adenosine
A2A receptor-mediated neurotransmission has been
implicated in the regulation of non-REM sleep [39].
The overall balance of activity of the common neu-
rotransmitters in the brain and, in particular, interac-
tions with dopamine is an important consideration in
the pathogenesis of PD and its associated motor and
non-motor symptoms. Although loss of dopamine
neurons in the basal ganglia is most often associated
with the disease and its characteristic motor symptoms
[40], it is clear that the changes in dopamine interactions
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
with other neurotransmitters and subsequent effects
both within and outside the basal ganglia need to be
considered when looking at the wider symptoms re-
ported in patients with PD. That is, perturbations in
one neurotransmitter system, either by disease pro-
gression or by drug treatment, often lead to functional
consequences in other systems (see Table 2). The future
of PD treatment will likely employ a polytherapeutic
approach once the interrelationships between the vari-
ous neurotransmitter systems in PD are more clearly
elucidated.
Non-dopaminergic neurotransmission systems
It has been widely established that the motor dysfunc-
tions of PD can be primarily attributed to degeneration
of the dopaminergic nigrostriatal system and the sub-
sequent changes in neurotransmitter activity. However,
it is clear that PD symptomatology extends beyond
motor dysfunctions and that PD neuropathology in-
volves disruptions in non-dopaminergic neurotrans-
mission systems as well as dopaminergic systems [41].
For example, pre-clinical work in mice with reduced
monoamine storage capacity suggested that the mono-
amines other than dopamine (i.e. serotonin and nor-
adrenaline) may be involved in olfactory dysfunction in
PD [42]. Dopamine replacement therapies often have
little or no effect on non-motor manifestations of PD
and, according to the Braak staging scheme, involve-
ment of the dopaminergic system is spared in early
disease and occurs instead at an intermediate PD stage
[43]. Thus, diagnosis and treatment of non-motor
symptoms are of clinical importance at early stages of
the disease even before motor symptoms have become
apparent.
Studies examining the relationship between motor
function impairment and the degree of cognitive dis-
turbance in patients with PD have found little or no
association between motor and non-motor symptoms
[7,44]. These findings suggest that the neuropathologi-
cal changes responsible for cognitive impairment in
early PD are distinct from those responsible for motor
dysfunctions [45,46], and might be related to non-
dopaminergic lesions [44].
Dementia in PD likely reflects the broader neurode-
generative process that affects multiple cerebral circuits,
including neocortex and limbic cortex, as marked by
Lewy body pathology. Similarly, multiple neurotrans-
mitter dysfunctions may contribute to dementia devel-
opment. Pillon et al. [47] have proposed that
cholinergic deficits underlie memory loss and cognitive
dysfunction, serotonergic deficits underlie depression
and mood disturbances, and adrenergic deficits underlie
attention dysfunction.
 2009 The Author(s)
 Neurotransmission in ParkinsonÕs disease 367

Table 1 Neurotransmitter involvement in non-motor symptoms associated with ParkinsonÕs disease

Neurotransmitter system

Non-motor symptom Adenosine-

Dopaminergic Cholinergic Serotonergic Adrenergic Glutamatergic GABAergic mediated

Anxiety [30] [124] [30] [30] [125] [126]

Apathy [127,128] [124]
Attention dysfunction [129] [47,124,130] [47]
Autonomic dysfunction [96] [67,91,131] [91] [67, 91]
Cognitive impairment [129,132–137] [47–52,58,124] [47] [47] [106,138] [123,138]
Depressiona [27,28,76] [27,28,47,131] [28,71,76] [107,125] [126]
Executive dysfunction [33,139,140] [47,55,140] [140] [33,140] [140,141]
Fatigue [142,143] [143] [143] [143]
Olfactory dysfunction [144] [145]
Pain [146] [80] [80] [125] [146]
Sleep disorders [37] [37,124] [38] [38,117] [91,122]

Numbers refer to citation number.

GABA, c-aminobutyric acid.
a
Includes Ômood disordersÕ.

In addition, glutamatergic systems may also play an
important role in the modulation of PD symptoms
related to both cognitive impairment and motor func-
tion. Finally, GABAergic and adenosine-mediated
neurotransmission have important roles in the modu-
lation of dopaminergic systems, and changes to these
interacting neurotransmitter systems result in altera-
tions in control of voluntary movement.
These interactions of these neurotransmitter systems
and their association with non-motor symptoms
commonly seen in PD are discussed in more detail later
and summarized in Table 1. The effects of stimulation,
inhibition, depletion or over-abundance within the non-
dopaminergic neurotransmitter systems are presented
in Table 2.
Cholinergic neurotransmission
Deficits in the cholinergic system are believed to play a
role in the aetiology of cognitive dysfunction and
dementia in PD [48]. In patients with PD, cellular loss
in the nucleus basalis of Meynert, a layer of nerve cells
in the substantia innominata which is located anterior
to the globus pallidus, has been linked with cognitive
impairment [49–51]. Cells in this area are rich in choline
acetyltransferase and also acetylcholine neurons which
project to the cortex. Reductions in choline acetyl-
transferase activity in the temporal neocortex have been
correlated with the degree of mental impairment
[51,52], and assessments using voxel-based morphome-
try analysis have shown that neocortical volume
reduction is the most relevant finding in patients with
PD having dementia [53]. In addition, the decrease in
neocortical choline acetyltransferase is associated with
the number of neurons in the nucleus of Meynert [51],
suggesting that declining cognitive function in PD is
closely associated with a reduction in cholinergic
activity in the cortex and degeneration of cholinergic
neurons in the nucleus of Meynert. Furthermore, in
dementia associated with PD, the decrease in choline
acetyltransferase activity is even higher than that
observed in AlzheimerÕs disease [54].
Clinical evidence has shown that anticholinergic
therapy effectively worsens memory impairments in
patients with PD without any other signs of cognitive
impairment [55] and increases the risk of Alzheimer
pathology [56]. Both observations suggest that in
patients with PD, there is an underlying subclinical
cholinergic deficit. Cholinesterase inhibitors, which en-
hance cholinergic function, have been used in the
treatment of dementia in AlzheimerÕs disease since 1978
[57], and studies in patients with PD dementia show
that the acetyl- and butinyl-cholinesterase inhibitors,
rivastigmine, provide sustained cognitive improvements
[58].
Cholinergic receptors are of two subtypes, muscarinic
and nicotinic. Whilst neurons in the basal ganglia pro-
jecting to the substantia nigra pars compacta,
subthalamic nucleus, globus pallidus and striatum con-
tain just muscarinic receptors, both subtypes of cholin-
ergic receptor are found on neurons projecting to the
substantia nigra pars reticulata [24]. Thus, damages to
this area of the basal ganglia and alterations to nicotinic
neurotransmission may have implications in the aetiol-
ogy of parkinsonism or symptoms associated with the
disease [59]. Epidemiological studies have identified a
negative correlation between smoking and the develop-
ment of neurodegenerative disorders such as PD [60].
Although effects of smoking are not only because of
nicotine, evidence from pre-clinical studies has shown
that treatment or pre-treatment with nicotine gave

