REVIEW

Therapeutic Role of 5-HT1A Receptors in The Treatment

of Schizophrenia and Parkinsons Disease
Yukihiro Ohno
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan

Keywords
Affective disorders; Cognitive impairment; Drug
discovery; Movement disorders; Parkinsons
disease; Schizophrenia; 5-HT1A receptors.
Correspondence
Yukihiro Ohno, Ph.D., Laboratory of
Pharmacology, Osaka University of
Pharmaceutical Sciences,
4-20-1 Nasahara, Takatsuki, Osaka 569-1094,
Japan.
Tel.: +81-72-690-1053;
Fax: +81-72-690-1053;
E-mail: yohno@gly.oups.ac.jp

SUMMARY
5-HT1A receptors have long been implicated in the pathogenesis and treatment of anxiety
and depressive disorders. Recently, several lines of studies have revealed new insights into
the therapeutic role of 5-HT1A receptors in treating schizophrenia and Parkinsons disease.
Specifically, 5-HT1A receptors seem to be a promising target for alleviating antipsychoticinduced extrapyramidal side effects (EPS) and cognitive/affective disorders in schizophrenia.
In the treatment of patients with Parkinsons disease, 5-HT1A agonists are expected to improve not only affective symptoms (e.g., anxiety and depression), but also the core parkinsonian symptoms as well as antiparkinsonian agents-induced side effects (e.g., L-DOPAinduced dyskinesia). Here, the therapeutic mechanisms mediated by 5-HT1A receptors in
schizophrenia and Parkinsons disease are reviewed. This evidence should encourage discovery of new 5-HT1A ligands, which can resolve the unmet clinical needs in the current
therapy.

doi: 10.1111/j.1755-5949.2010.00211.x

Introduction
The serotonergic system plays an important role in regulating
various physiological functions including psychoemotional, autonomic, sensory, and motor functions [1,2]. Serotonin (5-HT)
neurons are located in the raphe nuclei and project axons to
various brain regions including the cerebral cortex, limbic areas, basal ganglia, diencephalons, and the spinal cord. Serotonergic neurotransmissions are mediated by diverse 5-HT receptors
that can be divided into seven families (5-HT1 to 5-HT7 ) encompassing 14 subtypes (5-HT1A/1B/1D/1E/1F , 5-HT2A/2B/2C , 5-HT3 ,
5-HT4 , 5-HT5A/5B , 5-HT6 , and 5-HT7 ) according to their signal
transduction pathways [1,2]. Advances in research on 5-HT receptors have led to the discovery of various therapeutic agents
such as selective 5-HT reuptake inhibitors (SSRI) (e.g., fluoxetine,
fluvoxamine, and paroxetine), 5-HT1A agonistic anxiolytics (e.g.,
buspirone, gepirone, and tandospirone), atypical antipsychotics
(5-HT2A /D2 antagonists) (e.g., risperidone, olanzapine, and quetiapine), antiemetics (5-HT3 antagonists) (e.g., ondansetron, azasetron, and granisetron), and antimigraines (5-HT1B/1D agonists)
(e.g., sumatriptan, naratriptan, and zolmitriptan).
5-HT1A receptors have long been implicated in the pathogenesis and treatment of anxiety and depressive disorders [37].
5-HT1A receptors are G-protein coupled receptors with a 7-

58

transmembrane-spanning structure (Figure 1) and are predominantly expressed in the limbic areas (e.g., hippocampus, amygdale, and lateral septum) and the raphe nuclei (e.g., raphe nuclei)
[6,8,9]. Moderate to low levels of 5-HT1A receptors are also expressed in the cerebral cortex, thalamus, hypothalamus, and basal
ganglia (e.g., striatum) [6,8]. 5-HT1A receptors function both as
presynaptic autoreceptors and as postsynaptic receptors. Specifically, 5-HT1A receptors in the raphe nuclei are located on the cell
body and dendrites of 5-HT neurons, where they function as autoreceptors to negatively regulate their own activity [10]. Through
this mechanism, 5-HT1A receptors control the overall tone of serotonergic activity. On the other hand, postsynaptic 5-HT1A receptors exist on postsynaptic membranes of neurons or nerve
terminals (heteroreceptors), where 5-HT neurons are innervated.
Stimulation of postsynaptic 5-HT1A receptors inhibits firing of target neurons through G protein-mediated mechanisms in various
regions of the brain (e.g., hippocampus, lateral septum, and cerebral cortex) (Figure 1) [1116].
Recent advances in 5-HT1A receptor research generated new
insight into its therapeutic role in CNS disorders including schizophrenia, Parkinsons disease, and Alzheimers disease [5,1720]. Specifically, 5-HT1A receptors seem to be a
promising target for alleviating antipsychotic-induced EPS and
cognitive/affective (e.g., anxiety and depression) disorders in

