Improving the Treatment of Parkinson’s Disease: A Novel Approach by Modulating 5-HT_1A Receptors

Abstract

Parkinson’s disease, the most common neurological disorder in the elderly, is characterized by progressive extrapyramidal motor dysfunction including resting tremors, muscle rigidity, hypolocomotion (bradykinesia and akinesia) and postural instability. Various non-motor features are also seen such as cognitive impairments (deficits in learning and memory) and mood disorders (depression and anxiety). While the 5-HT_1A receptor has long been implicated in the pathogenesis and treatment of anxiety and depression, recent research has revealed new therapeutic roles for 5-HT_1A receptors in the treatment of Parkinson’s disease. These include the modulation of parkinsonian motor symptoms, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, cognitive impairments and emesis. Thus, 5-HT_1A agonists improve the various motor disorders associated with dopaminergic deficits, dyskinesia induced by chronic L-DOPA treatment, mood disturbances (anxiety and depression) and dopamine agonist-induced emesis. In addition, partial 5-HT_1A agonists are expected to improve cognitive impairment in Parkinson’s patients. These findings encourage research into new 5-HT_1A receptor ligands, which will improve efficacy and/or ameliorate adverse reactions in the treatment of Parkinson’s disease.

Parkinson’s disease is a serious neurological disorder in the elderly and is estimated to affect about 1% of people older than 60 years. Patients with the disease show progressive extrapyramidal motor dysfunction including rest tremor, hypolocomotion (bradykinesia and akinesia), muscle rigidity and postural instability [1]. Resting tremor in Parkinson’s disease have a frequency of 3–5 Hz, affecting the hands, head and other parts of the body. Bradykinesia refers to reduced and impaired motor activity and manifests as the slowed and/or interrupted flow of voluntary movements. In advanced cases, patients exhibit freezing gait caused by a depletion of central norepinephrine, which can be improved by treatment with the norepinephrine precursor droxydopa (L-threo-dihydroxyphenylserine). Various non-motor features are also seen, including cognitive impairments (deficits in learning and memory), mood disorders (depression and anxiety), sleep disturbances and autonomic dysfunction (orthostatic hypotension and constipation) [1–3].

The serotonergic system plays crucial roles in controlling various physiological processes including psycho-emotional, sensori-motor, cognitive and autonomic functions [4–7]. 5-HT neurons are located in the raphe nuclei and send axons to various regions of the brain including the cerebral cortex, limbic areas, basal ganglia, diencephalon and spinal cord. Serotonergic neurotransmission is mediated by multiple 5-HT receptors consisting of at least 14 subtypes (i.e., 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E, 5-HT_1F, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₃, 5-HT₄, 5-HT_5a, 5-HT_5b, 5-HT₆ and 5-HT₇ receptors), which can be classified into 7 families (5-HT₁ to 5-HT₇) [5–7]. These 5-HT receptors are mostly G-protein-coupled receptors with a 7-transmembrane spanning structure, except for the 5-HT₃ receptor which functions as a ligand-gated cation (e.g. Na⁺ and Ca²⁺) channel [6].

Several lines of evidence have revealed that 5-HT_1A receptors play an important role in controlling motor functions and ameliorate various extrapyramidal disorders such as parkinsonian motor symptoms [8–18] and L-DOPA-induced motor disabilities [19–22]. In addition, 5-HT_1A receptors are implicated in the pathogenesis and treatment of mood disorders (e.g., anxiety and depression) [9, 10, 23–25] and cognitive impairments [7, 26–30], which are often seen in patients with Parkinson’s disease. These findings suggest that 5-HT_1A receptors could serve as a promising therapeutic target for Parkinson’s disease. In this article, we review the functional roles of 5-HT_1A receptors in the treatment of Parkinson’s disease and illustrate therapeutic approaches by modulating 5-HT_1A receptors.