 2009 The Author(s)

Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
 368 P. Barone

partial protection against 1-methyl-4-phenyl-1,2,3,6-

Inhibition

[91,122] fl
[123] fl
Adenosine-mediated tetrahydropyridine (MPTP)-induced neurotoxicity in the
substantia nigra of black mice [61] and non-human pri-
mates [62,63]. A potential neuroprotective effect of nic-
Stimulation

otine on dopaminergic neurons is hypothesized to be

[122] fl
either because of an anti-inflammatory mechanism of
microglial activation [64] or because of direct control of
dopamine release in the striatum [65].
Inhibition

[126] ›

Autonomic nervous system dysfunction is common

[38] fl
in PD, affecting up to 80% of patients [66]. Symptoms
include abnormalities in the sudomotor, GI and urinary
GABAergic

Stimulation

systems, sleep disturbances and sexual dysfunction. It

[127] fl

[126] fl

[146] fl
[117] fl
has been suggested that cholinergic dysfunction might
be responsible for, or contribute to, autonomic
dysfunctions in PD [67].
Inhibition

[138] fl

[141] ›

[143] fl

Altogether, inhibition of or diminished cholinergic

neurotransmission in clinical and pre-clinical para-
Glutamatergic

digms of PD results in attention dysfunction, cognitive

[107,125] fl
Stimulation

[125,147] fl

impairment and executive dysfunction, whereas de-

AMPA
[106] ›

[125] fl

creased stimulation or enhanced cholinergic neuro-

[38] fl

transmission is associated with lessening of several

non-motor symptoms, including anxiety, apathy,
Inhibition

PD, ParkinsonÕs disease; GABA, c-aminobutyric acid; AMPA, a-amino-3-hydroxy-5-methylisoxazole propionic acid.

attention dysfunction, orthostatic hypotension, cogni-

[143] ›
[30] fl

[47] fl
[76] ›

tive impairment and sleep disorders (Table 2).

fl a2 a1 › [47]

Serotonergic neurotransmission
[28,47,71] fl
Stimulation
Adrenergic

The globus pallidus and substantia nigra receive a dense

› [140]
fl a2 a1

[145] fl
[67,91]
[30] fl

[80] fl

serotonin-mediated innervation that originates pre-

dominantly from the brainstem raphe nuclei. Serotonin
fl

[5-hydroxytryptamine (5-HT)] increases the firing

Inhibition

[140] ›

[143] ›

rate of neurons in the globus pallidus via pre- and

[47] ›

post-synaptic mechanisms mediated by activation of

Table 2 Effects of neurotransmitter modulation on non-motor symptoms of PD

serotonin receptors [68]. Decreased serotonin concen-

[27,28,47,71,131] fl

Black arrows indicate direct or indirect pre-clinical or clinical evidence in PD.

trations in the basal ganglia nuclei in PD may

contribute to reduced activity in the globus pallidus.
Serotonergic

Stimulation

Serotonin receptors in the brain modulate the func-

[30] fl

[80] fl

tion of dopaminergic pathways with several subtypes,

[91]

including 5-HT1A and 5-HT1B, facilitating dopamine

fl

release whilst stimulation of the 5-HT2C receptor

[47,55,58,71] ›

inhibits dopamine release [69]. This latter receptor type

Inhibition

is also unusual in that it inhibits tonic as well as evoked

[47] ›

[47] ›

dopamine release [69].