c 2010 Blackwell Publishing Ltd

CNS Neuroscience & Therapeutics 17 (2011) 5865 

Therapeutic Role of 5-HT1A Receptors

Y. Ohno

5-HT1A receptor
Membrane

GIRK
channel
hyperpolarizaton
Inhibition
Neuronal firing

G i/o

ATP

cAMP

Inhibition
PK A - mediated
phosphorylation

A n xio lytic actio n s

5- H T 1 A ag o n ists
Raphe

Adenylate
cyclase

C h ro n ic
treatm ent

D es e n sitizatio n o f
5 -H T 1 A auto recepto r

A m yg d ala
H ip p o cam p u s
In h ib itio n

L ateral S ep tu m
In h ib itio n

To n i c activatio n of
5-H T n e u ro n s

A n tid ep ressa n t
actio n s

H yp o th a la m u s

P s ych o so m atic
d iso rd ers

(D ys fu n c tio n o f a u to n o m ic
a n d e n d o c rin e s ys te m s )

Figure 1 Signal transduction pathways of 5-HT1A receptor (A) and the

mechanism underlying anxiolytic and antidepressant actions of 5-HT1A agonists (B). GIRK, G-protein-gated inwardly rectifying potassium channel; PK
A, protein kinase A.

schizophrenia. In the treatment of patients with Parkinsons disease, 5-HT1A agonists are expected to improve affective symptoms
and core motor symptoms in Parkinsons disease. They also should
ameliorate antiparkinsonian agents-induced side effects (e.g., LDOPA-induced dyskinesia and dopamine agonists-induced emesis). In this article, the potential utility of 5-HT1A receptors as a
therapeutic target for schizophrenia and Parkinsons disease and
their functional mechanisms are reviewed.

5-HT1A Receptor and AnxietyDepressive

Disorders
Buspirone is the prototype of 5-HT1A receptor agonist and was
originally developed as an antipsychotic drug [21]. Although buspirone was not found effective for the treatment of schizophrenia, it clinically showed significant anxiolytic actions. Thereafter,
numerous 5-HT1A agonists with different intrinsic activities (e.g.,
full agonists: 8-OH-DPAT, flesinoxan, and F-11440; partial agonists: ipsapirone, gepirone, and tandospirone) [12,2224] have