Current medications for Parkinson’s disease

Extrapyramidal motor functions are mainly regulated by the basal ganglia including the striatum and globus pallidus, which from the basal ganglia-thalamus-cerebral cortex neural network (Fig. 1). It is known that striatal neurons receive glutamatergic excitatory inputs from the cerebral cortex and are also positively regulated by acetylcholinergic interneurons within the striatum. Dopaminergic neurons forms the substantia nigra negatively regulate both striatal output neurons and acetylcholinergic interneurons. Pathological findings have revealed that Parkinson’s disease is a neurodegenerative disorder, involving the selective loss of nigrostriatal dopaminergic neurons (Fig. 1). In patients with the disease, therefore, nigro-striatal dopaminergic activity is largely diminished and the activity of striatal acetylcholinergic neurons is elevated (Fig. 1).

Figure 1.

Neural network regulating extrapyramidal motor functions and Parkinson’s disease. Striatal GABAergic (GABA) output neurons receive glutamatergic (Glu) excitatory inputs from the cerebral cortex and excitatory inputs from acetylcholinergic (ACh) interneurons within the striatum. Dopaminergic (DA) neurons from the substantia nigra pars compacta negatively regulate both striatal output neurons and ACh interneurons. In patients with Parkinson’s disease, the nigro-striatal dopaminergic neurons are degenerated, which causes hyperexcitation of both GABA and ACh striatal neurons. The serotonergic (5-HT) neurons derived from the raphe nuclei project to the striatum, substantia nigra and cerebral cortex, and modulate the expression of extrapyramidal motor disorders.

Patients with Parkinson’s disease are responsive to various dopaminergic drugs [1, 8]. The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) has long been the most common drug for Parkinson’s disease since it effectively supplements brain dopamine and improves various parkinsonian symptoms (Fig. 2) [1]. Bromocriptine, pergolide, cabergoline, ropinirole and talipexole are D₂ (D₂/D₃) agonists which directly stimulate these receptors, and amantadine acts as a dopamine releaser/NMDA antagonist (Fig. 2). Other drugs include the monoamine oxidase-B inhibitor selegiline and the catechol-O-methyltransferase (COMT) inhibitor entacapone, which are useful as an adjunct medication with L-DOPA, potentiating its actions. In addition, antagonists for muscarinic acetylcholine (mACh) receptors (trihexyphenidyl and biperidene) are also effective against parkinsonian symptoms through they often cause serious adverse reactions (e.g., intestinal constipation, urinary retention, tachycardia and cognitive impairments) (Fig. 2)

Figure 2.

Clinical unmet needs in the treatment of Parkinson’s disease. Although dopaminergic agents are generally effective for various symptoms of Parkinson’s disease (see Current therapy), there are residual unmet needs (see Clinical unmet needs), including a lack of effectual medications for neurodegeneration, non-motor symptoms (e.g., mood disturbances and cognitive impairments) of Parkinson’s disease, motor complications (e.g., dyskinesia) or psychosis associated with chronic L-DOPA treatment and a fluctuation (e.g., wearing-off and onoff phenomena) in L-DOPA efficacy. DCI: Aromatic L-amino acid decarboxylase inhibitor, MAO-B: monoamine oxydase–B, COMT: catechol-O-methyltransferase, mACh: muscarinic acetylcholine.

Although dopaminergic medications are widely used in the treatment of Parkinson’s disease, there still exist clinical unmet needs, including a lack of drugs suitable for treating neurodegeneration, motor complications (dyskinesia) or psychosis associated with chronic L-DOPA treatment and non-motor symptoms (e.g., cognitive impairments and mood disorders) (Fig. 2) [8, 31]. Specifically, no drugs can prevent the disease’s development (i.e., neurodegeneration) or restore damaged dopaminergic neurons. In addition, under long-term treatment, the efficacy of L-DOPA fluctuates (e.g., wearing-off and on-off phenomena) and L-DOPA sometimes causes serious side effects (e.g., L-DOPA-induced dyskinesia and psychosis) (Fig. 2) [1, 8, 19]. New medications effective not only for motor symptoms, but also for non-motor symptoms (e.g., cognitive impairments and mood disorders) are also required.