Low serotonin levels have been linked to alterations
Stimulation
Cholinergic

[124,130] fl

in mood, such as depression, and changes in sleep

[37,124] fl
[67,131]
[124] fl
[124] fl

[124] fl

architecture. Reductions in serotonin levels of nearly

50% have been reported in the cortex and basal ganglia
fl
fl

of patients with PD [70], and it has been estimated that

Includes Ômood disordersÕ.
Orthostatic hypotension

up to 45% of patients with PD have comorbid

Autonomic dysfunction
Attention dysfunction

Executive dysfunction

Olfactory dysfunction
Cognitive impairment
Non-motor symptom

depression [71] rising to up to 75% in elderly patients

[72]. Like other non-motor symptoms such as cognitive
Constipation

Sleep disorders

impairment, RBD and anxiety, depressive symptoms in

Depressiona

patients with PD may manifest years before any motor

Anxiety

Fatigue
Apathy

symptoms are experienced [71]. Although SSRIs are

Pain

often utilized to treat depression in patients with PD

a

 2009 The Author(s)

Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376

[73], there is only weak evidence supporting this
therapeutic approach; there have been two controlled
double-blind studies supporting the inferiority of sero-
tonergic agents when compared with the noradrenergic
agents, nortriptyline and desipramine [74,75]. In addi-
tion, recent neuropathological studies have suggested
that depression in PD is related more to dysfunction of
the catecholaminergic rather than the serotonergic
system [76].
Pain is a frequently reported manifestation of PD. In a
recent study of 176 home-dwelling subjects with PD, 83%
of patients experienced pain; of these, musculoskeletal
pain was the most commonly reported ailment (70%)
followed by dystonic (40%), radicular-neuropathic
(20%) and central neuropathic (10%) pain [77]. In an-
other recent study, 67% of patients with PD suffered
from pain, and a significant relationship between pain
and depression was uncovered [78]. Serotonergic path-
ways have been implicated in modulating pain. Treat-
ment of pain symptoms with the serotonin and adrenaline
reuptake inhibitor, duloxetine (Cymbalta), resulted in
varying degrees of pain relief for 65% of patients with PD
[79], whilst various 5-HT receptor agents are under
investigation for the treatment of pain [80,81].
Constipation, another common complaint of patients
with PD, is caused by decreased GI motility. Whilst the
dopaminergic agents apomorphine [82] and duodopa
[83] have provided improvement for patients with PD
suffering from constipation, the serotonergic system
is also believed to be involved in GI motility, as
pre-clinical evidence suggests that the activation of
5-HT4 receptors located along the GI tract enhances
motility by triggering acetylcholine release [84] and the
5-HT4 agonists mosapride [85] and tegaserod [86] pro-
vided relief to patients with PD suffering from consti-
pation.
Stimulation of the serotonergic system in PD appears
to result in decreases in several non-motor symptoms
including anxiety, constipation, depression and possibly
pain. In contrast, dampening the transmission of sero-
tonin leads to deficits in cognition, executive function
and possibly fatigue (Table 2).
Adrenergic neurotransmission
When compared with normal subjects, reduced levels of
noradrenaline have been observed in patients with PD
[87]. Loss of noradrenaline, which occurs at early stages
of PD, has been reported to worsen disease progression,
either by increasing the susceptibility of dopaminergic
neurons to degeneration or by inhibiting the repair of
neurons that are already damaged [88]. In addition, it
has been reported that loss of noradrenergic innerva-
tion facilitates the onset of dyskinesia during dopamine
replacement therapy [89].
 2009 The Author(s)
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
Neurotransmission in ParkinsonÕs disease 369
Noradrenergic systems, in conjunction with seroto-
nergic and dopaminergic mechanisms, appear to play
an important role in the aetiology of depression in PD.
A recent positron emission tomography study showed
that binding of [11C]RTI-32 in brain regions that receive
noradrenergic innervations was significantly lower
(P < 0.01) in depressed patients with PD when com-
pared with non-depressed patients with PD [90]. There
is a number of selective noradrenergic reuptake inhibi-
tors (SNRIs) that are currently undergoing clinical tri-
als for the treatment of depression and anxiety in PD
[91]. Furthermore, recent evidence suggests that SNRIs
appear to be more effective in treating depression in PD
than SSRIs [71,74,75].
Alpha 2-adrenergic a-2a and 2c receptors are widely
distributed throughout the basal ganglia. Pre-clinical
studies in mice have demonstrated that these receptors
modulate the sensitivity of dopaminergic receptors, and
activation of a-2 receptors facilitates movements pro-
duced by activation of the direct pathway of the basal
ganglia motor circuit [92].
In a community-based cohort of patients with PD,
47% of 89 patients had orthostatic hypotension [93],
although a study in hospital clinics suggested a preva-
lence as high as 58% [94]. It is thought that the
orthostatic hypotension is a result of abnormalities of
catecholamine function in the periphery, including
cardiac sympathetic denervation [95], as well as in the
brain [96]. However, as with many of the non-motor
symptoms of PD, the exact aetiology of the symptoms
may be complicated by administration of concomitant
therapies. For example, it is known that antidepressant
therapies, particularly tricyclic compounds, can cause
orthostatic hypotension [97].
Noradrenaline is a key neurotransmitter of the
endogenous pain system. As sustained pain induces
noradrenergic feedback inhibition [98], lower levels of
noradrenaline would most likely be associated with
increased symptoms of pain. Evidence from a recent
case–control study [99] showed that significantly more
patients with PD reported pain compared with controls
and in a quarter of the patients with PD, pain was
reported before starting antiparkinsonian therapy.
However, as stated earlier, the effective treatment of
pain symptoms with the serotonin and noradrenaline
reuptake inhibitor, duloxetine [79], suggests that there
may be interplay between various neurotransmitter
systems in the propagation of pain.
Inhibition of adrenergic neurotransmission results
in worsening of anxiety and depression whilst also
lessening cognitive impairment. However, the effects
of adrenergic stimulation appear to be receptor sub-
type-dependent. That is, stimulation of a-2 receptors
results in improved attention and executive functions;
370 P. Barone
activation of the a-1 receptors results in further dys-
function of these non-motor symptoms. Anxiety,
autonomic function, depression, pain and olfactory
functions are also lessened by adrenergic stimulation
(Table 2).
Glutamatergic neurotransmission
Glutamate is the most abundant excitatory neuro-
transmitter in the central nervous system (CNS). It
exerts its physiological actions on several classes of
predominately post-synaptic ionotropic receptors such
as a-amino-3-hydroxy-5-methylisoxazole propionic
acid (AMPA) and kainic acid receptors, which are
mainly permeable to sodium and potassium ions, and
N-methyl-D-aspartate (NMDA) receptors, which are
mainly permeable to calcium ions [100]. Synaptic
transmission can also be mediated via metabotropic
glutamate receptors, of which there are eight subtypes,
coupled to either phospholipase C (subtypes 1 and 5) or
adenylate cyclase (subtypes 2–4 and 6–8) that pre-syn-
aptically modulate GABA and glutamate release
[100,101]. Both ionotropic and metabotropic glutamate
receptors are expressed throughout the CNS and in a
variety of peripheral cells, which suggests that gluta-
mate is involved in biological processes other than
neuronal transmission [101,102].
Glutamate is associated with both the direct and the
indirect pathways of the basal ganglia, via metabotropic
receptors, although the roles of each of the receptor
subtypes are currently poorly understood [101,103]. The
receptors are heavily expressed throughout the basal
ganglia, and it has been postulated that antagonism of
subtypes 1 and 5 can protect against nigrostriatal
degeneration whilst enhancing the other receptor sub-
types may help relieve parkinsonian symptoms by
inhibiting glutamate release and/or reducing inhibition
of lateral globus pallidus neurons [101].
The loss of dopamine neurons is believed to cause an
increase in glutamatergic activity in the basal ganglia.
Pre-clinical studies using NMDA and AMPA antago-
nists have demonstrated improvements in various motor
symptoms of PD [104]. These findings suggest that the
selective inhibition of glutamatergic hyperactivity may
be an effective strategy for the treatment of some PD
symptoms, particularly those that do not respond to
L-dopa therapy [105]. Excess glutamate levels can also
result in excitotoxicity caused by pathophysiological
cascade of MPTP-induced neuronal cell death [104].
Modulation of glutamatergic neural tone in patients
with PD may also have a beneficial effect on cognitive
impairment. Both clinical and pre-clinical data suggest
that modulation of glutamate via AMPA receptor
potentiation is therapeutically effective in treating cog-
nitive defects and depression in PD and other CNS
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
disorders [106,107]. Pre-clinical studies have also shown
that the glutamatergic system, as mediated by NMDA
receptors, is responsible for severe perturbations in
learning, memory and cognition [104].
Altogether, data from pre-clinical and clinical studies
indicate that activation of glutamatergic receptors,
particularly mGlu4, may be effective in pre-clinical
models of anxiety, pain, depression (via AMPA) and
sleep dysfunction, whereas inhibition of glutamatergic
neurotransmission may result in increased anxiety and
executive dysfunction but also lessen depression (via
NMDA) and improve cognitive function (Table 2).
GABAergic neurotransmission
c-aminobutyric acid is the major inhibitory neuro-
transmitter in the CNS. GABAergic pathways largely
regulate signal processing throughout much of the basal
ganglia, in particular between the striatum and the
globus pallidus (both medial and lateral segments) and
connections to the thalamus from the medial segment of
the globus pallidus and the substantia nigra pars retic-
ulata. The striatal neurons of the direct pathway con-
tain GABA as the main neurotransmitter, and
neuropeptides derived from pre-proenkephalin-B (for
example, substance P) as co-transmitters [108]. In the
indirect pathway, neurons also use GABA as the main
neurotransmitter but use enkephalins derived from pre-
proenkephalin-A as co-transmitters [108].
The function of the striatal neurons of the direct and
indirect pathways is inhibited by the loss of dopamine
neuron input into the striatum from the substantia ni-
gra pars compacta. The decrease in dopamine levels is
associated with a corresponding increase in GABA
concentration within the striatum and a corresponding
increase in signal output from this area [109]. This effect
can be partly reversed by the administration of L-dopa,
which is thought to suppress GABA synthesis [110],
although in patients with PD, the combination of
nigrostriatal denervation and long-term L-dopa therapy
may actually result in an overall decrease in GABAergic
activity in the striatal neurons [111]. Although several
of the non-motor symptoms associated with PD have
been shown to involve GABAergic neurotransmission
such as pain, sleep disorders and depression (see
Tables 1 and 2), there is a lack of evidence as to how
these symptoms are modulated by changes in GABA
concentrations in PD. Studies in animals and in subjects
without PD suggest that decreases in GABAergic neu-
rotransmission generally result in the reduction of these
symptoms (Table 2).
Adenosine-mediated neurotransmission
Adenosine A2A receptors are widely expressed in
the basal ganglia, particularly on the GABAergic
 2009 The Author(s)