c 2010 Blackwell Publishing Ltd

CNS Neuroscience & Therapeutics 17 (2011) 5865 

been synthesized and shown anxiolytic activities in various animal models (e.g., Vogels or Gellar-Seifter conflict test and
elevated-plus maze, lightdark and conditioned-fear paradigms)
[3,7,2426]. It is also known that knockout mice lacking 5HT1A receptors exhibit an increased anxiety status in open-field,
elevated-plus maze, or lightdark tests [2729]. Conversely, transgenic mice overexpressing 5-HT1A receptors show reduced anxiety
behaviors [9].
Figure 1 illustrates the structure of 5-HT1A receptors and the
mechanisms underlying the anxiolytic actions of 5-HT1A agonists.
Although the possible involvement of presynaptic 5-HT1A autoreceptors cannot be completely ruled out, the crucial role of postsynaptic 5-HT1A receptors in regulating anxiety has been supported
by the following evidences: (1) the microinjection of 5-HT1A agonists (e.g., 8-OH-DPAT, buspirone, tandospirone, and flesinoxan)
directly into the limbic regions (e.g., hippocampus) causes a significant anxiolytic action [3033], (2) the denervation or inactivation
of 5-HT neurons, which abolishes presynaptic 5-HT1A autoreceptors in the raphe nuclei, does not alter the anxiolytic activity of
5-HT1A agonists [25,32,34], and (3) by using a tissue-specific conditional rescue strategy, Gross et al. (2002) [35] demonstrated that
expression of postsynaptic 5-HT1A receptors in the forebrain (e.g.,
hippocampus and cerebral cortex) effectively alleviate anxiety in
5-HT1A knockout mice. As previously described, postsynaptic 5HT1A receptors are predominantly expressed in the limbic areas
such as the hippocampus, amygdala, and lateral septum (Figure 1).
The former two structures are the major sites that control psychoemotional functions including anxiogenesis and stress reactions
[4,5,36,37], and the latter functions as a relay nucleus that transfers the neural outputs from the limbic system to the hypothalamus, the center of the autonomic nervous system [4,5,12,37].
5-HT1A agonists (e.g., 8-OH-DPAT, tandospirone, and flesinoxan)
reportedly inhibit the activity of both hippocampal and lateral
septal neurons probably through activating G-protein-gated inwardly rectifying potassium (GIRK) channels (Figure 1) [1116].
It is therefore conceivable that 5-HT1A agonists alleviate anxiety
and psychosomatic disorders by inhibiting anxiogenesis in the limbic areas and its propagation to the hypothalamus in the lateral
septum.
Besides anxiolytic actions, 5-HT1A agonists (e.g., 8-OH-DPAT,
buspirone, gepirone, and tandospirone) show a significant antidepressant activity in various animal models usually following repeated treatments [3841]. Although precise mechanisms underlying the antidepressant actions of 5-HT1A agonists are still uncertain, the desensitization (downregulation) of presynaptic 5HT1A autoreceptors has been implicated in the antidepressant
actions of 5-HT1A agonists (Figure 1) [10]. Namely, repeated treatment of animals with 5-HT1A agonists (e.g., gepirone, ipsapirone,
and tandospirone) desensitizes presynaptic 5-HT1A autoreceptors
in the raphe nuclei, which disengages 5-HT neurons from the
autoreceptor-mediated self-inhibition [10,4244]. Consequently,
5-HT neurons are tonically activated by chronic treatment with
5-HT1A agonists and this counteracts the serotonergic deficit (5HT reduction) in depression (Figure 1). In contrast to presynaptic 5-HT1A autoreceptors, the sensitivity of postsynaptic 5-HT1A
responses (e.g., anxiolytic actions) are not altered even after repeated administrations of 5-HT1A agonists [10,42].

59

Therapeutic Role of 5-HT1A Receptors

Y. Ohno

Schizophrenia symptoms

Therapeutic drugs

Positive symptoms

Typical antipsychotics

(Hallucination, Delusion, Excitation etc)

(Haloperidol, Chlorpromazine etc)

Negative symptoms

Atypical antipsychotics

(Apathy, Blunted affect, Social

withdrawal, Emotional withdrawal etc)

(Clozapine, Risperidone, Perospirone,

Olanzapine, Quetiapine, Aripiprazole etc)

Cognitive impairment
(Deficits in attention, working memory,
learning and social cognition etc)

Affective disorders
(Anxiety, depression etc)

antagonist/
partial
agonist

agonist/
partial agonist

Drug-related adverse reactions

Extrapyramidal side effects
(Akathisia, Bradykinesia, Akinesia, Tremor,
Muscle rigidity, dystonia, tardive dyskinesia etc)

Metabolic side effects

(Weight gain, Daibetic ketoacidosis etc)

5-HT1A receptor ligand

Endocrinological side effects

(Hyperprolactinemia etc)

Figure 2 Current therapeutics, unmet clinical needs and therapeutic role of 5-HT1A receptors in the treatment of schizophrenia.

Therapeutic Role of 5-HT1A Receptors

in Schizophrenia
Patients with schizophrenia exhibit diverse symptoms including positive symptoms (e.g., hallucinations, delusion, and excitation), negative symptoms (e.g., apathy, social and emotional
withdrawal), cognitive impairments, and affective disorders (e.g.,
anxiety and depression) [17,45] (Figure 2). Classical (typical) antipsychotics (e.g., phenothiazine, butyrophenone, and benzamide
derivatives) commonly possess dopamine D2 blocking activity and
effectively improve positive symptoms. These agents, however,
are not so effective for negative symptoms and frequently induce extrapyramidal side effects (EPS) such as parkinsonian symptoms, akathisia, and tardive dyskinesia, which significantly disrupt the quality of life in patients (Figure 2). Recently, several
new atypical antipsychotics have become available as first line
treatments, including 5-HT2A and D2 antagonists (e.g., clozapine,
risperidone, ziprasidone, perospirone, olanzapine, and quetiapine)
and the D2 partial agonist (i.e., aripiprazole) [36,46]. Some of the
above agents (e.g., clozapine, ziprasidone, perospirone, and aripiprazole) also possess a partial agonistic activity at 5-HT1A receptors [36,47]. These atypical antipsychotics, unlike the typical ones,
alleviate both positive and negative symptoms and have a reduced
EPS liability. Nonetheless, there are still clinical demands (unmet
needs) in the treatment of schizophrenia, such as (1) improving
any cognitive deficits or (2) alleviating affective disorders (e.g.,
anxiety and depression), (3) reducing antipsychotic-induced EPS,
metabolic (e.g., weight gain and diabetes mellitus) and endocrinological (e.g., hyperprolactinemia) side effects, and (4) controlling refractory symptoms (Figure 2). Indeed, recent comprehensive clinical reports of Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) or European First-Episode Schizophrenia
Trial (EUFEST) did not show significant advantages of the secondgeneration antipsychotics (e.g., risperidone, olanzapine, and quetiapine) beyond the first-generation antipsychotics (e.g., haloperi-