5-HT_1A receptors and Parkinson’s disease

5-HT_1A receptors are coupled to G_i/o protein, inhibit adenylate cyclase and c-AMP formation, and reduce protein kinase A (PK-A) activity (Fig. 3) [6–8, 32]. In addition, 5-HT_1A receptors activate G-protein-gated inwardly rectifying K⁺ (GIRK) channels, which facilitate the efflux of intracellular K⁺ and hyperpolarize target neurons. Thus, activation of 5-HT_1A receptors inhibits the neural firing of target neurons (Fig. 3) [33–39].

Figure 3.

Signal transduction pathways of 5-HT_1A receptors. The 5-HT_1A receptor is a GPCR coupled to G_i/o protein. Activation of 5-HT_1A receptors leads to inhibition of adenylate cyclase (AC) activity, cAMP formation and protein kinase A (PK-A)-mediated protein phosphorylation. 5-HT_1A receptors also activate G-protein-gated inwardly rectifying K⁺ (GIRK) channels and inhibit the activity of target neurons.

5-HT_1A receptors are highly expressed in the limbic regions (hippocampus and amygdala), septum (lateral septal nucleus) and raphe nuclei (dorsal raphe nucleus and median raphe nucleus) [6, 32, 40, 41]. Besides these regions, 5-HT_1A receptors are also expressed at moderate to low densities in the cerebral cortex, thalamus, hypothalamus and basal ganglia (e.g. striatum) [32, 40]. 5-HT_1A receptors function both as pre-synaptic autoreceptors in the raphe nuclei and as post-synaptic receptors in other brain regions. 5-HT_1A autoreceptors are located on somata and dendrites of 5-HT neurons in the raphe, where they negatively regulate 5-HT neuron activity [33]. Through this function, 5-HT_1A autoreceptors can control the overall activity of the serotonergic system. On the other hand, post-synaptic 5-HT_1A receptors are located on membranes of neurons or nerve terminals (heteroreceptors) innervated by 5-HT neurons.

In Parkinson’s disease, loss of 5-HT neurons in the raphe nuclei has been reported [42]. Thus, 5-HT content and the density of 5-HT transporters (a marker for 5-HT nerve terminals) in the forebrain regions (e.g. striatum and neocortex) are reduced in patients with Parkinson’s disease. Alternatively, post-synaptic 5-HT_1A and 5-HT_2A receptors are up-regulated in response to the functional deficit of 5-HT neurons [42]. Furthermore, recent clinical study demonstrated that parkinsonian patients with depression show further pronounced dysfunction of 5-HT neurons as compared to the patients without depression [43]. Thus, there is a close relationship between dysfunction of the serotonergic system and Parkinson’s disease.

Roles of 5-HT_1A receptors in the treatment of Parkinson’s disease

1. Parkinsonian motor symptoms

5-HT_1A receptor stimulation ameliorates various extrapyramidal motor disorders [8–18]. A line of studies suggests that 5-HT_1A agonists or partial agonists can ameliorate extrapyramidal disorders induced by the denervation of dopaminergic neurons or depletion of cerebral dopamine (Table. 1) [11, 12, 17, 44]. Namely, selective 5-HT_1A agonists (e.g., 8-hydroxy-2-(di-npropylamino) tetralin (8-OH-DPAT)) ameliorate bradykinesia or hypolocomotion induced by dopaminergic neurotoxins (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)) or akinesia induced by reserpine which depletes central monoamines (Fig. 4). Also, 5-HT_1A agonists, like antiparkinsonian agents, produce contralateral rotation behavior in the 6-hydroxydopamine (6-OH-DA)-hemilesioned rat model of Parkinson’s disease and ameliorate dyskinesia or hypolocomotion in MPTP-treated primate models (Table 1) [12, 13, 17, 45–50]. In addition, numerous studies have shown that activation of 5-HT_1A receptors improves extrapyramidal disorders elicited by dopamine D₂ antagonists (e.g., antipsychotics-induced parkinsonian symptoms). 5-HT_1A full agonists (e.g., 8-OH-DPAT and flesinoxan) and 5-HT_1A partial agonists (e.g., tandospirone and buspirone) attenuated D₂ antagonist (e.g., haloperidol)-induced catalepsy, bradykinesia and other parkinsonian symptoms (Fig. 4, Fig 5 and Table. 1) [11–17, 51]. The improvement of extrapyramidal symptoms by 5-HT_1A agonists is as potent as that by L-DOPA, the mACh receptor antagonist trihexyphenidyl or the D₂ agonist bromocriptine, and is reversed by 5-HT_1A antagonists (e.g., WAY-100135 and WAY-100635) (Fig. 4 and Fig. 5) [14, 15]. Furthermore, the ameliorative effect of 5-HT_1A agonists is supported by the neurochemical findings that D₂ antagonist-induced Fos expression in the striatum could be reversed by 5-HT_1A agonists (e.g., 8-OH-DPAT and tandospirone), suggesting that stimulation of 5-HT_1A receptors counteracts the D₂ blocking actions of antipsychotics in striatum [15, 16].