striatopallidal neurons. They are able to interact
antagonistically with post-synaptic dopamine D2
receptors and are also thought to interact with
pre-synaptic glutamatergic receptors. Thus, A2A recep-
tors are functionally relevant to the operation of the
indirect pathway of the basal ganglia system [112,113].
In animal models of PD, adenosine A2A receptor-
specific antagonists have been shown to consistently
reverse motor deficits such as tremors and rigidity and/
or enhance the effect of dopamine-based pharmaceuti-
cals [114]. Activation of A2A receptors causes the sup-
pression of GABAergic neurotransmission and release
in the striatum, and activation in the globus pallidus.
Together, these findings suggest a potential role of these
receptors in the management of PD symptoms [115].
However, istradefylline, the first adenosine A2A recep-
tor antagonist submitted to regulatory authorities, re-
cently received a Ônot approvableÕ letter from the Food
and Drug Administration over concerns that the effi-
cacy findings did not support clinical utility of the
treatment [116].
Disorders of sleep and wakefulness are extremely
common in PD, with an estimated prevalence of 98%
[117]. These include, but are not limited to, RBD, which
affects up to 33% of patients with PD [118], and
excessive daytime sleepiness, which has a prevalence of
approximately 50% in PD [119]. Adenosine has long
been accepted as a mediator of sleep, although the
contributions of the adenosine receptor subtypes are
still a matter of intense debate. For example, adenosine
A1 receptor stimulation causes inhibition of hypotha-
lamic hypocretin neurons which are believed to be in-
volved in arousal systems [120]. Recent studies have
demonstrated low levels of hypocretin in patients with
PD [121]. Therefore, it has been suggested that adeno-
sine A1 receptor antagonists may promote wakefulness
in subjects with PD [91]. Conversely, there is increasing
evidence that adenosine A2A receptors play a critical
role in the sleep-promoting effects of adenosine and
likely mediates the sleep-inhibiting effects of the non-
selective adenosine antagonist, caffeine [122]. To this
end, it has been suggested that insomnia be considered
as a possible side effect of A2A receptor antagonists
used in the treatment of PD [122].
Animal models of neurological disorders have un-
veiled the neuroprotective effect of adenosine A2A
antagonists, as these agents have been shown to control
neuronal damage initiated by ischaemic injury, gluta-
mate excitotoxicity and free radical toxicity as well as
neurotoxins such as b-amyloid, 6-hydroxydopamine
and others [123]. In fact, this neuroprotective effect has
been correlated with improved cognitive behaviour in
animal models of neurological disorders [123]. There-
fore, it is possible that central A2A receptor activity may
 2009 The Author(s)
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
Neurotransmission in ParkinsonÕs disease 371
be responsible for the modulation of cognitive function
in PD via its neuroprotective effect on cell death,
although this has yet to be determined definitively.
Altogether, alterations in adenosine-mediated
neurotransmission impact upon cognition, pain and
sleep disturbances, although the effect of adenosine
modulation has not yet been determined in PD models
(Table 2).
Conclusions
ParkinsonÕs disease is generally considered to be a
movement disorder; however, non-motor symptoms,
such as depression, sleep problems, cognitive dysfunc-
tion and constipation, are greatly debilitating and can
have a major impact on the quality of life of patients.
As there is currently no cure for PD, the goal of existing
treatment options is threefold: to delay the progression
of the disease, to achieve symptomatic relief and to
cause as few adverse effects as possible. No single agent
currently treats both the motor and the non-motor
manifestations of the disorder. Indeed, effective treat-
ment of the non-motor symptoms remains a major
unmet need in PD.
Deficits in dopaminergic neurotransmitters are lar-
gely responsible for the characteristic motor symptoms
observed in patients with PD. However, PD is a mul-
tifactorial disease, and non-motor disorders are pre-
valent in many patients, even those with mild or early-
stage disease. The neuropathology of these non-motor
disorders has shown that modulation of cholinergic,
serotonergic, glutamatergic and noradrenergic neuro-
transmitter systems is involved in the aetiology of these
symptoms in addition to also having a role in mainte-
nance of smooth motor function via interactions with
the dopaminergic system. The development of PD
symptoms arises from a comprehensive disruption of
normal signal transmission throughout the basal gan-
glia because of modulation of each of these types of
neurotransmitters.
It is evident from the complex interactions of the
various neurotransmitter systems involved in PD that
focusing on the dopaminergic system alone is insuffi-
cient for the treatment of all the symptoms of PD,
particularly those that occur at early stages of the dis-
ease. The development of agents that can alleviate both
the motor and the non-motor symptoms through
interaction with several of the affected neurotransmis-
sion systems in the CNS could prove invaluable for the
treatment of this devastating and widespread disease.
Because of the plethora of dynamic alterations in the
various neurotransmitter systems that occur in the PD
brain, it is likely that the future of PD treatment will
bring about a polytherapeutic approach, tailored to the
372 P. Barone