60

dol and perphenazine), especially in their neurocognitive effects,

in the treatment of schizophrenia [4850].
It is known that the density of 5-HT1A receptors is elevated in
the brains of patients with chronic schizophrenia, implying a close
relationship between 5-HT1A receptors and the pathogenesis of
schizophrenia [18,36,51,52]. 5-HT1A receptors are now thought
to be a favored therapeutic target for schizophrenia based on the
following evidences: (1) stimulation of 5-HT1A receptors can ameliorate antipsychotic-induced EPS [18,5357] and (2) affective disorders (e.g., anxiety and depression) [3,7,10], and (3) antagonism of 5-HT1A receptors can improve cognitive impairment in
schizophrenia [19,20,5860] (Figure 2).
A line of studies has shown that selective 5-HT1A agonists (e.g.,
8-OH-DPAT, buspirone, and tandospirone) attenuated antipsychotic (e.g., haloperidol)-induced catalepsy, bradykinesia, and
other parkinsonian symptoms (Figure 2) [5357]. In our studies, the ameliorative effects of 5-HT1A agonists on extrapyramidal disorders were as potent as the antiparkinsonian agent trihexyphenidyl (a muscarinic acetylcholine [mACh] antagonist) or
selective 5-HT2 antagonists (e.g., ritanserin) [57,61]. It is likely
that 5-HT1A agonists alleviate antipsychotic-induced EPS by stimulating postsynaptic 5-HT1A receptors (Figure 3), because the inactivation of 5-HT neurons by p-chlorophenylalanine did not affect the anti-EPS actions of 5-HT1A agonists (e.g., 8-OH-DPAT
and buspirone) [53,57,62,63]. Interestingly, analysis of the 5HT1A agonists actions (i.e., 8-OH-DPAT and tandospirone) on
antipsychotic-induced forebrain Fos expression revealed that they
counteract the D2 blocking action of haloperidol in the striatum,
which is closely associated with EPS induction [64,65]. In contrast, the 5-HT1A agonists did not alter the haloperidol-induced
Fos expression in the nucleus accumbens (shell region), which
is responsible for the therapeutic action of antipsychotic agents.
These data suggest that 5-HT1A agonists may preferentially alleviate antipsychotic-induced EPS without interrupting the therapeutic actions of antipsychotic agents.

c 2010 Blackwell Publishing Ltd

CNS Neuroscience & Therapeutics 17 (2011) 5865 

Therapeutic Role of 5-HT1A Receptors

Y. Ohno

5 -HT
Raphe nuclei neurons

(-)
) Cerebral cortex

5 -HT

Glu neurons
5-HT1A1Aagonist
5-HT

5 --HT 2A antagonist
Striatum
5-HT
5 - HT

Substantia
nigra

Glu
(+)

(-)

(-)

DA neurons

DA

5-HT 2A
2 receptor

5-HT1A receptor
D 2 receptor
NMDA receptor
Extrapyramidal
motor disorders

Figure 3 Therapeutic mechanisms and action sites of 5-HT1A agonists and 5-HT2A antagonists in ameliorating the extrapyramidal motor disorders. DA,
dopamine; Glu, glutamate; (+), excitation; (), inhibition.