Table 1.

Anti-parkinsonian and anti-dyskinetic actions of 5-HT_1A agonists.

	Animal models	Drugs	References
Anti-parkinsonian actions	MPTP-induced bradykinesia and motor disturbance	8-OH-DPAT, BAY-639044, repinotan, SLV308, sarizotan	[17, 45–47]
	6-OH-DA-induced rotation behavior	8-OH-DPAT, tandospirone	[12, 13, 48]
	6-OH-DA-induced catalepsy	Buspirone, 8-OH-DPAT	[49, 50]
	Reserpine-induced hypokinesia	8-OH-DPAT, flesinoxan, buspirone, tandospirone	[12, 52, 53]
	D2 antagonist-induced catalepsy and bradykinesia	8-OH-DPAT, tandospirone, buspirone, ipsapirone, eptapirone	[12, 14, 51]
Anti-dyskinetic actions	L-DOPA-induced dyskinesia	8-OH-DPAT, tandospirone, buspirone, sarizotan	[80, 82, 83]
	D1 receptor-induced dyskinesia	8-OH-DPAT	[44]

Figure 4.

Ameliorative actions of the 5-HT_1A agonist 8-OH-DPAT on MPTP- and D₂ antagonist (i.e., haloperidol)-induced bradykinesia and its reversal by the 5-HT_1A antagonist WAY-100135 in mice. T_turn and T_total values are the time required for mice to rotate on the pole and to descent to the floor, respectively, in the mouse pole-test. Increases in T_turn and T_total values represent the induction of bradykinesia. ^$p<0.05 vs. Pre-MPTP (Normal). ^#p<0.05 vs. Vehicle + MPTP or Haloperidol. *p<0.05 vs. Normal. ^†p<0.05 vs. 8-OH-DPAT + Haloperidol.

Figure 5.

Ameliorative actions of the 5-HT_1A agonist tandospirone and antiparkinsonian agents, L-DOPA and bromocriptine, on D₂ antagonist (i.e., haloperidol)-induced catalepsy in rats. The 5-HT_1A agonist tandospirone ameliorated catalepsy with a similar potency to L-DOPA and greater potency than the D₂ agonist bromocriptine. *p<0.05, **p<0.01 vs. Haloperidol alone.

The fact that the activation of 5-HT_1A receptors ameliorates the motor dysfunction caused by damage to dopaminergic neurons [12, 13, 17, 45] implies that 5-HT_1A agonists alleviate extrapyramidal symptoms through non-dopaminergic mechanisms. Moreover, the ameliorative effect of 5-HT_1A agonists on akinesia in reserpine-treated rats was reversed by the 5-HT_1A antagonist WAY-100135, but not by the D₂ antagonist haloperidol [12, 52, 53]. It is therefore likely that 5-HT_1A agonists produce antiparkinsonian actions in an additive fashion with currently used dopaminergic agents (Fig. 6).