type (and timing) of symptoms displayed by each pa-
tient to provide more effective treatment of both the
motor and the non-motor symptoms.
Acknowledgement
The author thanks Mark Hughes, PhD, Complete
Medical Communications, who provided editorial
assistance. The study was funded by Merck Serono SA,
an affiliate of Merck KGaA.
References
1. Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M,
Chaudhuri AR, Zalutsky R. How common are the
‘‘common’’ neurologic disorders? Neurology 2007; 68:
326–337.
2. Dorsey ER, Constantinescu R, Thompson JP, et al.
Projected number of people with Parkinson disease in the
most populous nations, 2005 through 2030. Neurology
2007; 68: 384–386.
3. Van Den Eeden SK, Tanner CM, Bernstein AL, et al.
Incidence of ParkinsonÕs disease: variation by age, gen-
der, and race/ethnicity. Am J Epidemiol 2003; 157: 1015–
1022.
4. Jankovic J. ParkinsonÕs disease: clinical features and
diagnosis. J Neurol Neurosurg Psychiatry 2008; 79: 368–
376.
5. Chaudhuri KR, Healy DG, Schapira AH. Non-motor
symptoms of ParkinsonÕs disease: diagnosis and man-
agement. Lancet Neurol 2006; 5: 235–245.
6. Przuntek H, Muller T, Riederer P. Diagnostic staging of
ParkinsonÕs disease: conceptual aspects. J Neural Transm
2004; 111: 201–216.
7. McNamara P, Durso R. Neuropharmacological treat-
ment of mental dysfunction in ParkinsonÕs disease. Behav
Neurol 2006; 17: 43–51.
8. Chaudhuri KR, Schapira AH. Non-motor symptoms of
ParkinsonÕs disease: dopaminergic pathophysiology and
treatment. Lancet Neurol 2009; 8: 464–474.
9. Santens P, Boon P, Van Roost D, Caemaert J. The
pathophysiology of motor symptoms in ParkinsonÕs
disease. Acta Neurol Belg 2003; 103: 129–134.
10. Pollack AE. Anatomy, physiology, and pharmacology of
the basal ganglia. Neurol Clin 2001; 19: 523–534, v.
11. Galvan A, Wichmann T. Pathophysiology of parkin-
sonism. Clin Neurophysiol 2008; 119: 1459–1474.
12. Halliday GM, Macdonald V, Henderson JM. A com-
parison of degeneration in motor thalamus and cortex
between progressive supranuclear palsy and ParkinsonÕs
disease. Brain 2005; 128: 2272–2280.
13. Belin D, Jonkman S, Dickinson A, Robbins TW,
Everitt BJ. Parallel and interactive learning processes
within the basal ganglia: relevance for the under-
standing of addiction. Behav Brain Res 2009; 199: 89–
102.
14. Rektor I, Bares M, Brazdil M, et al. Cognitive- and
movement-related potentials recorded in the human ba-
sal ganglia. Mov Disord 2005; 20: 562–568.
15. Packard MG, Knowlton BJ. Learning and memory
functions of the Basal Ganglia. Annu Rev Neurosci 2002;
25: 563–593.
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
16. Doya K. Complementary roles of basal ganglia and
cerebellum in learning and motor control. Curr Opin
Neurobiol 2000; 10: 732–739.
17. Yin HH, Ostlund SB, Balleine BW. Reward-guided
learning beyond dopamine in the nucleus accumbens: the
integrative functions of cortico-basal ganglia networks.
Eur J Neurosci 2008; 28: 1437–1448.
18. Chang C, Crottaz-Herbette S, Menon V. Temporal
dynamics of basal ganglia response and connectivity
during verbal working memory. Neuroimage 2007; 34:
1253–1269.
19. Carbon M, Ma Y, Barnes A, et al. Caudate nucleus:
influence of dopaminergic input on sequence learning
and brain activation in Parkinsonism. Neuroimage 2004;
21: 1497–1507.
20. Grahn JA, Parkinson JA, Owen AM. The cognitive
functions of the caudate nucleus. Prog Neurobiol 2008;
86: 141–155.
21. Benke T, Delazer M, Bartha L, Auer A. Basal ganglia
lesions and the theory of fronto-subcortical loops: neu-
ropsychological findings in two patients with left caudate
lesions. Neurocase 2003; 9: 70–85.
22. Grabli D, McCairn K, Hirsch EC, et al. Behavioural
disorders induced by external globus pallidus dysfunc-
tion in primates: I. Behavioural study. Brain 2004; 127:
2039–2054.
23. Sakakibara R, Uchiyama T, Yamanishi T, Shirai K,
Hattori T. Bladder and bowel dysfunction in ParkinsonÕs
disease. J Neural Transm 2008; 115: 443–460.
24. Zhou FM, Wilson C, Dani JA. Muscarinic and nicotinic
cholinergic mechanisms in the mesostriatal dopamine
systems. Neuroscientist 2003; 9: 23–36.
25. Roth RH, Elsworth J. Biochemical pharmacology of
midbrain dopamine neurons. In: Bloom F, Kupfer D,
eds. Psychopharmacology: The Fourth Generation of
Progress. New York: Lippincott Williams & Wilkins,
1995: 227–243.
26. Fink KB, Gothert M. 5-HT receptor regulation of neu-
rotransmitter release. Pharmacol Rev 2007; 59: 360–417.
27. Sasaki-Adams DM, Kelley AE. Serotonin-dopamine
interactions in the control of conditioned reinforcement
and motor behavior. Neuropsychopharmacology 2001;
25: 440–452.
28. Nutt DJ. Relationship of neurotransmitters to the
symptoms of major depressive disorder. J Clin Psychia-
try 2008; 69(Suppl. E1): 4–7.
29. Nuti A, Ceravolo R, Piccinni A, et al. Psychiatric com-
orbidity in a population of ParkinsonÕs disease patients.
Eur J Neurol 2004; 11: 315–320.
30. Richard IH. Anxiety disorders in ParkinsonÕs disease.
Adv Neurol 2005; 96: 42–55.
31. Vajda FJ, Solinas C. Current approaches to management
of depression in ParkinsonÕs Disease. J Clin Neurosci
2005; 12: 739–743.
32. Kulisevsky J, Pagonabarraga J, Pascual-Sedano B,
Gironell A, Garcia-Sanchez C, Martinez-Corral M.
Motor changes during sertraline treatment in depressed
patients with ParkinsonÕs disease. Eur J Neurol 2008; 15:
953–959.
33. Harley CW. Norepinephrine and dopamine as learning
signals. Neural Plast 2004; 11: 191–204.
34. Postuma RB, Gagnon JF, Vendette M, Charland K,
Montplaisir J. REM sleep behaviour disorder in
ParkinsonÕs disease is associated with specific motor
 2009 The Author(s)