It is postulated that blockade of 5-HT2A receptors reduces

EPS by stimulating dopaminergic neurons via blocking (a) 5HT2A receptor-mediated inhibition of dopamine neuron firing in
the substantia nigra and (b) dopamine release in the striatum
(Figure 3) [36,46,6668]. However, the action of 5-HT1A agonists
does not seem to depend on the activity of dopamine neurons
because the antiparkinsonian actions of 5-HT1A agonists (e.g., 8OH-DPAT) were not altered by D2 antagonists or were apparently
observed even in animals where dopamine neurons were denervated [46,56,62,69]. In addition, we have recently shown that microinjections of 8-OHDPAT into the cerebral cortex or the striatum
significantly alleviate the haloperidol-induced EPS [70]. Although
systemic interactions (e.g., pharmacokinetics) between 5-HT1A agonists and antipsychotic cannot be ruled out, these findings suggest that 5-HT1A agonists can alleviate antipsychotic-induced EPS
by activating postsynaptic 5-HT1A receptors both in the striatum
and cerebral cortex, probably through non-dopaminergic mechanisms (Figure 3). Because these mechanisms underlying the antiEPS actions of 5-HT1A agonists are distinct from those of 5-HT2A
antagonists, it is conceivable that 5-HT1A agonism and 5-HT2A antagonism can work in an additive fashion in alleviating EPS and
that 5-HT1A agonists improve EPS induced not only by the classical antipsychotics (D2 antagonists), but also by the new atypical antipsychotics with 5-HT2A blocking actions. Furthermore,
although the activation of 5-HT1A receptors did not affect
dopamine release in the striatum [71], several studies [7274]
have suggested that 5-HT1A agonist (e.g., BAY 3702 and osemozotan) enhance dopamine release in the cerebral cortex and
hippocampus, which may provide benefits in alleviating the negative symptoms of schizophrenia.
Another important role of 5-HT1A receptors in treating
schizophrenia is amelioration of cognitive deficits (Figure 2)
[19,20,5860]. Cognitive impairment is one of the core symptoms in schizophrenia, for which most of the currently available
antipsychotics are not very effective. Recent clinical studies have
shown that the partial 5-HT1A agonist tandospirone significantly
improved the cognitive deficits (assessed by Wisconsin Card Sort
test or California verbal learning test) in patients with schizophre-

c 2010 Blackwell Publishing Ltd

CNS Neuroscience & Therapeutics 17 (2011) 5865 

nia [58,59]. Data from animal studies also revealed that 5-HT1A
antagonists (e.g., WAY-100635, WAY-101405, and lecozotan) reversed the cognitive impairment induced by mACh receptor antagonists (e.g., scopolamine) or N-methyl-D-aspartate (NMDA)
receptor antagonists (e.g., MK-801) [19,20,75,76]. On the other
hand, full 5-HT1A agonists (e.g., 8-OH-DPAT) reportedly exhibit
a biphasic effects on cognitive functions, facilitation at low doses
and inhibition at high doses, which is probably mediated by stimulation of presynaptic and postsynaptic 5-HT1A receptors, respectively [19,75]. Although further validation studies are required,
the above findings suggest that antagonism of 5-HT1A receptors
provide benefits in treating cognitive impairment in schizophrenia. In this regard, the new antipsychotic lurasidone, with a 5HT1A antagonistic (weak partial agonistic) action [77], has been
shown to improve the learning and memory impairment induced
by MK-801 [78] and to ameliorate the cognitive impairment in
schizophrenia patients [79].
It is suggested that the cognitive enhancement by 5-HT1A antagonists (e.g., WAY-100635 and NAD-299) is mediated by postsynaptic 5-HT1A receptors located in the medial septum and/or
diagonal band of Broca, where 5-HT1A receptors tonically inhibit neuronal activity of acetylcholine and/or glutamate neurons
[19,20,75,76,80]. Through disinhibition of this negative regulation, 5-HT1A antagonists can enhance activities of the
septo-hippocampal/cortical acetylcholinergic and/or glutamatergic
neurons and improve cognitive functions. Conversely, full 5-HT1A
agonists (e.g., 8-OH-DPAT) impairs cognition by inhibiting the release of glutamate and acetylcholine in various regions of the brain
including the cerebral cortex [20]. A potential benefit of 5-HT1A
antagonists (e.g., WAY-101405 and lecozotan) in the treatment of
Alzheimers disease has also been suggested [19,20].

Therapeutic Role of 5-HT1A Receptors

in Parkinsons Disease
Parkinsons disease is a major neurological disease with specific
neurodegeneration of the nigrostriatal dopamine neurons [81].