Figure 6.

Post-synaptic mechanisms underlying the antiparkinsonian actions of 5-HT_1A agonists. 5-HT_1A agonists ameliorated extrapyramidal motor disfunction through post-synaptic 5-HT_1A receptors even in animals with denervated serotonergic neurons. In addition, the local microinjection of 5-HT_1A agonists into the striatum or the cerebral cortex (motor cortex) exerted antiparkinsonian actions. DA: dopamine, ACh: acetylcholine, Glu: glutamate.

5-HT_1A agonists alleviate extrapyramidal symptoms even in animals in which pre-synaptic 5-HT_1A autoreceptors were inactivated by the tryptophan hydroxylase inhibitor, p-chlorophenylalanine (PCPA). Therefore 5-HT_1A agonists seem to exert antiparkinsonian actions at least partly by activating post-synaptic 5-HT_1A receptors (Fig. 6 and Fig. 7) [14]. In addition, bilateral microinjections of 8-OH-DPAT into the cerebral cortex or striatum significantly attenuated D₂ antagonist-induced catalepsy in rats [17]. Thus, it is likely that the ameliorative action of 5-HT_1A agonists is mediated by post-synaptic 5-HT_1A receptors in the cerebral cortex and striatum, probably by inhibiting the neuronal activity in these regions (Fig. 6 and Fig. 7). As the activities of striatal neurons are positively regulated by glutamatergic neurons derived from the motor cortex [8], and since NMDA antagonists reduce the neural activity of striatal neurons as well as extrapyramidal motor disorders [54–57], activation of 5-HT_1A receptors in the motor cortex seems to exert ameliorative actions by inhibiting the corticostriatal glutamatergic neurons (Fig. 6 and Fig. 7). On the other hand, previous studies showed that the microinjection of 8-OH-DPAT into the raphe nuclei also alleviated haloperidol-induced catalepsy [58–60]. Therefore, it is also possible that the activation of pre-synaptic 5-HT_1A autoreceptors inhibits serotonergic neuron activities, which consequently reduces the activity of post-synaptic 5-HT_2A/2C, 5-HT₃ and 5-HT₆ receptors and alleviates extrapyramidal motor symptoms (Fig. 7) [61, 62].

Figure 7.

Mechanisms of action of 5-HT_1A agonists in modulating extrapyramidal, cognitive and psycho-emotional functions. A: Stimulation of post-synaptic 5-HT_1A receptors reduces the activity of striatal neurons directly by hyperpolarizing striatal neurons and indirectly by inhibiting Glu neurons in the motor cortex. In addition, stimulation of pre-synaptic 5-HT_1A autoreceptors inhibits serotonergic neuronal activities, thereby reducing the functions of 5-HT_2A/2C, 5-HT₃ and 5-HT₆ receptors. B: Stimulation of post-synaptic 5-HT_1A receptors inhibits cognitive functions by reducing the activity of cholinergic and/or glutamatergic neurons in the basal forebrain and medial septum, and by inhibiting ACh release in the hippocampus. By contrast, stimulation of pre-synaptic 5-HT_1A autoreceptors enhances cognitive functions by reducing serotonergic neuron activities (e.g., inhibition of 5-HT_1A, 5-HT₃ and 5-HT₆ receptors which impair cognitive functions). C: 5-HT_1A receptors are highly expressed in the limbic areas (e.g., hippocampus and amygdala) and lateral septum, which are involved in generation of depression and anxiety. Stimulation of post-synaptic 5-HT_1A receptors exert anxiolytic and/or antidepressant effects by inhibiting the activity of the limbic neurons (i.e., hippocampus and amygdala) and the lateral septal neurons. In addition, activation of pre-synaptic 5-HT_1A autoreceptors reduce the activity of 5-HT_2A/2C, 5-HT₃ and 5-HT₇ receptors which are implicated in generation of mood disorders.