features. J Neurol Neurosurg Psychiatry 2008; 79:
1117–1121.
35. Vendette M, Gagnon JF, Decary A, et al. REM sleep
behavior disorder predicts cognitive impairment in
Parkinson disease without dementia. Neurology 2007; 69:
1843–1849.
36. Sinforiani E, Pacchetti C, Zangaglia R, Pasotti C, Manni
R, Nappi G. REM behavior disorder, hallucinations and
cognitive impairment in ParkinsonÕs disease: a two-year
follow up. Mov Disord 2008; 23: 1441–1445.
37. Askenasy JJ. Approaching disturbed sleep in late Par-
kinsonÕs Disease: first step toward a proposal for a revised
UPDRS. Parkinsonism Relat Disord 2001; 8: 123–131.
38. Luppi PH, Gervasoni D, Verret L, et al. Paradoxical
(REM) sleep genesis: the switch from an aminergic-
cholinergic to a GABAergic-glutamatergic hypothesis.
J Physiol Paris 2006; 100: 271–283.
39. Hayaishi O, Urade Y, Eguchi N, Huang ZL. Genes for
prostaglandin d synthase and receptor as well as aden-
osine A2A receptor are involved in the homeostatic
regulation of nrem sleep. Arch Ital Biol 2004; 142: 533–
539.
40. Obeso JA, Rodriguez-Oroz MC, itez-Temino B, et al.
Functional organization of the basal ganglia: therapeutic
implications for ParkinsonÕs disease. Mov Disord 2008;
23(Suppl. 3): S548–S559.
41. Ahlskog JE. Beating a dead horse: dopamine and Par-
kinson disease. Neurology 2007; 69: 1701–1711.
42. Taylor TN, Caudle WM, Shepherd KR, et al. Nonmotor
symptoms of ParkinsonÕs disease revealed in an animal
model with reduced monoamine storage capacity.
J Neurosci 2009; 29: 8103–8113.
43. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del TK.
Stages in the development of ParkinsonÕs disease-related
pathology. Cell Tissue Res 2004; 318: 121–134.
44. Pillon B, Dubois B, Cusimano G, Bonnet AM, Lhermitte
F, Agid Y. Does cognitive impairment in ParkinsonÕs
disease result from non-dopaminergic lesions? J Neurol
Neurosurg Psychiatry 1989; 52: 201–206.
45. Cooper JA, Sagar HJ, Jordan N, Harvey NS, Sullivan
EV. Cognitive impairment in early, untreated Parkin-
sonÕs disease and its relationship to motor disability.
Brain 1991; 114(Pt 5): 2095–2122.
46. Muslimovic D, Post B, Speelman JD, Schmand B.
Cognitive profile of patients with newly diagnosed Par-
kinson disease. Neurology 2005; 65: 1239–1245.
47. Pillon B, Boller F, Levi R, et al. Cognitive deficits and
dementia in ParkinsonÕs disease. In: Boller F, Cappa S,
eds. Handbook of Neuropsychiatry. Amsterdam: Elsevier,
2001: 311–371.
48. Williams-Gray CH, Foltynie T, Lewis SJ, Barker RA.
Cognitive deficits and psychosis in ParkinsonÕs disease: a
review of pathophysiology and therapeutic options. CNS
Drugs 2006; 20: 477–505.
49. Candy JM, Perry RH, Perry EK, et al. Pathological
changes in the nucleus of Meynert in AlzheimerÕs and
ParkinsonÕs diseases. J Neurol Sci 1983; 59: 277–289.
50. Whitehouse PJ, Hedreen JC, White CL III, Price DL.
Basal forebrain neurons in the dementia of Parkinson
disease. Ann Neurol 1983; 13: 243–248.
51. Perry EK, Curtis M, Dick DJ, et al. Cholinergic corre-
lates of cognitive impairment in ParkinsonÕs disease:
comparisons with AlzheimerÕs disease. J Neurol Neuro-
surg Psychiatry 1985; 48: 413–421.
 2009 The Author(s)
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
Neurotransmission in ParkinsonÕs disease 373
52. Mattila PM, Röyttä M, Lönnberg P, Marjamäki P,
Helenius H, Rinne JO. Choline acetytransferase activity
and striatal dopamine receptors in ParkinsonÕs disease in
relation to cognitive impairment. Acta Neuropathol 2001;
102: 160–166.
53. Ramı́rez-Ruiz B, Martı́ MJ, Tolosa E, et al. Longitudi-
nal evaluation of cerebral morphological changes in
ParkinsonÕs disease with and without dementia. J Neurol
2005; 252: 1345–1352.
54. Tiraboschi P, Hansen LA, Alford M, et al. Cholinergic
dysfunction in diseases with Lewy bodies. Neurology
2000; 54: 407–411.
55. Dubois B, Danze F, Pillon B, Cusimano G, Lhermitte F,
Agid Y. Cholinergic-dependent cognitive deficits in
ParkinsonÕs disease. Ann Neurol 1987; 22: 26–30.
56. Perry EK, Kilford L, Lees AJ, Burn DJ, Perry RH.
Increased Alzheimer pathology in ParkinsonÕs disease
related to antimuscarinic drugs. Ann Neurol 2003; 54:
235–238.
57. Comfort. Cholinesterase inhibition in treatment of Alz-
heimerÕs dementia. Lancet 1978; 1: 659–660.
58. Emre M, Aarsland D, Albanese A, et al. Rivastigmine
for dementia associated with ParkinsonÕs disease. N Engl
J Med 2004; 351: 2509–2518.
59. Quik M, Bordia T, OÕLeary K. Nicotinic receptors as
CNS targets for ParkinsonÕs disease. Biochem Pharmacol
2007; 74: 1224–1234.
60. Picciotto MR, Zoli M. Neuroprotection via nAChRs:
the role of nAChRs in neurodegenerative disorders such
as AlzheimerÕs and ParkinsonÕs disease. Front Biosci
2008; 13: 492–504.
61. Janson AM, Fuxe K, Goldstein M. Differential effects
of acute and chronic nicotine treatment on MPTP-
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced
degeneration of nigrostriatal dopamine neurons in the
black mouse. Clin Investig 1992; 70: 232–238.
62. Quik M, Jeyarasasingam G. Nicotinic receptors and
ParkinsonÕs disease. Eur J Pharmacol 2000; 393: 223–
230.
63. Quik M, Parameswaran N, McCallum SE, et al. Chronic
oral nicotine treatment protects against striatal degen-
eration in MPTP-treated primates. J Neurochem 2006;
98: 1866–1875.
64. Park HJ, Lee PH, Ahn YW, et al. Neuroprotective effect
of nicotine on dopaminergic neurons by anti-inflamma-
tory action. Eur J Neurosci 2007; 26: 79–89.
65. Exley R, Cragg SJ. Presynaptic nicotinic receptors: a
dynamic and diverse cholinergic filter of striatal dopa-
mine neurotransmission. Br J Pharmacol 2008;
153(Suppl. 1): S283–S297.
66. Zesiewicz TA, Baker MJ, Wahba M, Hauser RA.
Autonomic nervous system dysfunction in ParkinsonÕs
disease. Curr Treat Options Neurol 2003; 5: 149–160.
67. Vernino S, Sandroni P, Singer W, Low PA. Invited
article: autonomic ganglia: target and novel therapeutic
tool. Neurology 2008; 70: 1926–1932.
68. Rav-Acha M, Bergman H, Yarom Y. Pre and post
synaptic serotoninergic excitation of globus pallidus
neurons. J Neurophysiol 2008; 100: 1053–1066.
69. Alex KD, Pehek EA. Pharmacologic mechanisms of
serotonergic regulation of dopamine neurotransmission.
Pharmacol Ther 2007; 113: 296–320.
70. Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid
Y. Reduction of cortical dopamine, noradrenaline,