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Therapeutic Role of 5-HT1A Receptors

Y. Ohno

Parkinson symptoms

Therapeutic drugs

Extrapyramidal motor
disorders

L-DOPA + AADCI

(Bradykinesia, Akinesia, Tremor,

Muscle rigidity, Dystonia etc)

Motor fluctuation
in L-DOPA therapy

Dopamine D2/3 agonists

muscarinic ACh antagonists
MAO-B or COMT Inhibitors

(Wearing-off, On-off etc)

Affective disorders
(Anxiety, depression etc)

Drug-related adverse reactions

L-DOPA -induced dyskinesia
Dopamine agonist -induced emesis

5-HT1A receptor
agonist/partial agonist

L-DOPA -induced psychoses

Figure 4 Current therapeutics, unmet clinical needs and therapeutic role of 5-HT1A receptors in the treatment of Parkinsons disease. AADCI, aromatic
L-amino acid decarboxylase inhibitors; ACh, acetylcholine; MAO-B, monoamine oxidase-B; COMT, catechol-O-methyltransferase.

Patients with Parkinsons disease show progressive extrapyramidal

motor deficits such as hypokinesia (e.g., bradykinesia and akinesia), tremors, muscle rigidity, difficulty in balance, and frozen gait
(Figure 4). The dopamine precursor L-DOPA is a key drug that effectively restores the depletion of brain dopamine and improves
most parkinsonian symptoms. Other antiparkinsonian agents
include dopamine D2 /D3 agonists (e.g., bromocriptine, cabergoline, pramipexole, and ropinirol), dopamine releasers (e.g., amantazine) and mACh receptor antagonists (e.g., trihexyphenidyl).
Inhibitors of monoamine oxidase-B (MAO-B) (e.g., selegiline) or
catechol-O-methyltransferase (COMT) (e.g., entacapone) are effective adjunctive drugs which potentiate the L-DOPAs efficacy
and improve the motor fluctuations in L-DOPA therapy (Figure 4)
[81].
A primary concern in Parkinsons disease therapy is the lack of
a drug which can prevent the development of Parkinsons disease
or restore degenerated dopamine neurons. Extensive studies are
now ongoing to develop neuroprotective agents or establish the
gene-, transplantation-, or regenerative medication therapy. Other
unmet needs include (1) reduction in the treatment side effects
(e.g., L-DOPA-induced dyskinesia and psychosis and D2 agonistinduced emesis), (2) control of motor fluctuations (e.g., wearingoff or on-off phenomena) in L-DOPA therapy or (3) non-motor
symptoms including affective disorders, and (4) lack of efficacious
substitutes for L-DOPA or new antiparkinsonian agents (Figure 4).
Stimulation of 5-HT1A receptors provides benefits in the treatment of Parkinsons disease, because 5-HT1A agonists (e.g., 8-OHDPAT) improve (1) core extrapyramidal motor disorders caused
by degeneration of dopaminergic neurons [56,62,69,70,82], (2) LDOPA-induced dyskinesia in animals chronically primed with LDOPA [70,8385], and (3) affective symptoms (e.g., anxiety and
depressive) which are frequently observed in patients with Parkin-

62

sons disease. In addition, 5-HT1A agonists (e.g., 8-OH-DPAT) reportedly possess a potent antiemetic action [8688] (Figure 4).
agonists
alleviate
As
described
previously,
5-HT1A
antipsychotic-induced EPS associated with the striatal D2 receptor antagonism in animals [5357]. In addition, studies using
animal models of Parkinsons disease have revealed that stimulation of 5-HT1A receptors restores the motor disorders caused by
lesions of dopaminergic neurons or dopamine depletion (Figure 4)
[56,62,69,70]. Like L-DOPA or D2 agonists (e.g., bromocriptine),
5-HT1A agonists (e.g., 8-OH-DPAT and tandospirone) induce
contralateral rotation behaviors in unilaterally dopamine-lesioned
(hemiparkinsonian) animals and reverse akinesia in dopaminedepleted animals [56,82]. It should be noted that enhancement
of locomotor activity by 5-HT1A agonists in Parkinsons models
could not be blocked by a D2 antagonist (i.e., haloperidol), but
was antagonized by a 5-HT1A antagonist (i.e., WAY-100635) [56],
indicating that the antiparkinsonian effects of 5-HT1A agonists are
independent of dopaminergic activity (Figure 3). 5-HT1A agonists
are therefore expected to exert antiparkinsonian actions in an
additive fashion when combined with dopaminergic stimulants
(e.g., L-DOPA and D2 /D3 agonists).
Besides the antiparkinsonian actions, several studies showed
that 5-HT1A agonists can alleviate L-DOPA-induced dyskinesia
(Figure 4) [69,8385]. 8-OH-DPAT significantly reduced the induction of L-DOPA-induced dyskinesia (e.g., limb and orolingual abnormal involuntary movements) in L-DOPA-primed hemiparkinsonian animals. Interestingly, 8-OH-DPAT did not affect the
antiparkinsonian actions (e.g., induction of rotation behaviors and
improvement in ataxic gait) of L-DOPA or even potentiated it
[69,85,89]. In addition, the antidyskinetic action of 5-HT1A agonists is mediated at least partly by striatal 5-HT1A receptors, because the microinjection of 8-OH-DPAT into the striatum reverses