2. Non-motor symptoms in Parkinson’s Disease

Parkinson’s disease accompanies diverse non-motor symptoms including cognitive impairments, psycho-emotional changes (e.g., anxiety and depression), sleep disturbances and autonomic dysfunction (Fig. 2) [1–3, 9, 63]. Among these, cognitive impairments develop in about 40% of patients and most patients (more than 80%) have dementia at the end-stage of the disease [3]. Moreover, anxiety and depression are very common, affecting about 50% of individuals with Parkinson’s disease [63]. Thus, besides the treatment of core motor symptoms, control of non-motor symptoms, especially psycho-emotional disturbances and cognitive impairments, is key to improving the quality of life of patients with Parkinson’s disease [1].

2.1. Cognitive impairments

5-HT_1A receptors play an important role in modulating cognitive functions (e.g., learning and memory) [27, 30, 64–66]. It has been reported that 8-OH-DPAT exhibits biphasic effects, in that high doses impair and low doses enhance cognitive functions [27, 30]. These inhibitory and stimulatory actions seem to be mediated by activation of post-synaptic and pre-synaptic 5-HT_1A receptors, respectively (Fig. 7). Namely, cognitive impairment by the stimulation of post-synaptic 5-HT_1A receptors probably occurs through 1) inhibition of the activity of acetylcholinergic and/or glutamatergic neurons projecting to the cerebral cortex or hippocampus in the basal forebrain (e.g., diagonal band of Broca and medial septum), 2) inhibition of the activity of the hippocampal and cortical neurons, receiving the above acetylcholinergic or glutamatergic inputs, and 3) a reduction in the release of ACh within the hippocampus (Fig. 7). On the other hand, stimulation of pre-synaptic 5-HT_1A receptors inhibits the activity of 5-HT neurons, thereby reducing the activity of post-synaptic 5-HT_1A, 5-HT₃ and 5-HT₆ receptors which impair cognitive functions [7]. Indeed, it is reported that 5-HT_1A antagonists (e.g., WAY-100635, WAY-101405, NAD-299 and lecozotan) and partial 5-HT_1A agonists (e.g., tandospirone) improve the cognitive impairments induced by mACh receptor antagonists (e.g., scopolamine) or N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., MK-801) [27, 30, 64–66].^{28,31,89–91} Thus, 5-HT_1A antagonists or partial agonists are expected to improve the cognitive deficits in Parkinson’s disease. However, this is not conclusive since several studies reported that 5-HT_1A agonists improve cognitive impairments in Parkinson’s disease [18, 67].

2.2. Mood disorders

It is well known that 5-HT_1A receptors are involved in the pathogenesis and treatment of anxiety and depressive disorders. 5-HT_1A full agonists and partial agonists produce anti-anxiety effects in various animal models (e.g., Vogel’s conflict, elevated-plus maze, social interaction and conditioned-fear freezing tests) [10, 25, 68–71]. These anxiolytic actions of 5-HT_1A agonists (e.g., 8-OH-DPAT, buspirone and tandospirone) are reversed by selective 5-HT_1A antagonists (e.g., WAY-100635 and WAY-100135) [69, 70]. In addition, knockout mice lacking 5-HT_1A receptors exhibit signs of advanced anxiety [72–74]. Conversely, transgenic mice overexpressing 5-HT_1A receptors show reduced anxiety behavior [41]. Moreover, 5-HT_1A agonists significantly improve depressive behavior (e.g., increase in immobility time in the forced swim test) following repeated administrations [75–78].

It is likely that the anxiolytic and antidepressant actions of 5-HT_1A agonists are mediated by both post-synaptic and pre-synaptic receptors (Fig. 7). 5-HT_1A receptors are mainly located in the limbic regions (hippocampus and amygdala) and lateral septum, which are implicated in the generation of mood disorders. It is suggested that 5-HT_1A agonists produce anxiolytic and antidepressant effects by inhibiting the neural activity of limbic neurons and lateral septal neurons via 5-HT_1A-activated GIRK channels (Fig. 3) [8, 10, 33–39, 69–79]. On the other hand, activation of pre-synaptic 5-HT_1A autoreceptors in the raphe nuclei inhibit the activity of 5-HT_2A/2C, 5-HT₃ and 5-HT₇ receptors, which are implicated in the generation of depression and/or anxiety (Fig. 7).