374 P. Barone
serotonin and their metabolites in ParkinsonÕs disease.
Brain Res 1983; 275: 321–328.
71. Lemke MR. Depressive symptoms in ParkinsonÕs dis-
ease. Eur J Neurol 2008; 15(Suppl. 1): 21–25.
72. Strober LB, Arnett PA. Assessment of depression in
three medically ill, elderly populations: AlzheimerÕs dis-
ease, ParkinsonÕs disease, and stroke. Clin Neuropsychol
2009; 23: 205–230.
73. Richard IH, Kurlan R. A survey of antidepressant drug
use in ParkinsonÕs disease. Parkinson Study Group.
Neurology 1997; 49: 1168–1170.
74. Devos D, Dujardin K, Poirot I, et al. Comparison of
desipramine and citalopram treatments for depression
in ParkinsonÕs disease: a double-blind, randomized,
placebo-controlled study. Mov Disord 2008; 23: 850–
857.
75. Menza M, Dobkin RD, Marin H, et al. A controlled
trial of antidepressants in patients with Parkinson dis-
ease and depression. Neurology 2009; 72: 886–892.
76. Frisina PG, Haroutunian V, Libow LS. The neuro-
pathological basis for depression in ParkinsonÕs disease.
Parkinsonism Relat Disord 2009; 15: 144–148.
77. Beiske AG, Loge JH, Ronningen A, Svensson E. Pain in
ParkinsonÕs disease: prevalence and characteristics. Pain
2009; 141: 173–177.
78. Ehrt U, Larsen JP, Aarsland D. Pain and its relationship
to depression in Parkinson disease. Am J Geriatr
Psychiatry 2009; 17: 269–275.
79. Djaldetti R, Yust-Katz S, Kolianov V, Melamed E,
Dabby R. The effect of duloxetine on primary pain
symptoms in Parkinson disease. Clin Neuropharmacol
2007; 30: 201–205.
80. Fava M. The role of the serotonergic and noradrenergic
neurotransmitter systems in the treatment of psycho-
logical and physical symptoms of depression. J Clin
Psychiatry 2003; 64(Suppl. 13): 26–29.
81. Lacivita E, Leopoldo M, Berardi F, Perrone R. 5-HT1A
receptor, an old target for new therapeutic agents. Curr
Top Med Chem 2008; 8: 1024–1034.
82. Edwards LL, Quigley EM, Pfeiffer RF. Gastrointestinal
dysfunction in ParkinsonÕs disease: frequency and path-
ophysiology. Neurology 1992; 42: 726–732.
83. Honig H, Antonini A, Martinez-Martin P, et al. Intra-
jejunal levodopa infusion in ParkinsonÕs disease: a pilot
multicenter study of effects on nonmotor symptoms and
quality of life. Mov Disord 2009; 24: 1468–1474.
84. Cellek S, John AK, Thangiah R, et al. 5-HT4 receptor
agonists enhance both cholinergic and nitrergic activities
in human isolated colon circular muscle. Neurogastro-
enterol Motil 2006; 18: 853–861.
85. Liu Z, Sakakibara R, Odaka T, et al. Mosapride citrate,
a novel 5-HT4 agonist and partial 5-HT3 antagonist,
ameliorates constipation in parkinsonian patients. Mov
Disord 2005; 20: 680–686.
86. Sullivan KL, Staffetti JF, Hauser RA, Dunne PB, Zes-
iewicz TA. Tegaserod (Zelnorm) for the treatment of
constipation in ParkinsonÕs disease. Mov Disord 2006;
21: 115–116.
87. Barbic F, Perego F, Canesi M, et al. Early abnormalities
of vascular and cardiac autonomic control in ParkinsonÕs
disease without orthostatic hypotension. Hypertension
2007; 49: 120–126.
88. Fornai F, di Poggio AB, Pellegrini A, Ruggieri S,
Paparelli A. Noradrenaline in ParkinsonÕs disease: from
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
disease progression to current therapeutics. Curr Med
Chem 2007; 14: 2330–2334.
89. Colosimo C, Craus A. Noradrenergic drugs for levo-
dopa-induced dyskinesia. Clin Neuropharmacol 2003; 26:
299–305.
90. Remy P, Doder M, Lees A, Turjanski N, Brooks D.
Depression in ParkinsonÕs disease: loss of dopamine and
noradrenaline innervation in the limbic system. Brain
2005; 128: 1314–1322.
91. Fox SH, Brotchie JM, Lang AE. Non-dopaminergic
treatments in development for ParkinsonÕs disease.
Lancet Neurol 2008; 7: 927–938.
92. Colosimo C, Fabbrini G, Berardelli A. Drug insight: new
drugs in development for ParkinsonÕs disease. Nat Clin
Pract Neurol 2006; 2: 600–610.
93. Allcock LM, Ullyart K, Kenny RA, Burn DJ. Frequency
of orthostatic hypotension in a community based cohort
of patients with ParkinsonÕs disease. J Neurol Neurosurg
Psychiatry 2004; 75: 1470–1471.
94. Senard JM, Rai S, Lapeyre-Mestre M, et al. Prevalence
of orthostatic hypotension in ParkinsonÕs disease.
J Neurol Neurosurg Psychiatry 1997; 63: 584–589.
95. Sharabi Y, Imrich R, Holmes C, Pechnik S, Goldstein
DS. Generalized and neurotransmitter-selective norad-
renergic denervation in ParkinsonÕs disease with ortho-
static hypotension. Mov Disord 2008; 23: 1725–1732.
96. Goldstein DS, Holmes C, Li ST, Bruce S, Metman
LV, Cannon RO III. Cardiac sympathetic denervation
in Parkinson disease. Ann Intern Med 2000; 133: 338–
347.
97. Rodriguez de la TB, Dreher J, Malevany I, et al. Serum
levels and cardiovascular effects of tricyclic antidepres-
sants and selective serotonin reuptake inhibitors in
depressed patients. Ther Drug Monit 2001; 23: 435–440.
98. Pertovaara A. Noradrenergic pain modulation. Prog
Neurobiol 2006; 80: 53–83.
99. Defazio G, Berardelli A, Fabbrini G, et al. Pain as a
nonmotor symptom of Parkinson disease: evidence from
a case-control study. Arch Neurol 2008; 65: 1191–1194.
100. Grillner P, Mercuri NB. Intrinsic membrane properties
and synaptic inputs regulating the firing activity of the
dopamine neurons. Behav Brain Res 2002; 130: 149–169.
101. Conn PJ, Battaglia G, Marino MJ, Nicoletti F. Metab-
otropic glutamate receptors in the basal ganglia motor
circuit. Nat Rev Neurosci 2005; 6: 787–798.
102. Nicoletti F, Battaglia G, Storto M, et al. Metabotropic
glutamate receptors: beyond the regulation of synaptic
transmission. Psychoneuroendocrinology 2007; 32(Suppl.
1): S40–S45.
103. Bonsi P, Platania P, Martella G, et al. Distinct roles of
group I mGlu receptors in striatal function. Neurophar-
macology 2008; 55: 392–395.
104. Lange KW, Kornhuber J, Riederer P. Dopamine/gluta-
mate interactions in ParkinsonÕs disease. Neurosci Bio-
behav Rev 1997; 21: 393–400.
105. Rodriguez MC, Obeso JA, Olanow CW. Subthalamic
nucleus-mediated excitotoxicity in ParkinsonÕs disease: a
target for neuroprotection. Ann Neurol 1998; 44:
S175–S188.
106. OÕNeill MJ, Dix S. AMPA receptor potentiators as
cognitive enhancers. IDrugs 2007; 10: 185–192.
107. OÕNeill MJ, Witkin JM. AMPA receptor potentiators:
application for depression and ParkinsonÕs disease. Curr
Drug Targets 2007; 8: 603–620.
 2009 The Author(s)