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CNS Neuroscience & Therapeutics 17 (2011) 5865 

Therapeutic Role of 5-HT1A Receptors

Y. Ohno

L-DOPA-induced dyskinesia (Figure 3) [69]. Because orolingual

dyskinesia is known to be mediated by D1 receptor activation
[69,90], interactions between 5-HT1A and D1 receptors in the
striatum may be involved in the regulation of L-DOPA-induced
dyskinesia. Furthermore, microdialysis studies showed that local
application of 5-HT1A agonists into the cerebral cortex (primary
motor areas) reduces glutamate release in the striatum [89], which
could inhibit the induction of extrapyramidal disorders [91]. Thus,
postsynaptic 5-HT1A receptors in the cerebral cortex, which regulate the activity of the cortico-striato glutamatergic neurons, are
also involved in the expression of L-DOPA-induced dyskinesia
(Figure 3). Several studies also suggest that 5-HT1A agonists exert protective actions against dopaminergic neurotoxicity [92].
Anxiolytic and antidepressant actions of 5-HT1A agonists are
beneficial in the treatment of Parkinsons disease (Figure 4). Anxiety often coexists with depression in Parkinsons disease and
the prevalence of these symptoms is reported to be very high
(40%) in the patient population [5,93]. 5-HT1A agonist anxiolytics are superior to the standard benzodiazepine anxiolytics, especially in terms of their safety profiles and efficacy for depression.
Specifically, anxiolytic doses of benzodiazepines (e.g., diazepam)
cause diverse adverse reactions including sedation, muscle relaxation, impaired motor coordination, cognitive impairments and
induction of psychophysical dependence, whereas 5-HT1A agonistic anxiolytics (e.g., buspirone, gepirone and tandospirone) do not
cause these side effects [3,5]. The selective anxiolytic action of 5HT1A agonists is probably due to specific localization of 5-HT1A receptors in brain regions (e.g., hippocampus, amygdale, and lateral
septum) related to anxiogenesis and emotional regulation [6,7].
5-HT1A agonists thereby appear to be more favorable in treating
emotional symptoms in Parkinsons disease. Finally, a line of stud-

References

ies demonstrated that 5-HT1A agonists (e.g., 8-OH-DPAT) show

an antiemetic action against various types of emesis induced by
chemicals, motion and mechanical stimulation [8688]. Because
many of the antiparkinsonian agents cause emesis as the adverse
reactions, antiemetic activity of 5-HT1A agonists also may provide
a benefit in the treatment of Parkinsons disease (Figure 4).

Conclusions
This article reviewed the functions and therapeutic roles of 5HT1A receptors in treating CNS disorders. Recent studies have revealed new insights into the therapeutic role of 5-HT1A receptors
in treating CNS disorders including schizophrenia (e.g., reduction in antipsychotic-induced EPS, control of cognitive impairment and affective disorders) and Parkinsons disease (e.g.,
improvement in core motor disability, L-DOPA-induced dyskinesia, and efficacy for affective disorders). This evidence will encourage drug discovery research into novel 5-HT1A ligands with greater
potency, higher selectivity, and favorable pharmacokinetic properties. Furthermore, designing 5-HT1A ligands which combine multiple pharmacological actions (e.g., D2 and 5-HT2A blocking activity
for schizophrenia, D2 agonistic and 5-HT2A blocking activity for
Parkinsons disease) appears to be promising approach that may
overcome unmet clinical needs in current CNS therapies.

Conict of Interest
The author has no conflict of interest with any commercial or
other associations in connection with the submitted article.

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