108. Blandini F, Porter RH, Greenamyre JT. Glutamate and
ParkinsonÕs disease. Mol Neurobiol 1996; 12: 73–94.
109. Kish SJ, Rajput A, Gilbert J, et al. Elevated gamma-
aminobutyric acid level in striatal but not extrastriatal
brain regions in ParkinsonÕs disease: correlation with
striatal dopamine loss. Ann Neurol 1986; 20: 26–31.
110. Levy R, Herrero MT, Ruberg M, et al. Effects of
nigrostriatal denervation and L-dopa therapy on the
GABAergic neurons in the striatum in MPTP-treated
monkeys and ParkinsonÕs disease: an in situ hybridiza-
tion study of GAD67 mRNA. Eur J Neurosci 1995; 7:
1199–1209.
111. Bonnet AM. Involvement of non-dopaminergic path-
ways in ParkinsonÕs disease: pathophysiology and ther-
apeutic implications. CNS Drugs 2000; 13: 351–364.
112. Morelli M, Di PT, Wardas J, Calon F, Xiao D,
Schwarzschild MA. Role of adenosine A2A receptors in
parkinsonian motor impairment and L-DOPA-induced
motor complications. Prog Neurobiol 2007; 83: 293–309.
113. Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferre
S. Adenosine A2A receptors and basal ganglia physiol-
ogy. Prog Neurobiol 2007; 83: 277–292.
114. Hauser RA, Schwarzschild MA. Adenosine A2A recep-
tor antagonists for ParkinsonÕs disease: rationale, thera-
peutic potential and clinical experience. Drugs Aging
2005; 22: 471–482.
115. Konitsiotis S. Novel pharmacological strategies for mo-
tor complications in ParkinsonÕs disease. Expert Opin
Investig Drugs 2005; 14: 377–392.
116. pdpipeline.org. http://www.pdpipeline.org/clinicaltrials/
terminated_thearpy_thru2004.htm (accessed 03/11/
2009).
117. Simuni T. Somnolence and other sleep disorders in
ParkinsonÕs disease: the challenge for the practicing
neurologist. Neurol Clin 2004; 22: S107–S126.
118. Gagnon JF, Postuma RB, Mazza S, Doyon J, Mont-
plaisir J. Rapid-eye-movement sleep behaviour disorder
and neurodegenerative diseases. Lancet Neurol 2006; 5:
424–432.
119. Hobson DE, Lang AE, Martin WR, Razmy A, Rivest J,
Fleming J. Excessive daytime sleepiness and sudden-on-
set sleep in Parkinson disease: a survey by the Canadian
Movement Disorders Group. JAMA 2002; 287: 455–463.
120. Liu ZW, Gao XB. Adenosine inhibits activity of hypo-
cretin/orexin neurons by the A1 receptor in the lateral
hypothalamus: a possible sleep-promoting effect.
J Neurophysiol 2007; 97: 837–848.
121. Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin)
cell loss in ParkinsonÕs disease. Brain 2007; 130: 1586–
1595.
122. Ferre S, Diamond I, Goldberg SR, et al. Adenosine A2A
receptors in ventral striatum, hypothalamus and noci-
ceptive circuitry implications for drug addiction, sleep
and pain. Prog Neurobiol 2007; 83: 332–347.
123. Cunha RA, Ferre S, Vaugeois JM, Chen JF. Potential
therapeutic interest of adenosine A2A receptors in psy-
chiatric disorders. Curr Pharm Des 2008; 14: 1512–1524.
124. Burn DJ, McKeith IG. Current treatment of dementia
with Lewy bodies and dementia associated with Parkin-
sonÕs disease. Mov Disord 2003; 18(Suppl. 6): S72–S79.
125. Lavreysen H, Dautzenberg FM. Therapeutic potential of
group III metabotropic glutamate receptors. Curr Med
Chem 2008; 15: 671–684.
 2009 The Author(s)
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
Neurotransmission in ParkinsonÕs disease 375
126. Kalueff AV, Nutt DJ. Role of GABA in anxiety and
depression. Depress Anxiety 2007; 24: 495–517.
127. Czernecki V, Schupbach M, Yaici S, et al. Apathy fol-
lowing subthalamic stimulation in Parkinson disease: a
dopamine responsive symptom. Mov Disord 2008; 23:
964–969.
128. Levy R, Czernecki V. Apathy and the basal ganglia.
J Neurol 2006; 253(Suppl. 7): VII54–VII61.
129. Nieoullon A. Dopamine and the regulation of cognition
and attention. Prog Neurobiol 2002; 67: 53–83.
130. Parikh V, Sarter M. Cholinergic mediation of attention:
contributions of phasic and tonic increases in prefrontal
cholinergic activity. Ann N Y Acad Sci 2008; 1129:
225–235.
131. Simuni T, Lyons KE, Pahwa R, et al. Treatment of early
ParkinsonÕs disease. Part 2. Eur Neurol 2009; 61: 206–
215.
132. Péron J, Vicente S, Leray E, et al. Are dopaminergic
pathways involved in theory of mind? A study in
ParkinsonÕs disease. Neuropsychologia 2009; 47: 406–
414.
133. Grace AA. Physiology of the normal and dopamine-de-
pleted basal ganglia: insights into levodopa pharmaco-
therapy. Mov Disord 2008; 23(Suppl. 3): S560–S569.
134. González-Burgos I, Feria-Velasco A. Serotonin/dopa-
mine interaction in memory formation. Prog Brain Res
2008; 172: 603–623.
135. Moustafa AA, Sherman SJ, Frank MJ. A dopaminergic
basis for working memory, learning and attentional
shifting in Parkinsonism. Neuropsychologia 2008; 46:
3144–3156.
136. Kulisevsky J, Garcia-Sanchez C, Berthier ML, et al.
Chronic effects of dopaminergic replacement on cogni-
tive function in ParkinsonÕs disease: a two-year follow-up
study of previously untreated patients. Mov Disord 2000;
15: 613–626.
137. Kulisevsky J. Role of dopamine in learning and memory:
implications for the treatment of cognitive dysfunction in
patients with ParkinsonÕs disease. Drugs Aging 2000; 16:
365–379.
138. De Leonibus E, Manago F, Giordani F, et al. Metabo-
tropic glutamate receptors 5 blockade reverses spatial
memory deficits in a mouse model of parkinsonÕs disease.
Neuropsychopharmacology 2009; 34: 729–738.
139. Saint-Cyr JA. Frontal-striatal circuit functions: context,
sequence, and consequence. J Int Neuropsychol Soc 2003;
9: 103–127.
140. Royall DR, Lauterbach EC, Cummings JL, et al. Exec-
utive control function: a review of its promise and
challenges for clinical research. A report from the
Committee on Research of the American Neuropsychi-
atric Association. J Neuropsychiatry Clin Neurosci 2002;
14: 377–405.
141. Kashani A, Betancur C, Giros B, Hirsch E, El MS. Al-
tered expression of vesicular glutamate transporters
VGLUT1 and VGLUT2 in Parkinson disease. Neurobiol
Aging 2007; 28: 568–578.
142. Schifitto G, Friedman JH, Oakes D, et al. Fatigue in
levodopa-naive subjects with Parkinson disease. Neurol-
ogy 2008; 71: 481–485.
143. Brola W, Ziomek M, Czernicki J. [Fatigue syndrome in
chronic neurological disorders]. Neurol Neurochir Pol
2007; 41: 340–349.
376 P. Barone
144. Huisman E, Uylings HB, Hoogland PV. A 100% in-
crease of dopaminergic cells in the olfactory bulb may
explain hyposmia in ParkinsonÕs disease. Mov Disord
2004; 19: 687–692.
145. Farooqui T. Octopamine-mediated neuronal plasticity in
honeybees: implications for olfactory dysfunction in
humans. Neuroscientist 2007; 13: 304–322.
Journal compilation  2009 EFNS European Journal of Neurology 17, 364–376
146. Chudler EH, Dong WK. The role of the basal ganglia in
nociception and pain. Pain 1995; 60: 3–38.
147. Mathew SJ, Price RB, Charney DS. Recent advances in
the neurobiology of anxiety disorders: implications for
novel therapeutics. Am J Med Genet C Semin Med Genet
2008; 148: 89–98.
 2009 The Author(s)