3. Drug-related adverse reactions

3.1. L-DOPA-induced dyskinesia

For more than 40 years, dopamine replacement therapy using L-DOPA has been the mainstay of treatments for Parkinson’s disease [1, 8, 19, 31]. However, L-DOPA often has fluctuations in its efficacy (e.g., wearing-off and on-off phenomena) and/or serious side effects (e.g., dyskinesia and psychosis) after long-term treatment (Fig. 2) [8, 19, 31]. L-DOPA-induced dyskinesia manifests as dystonic, choreic and athetotic movements, which affect the limbs, hands, trunk and lingual-facial-buccal muscular systems at various points of the L-DOPA cycle. The prevalence of L-DOPA-induced dyskinesia during the treatment is reported at 30–80% [31]. Risk factors for L-DOPA-induced dyskinesia include an earlier onset of Parkinson’s disease, longer duration of the disease, longer duration of L-DOPA therapy, total L-DOPA exposure and female gender. As L-DOPA-induced dyskinesia is generally difficult to treat and often hampers continued treatment, there is a great clinical need to modulate it (Fig. 2) [1, 8, 19, 31].

Although the precise mechanisms underlying the dyskinesia are still unknown, activation of the D₁ receptor and/or an imbalance of D₁-D₂ receptor functions are thought to be important in the generation of dyskinesia [19, 31]. Indeed, stimulation of D₁ receptors by D₁ agonists (e.g., SKF-81297) induces abnormal involuntary movements (vacuous chewing, tongue extrusion, repetitive jaw movements etc) in several animal models [44]. Furthermore, various neurotransmitter systems including the serotonergic, noradrenergic and glutamatergic systems are also suggested to be involved in the development of L-DOPA-induced dyskinesia [31].

It has been reported that 5-HT_1A receptor agonists inhibit dyskinesia in animals chronically treated with L-DOPA (Table 1) [20–22]. Previous studies also showed that 5-HT_1A agonists (e.g., 8-OH-DPAT and tandospirone) improved dyskinesia in MPTP-treated primates without affecting the antiparkinsonian action of L-DOPA [80–85]. Microinjection studies revealed that activation of 5-HT_1A receptors in the striatum and motor cortex by 8-OH-DPAT alleviated L-DOPA-induced dyskinesia [22, 44, 83, 86], indicating that the anti-dyskinetic actions of 5-HT_1A agonists are mediated at least partly by post-synaptic 5-HT_1A receptors in both the striatum and motor cortex. Furthermore, microdialysis studies showed that the actions of 5-HT_1A agonists in the cerebral cortex (primary motor areas) reduce glutamate release in the striatum, which contributes to inhibition of the induction of dyskinesia [56, 87]. Thus, the activation by 5-HT_1A receptors agonists is conceivably a favorable treatment approach for L-DOPA-induced dyskinesia in Parkinson’s disease.

3.2. Dopamine agonist-induced emesis

Dopaminomimetic agents for Parkinson’s disease including L-DOPA and D₂ agonists (bromocriptine, pergolide, cabergoline, ropinirole and talipexole) induce nausea and emesis. It is known that 5-HT_1A receptors modulate neural control of nausea and emesis. Studies have shown that the activation of 5-HT_1A receptors by 5-HT_1A agonists inhibits apomorphine (D₂ agonist)-induced emesis in various animal models (e.g., pigeons, cats and house shrews) [88]. It is therefore likely that the activation of 5-HT_1A receptors is a useful approach to preventing dopamine agonist-induced nausea and emesis in the treatment of Parkinson’s disease.

Conclusion

In this article, we reviewed the therapeutic roles of 5-HT_1A receptors in the treatment of Parkinson’s disease. It is now evident that the activation of 5-HT_1A receptors ameliorates parkinsonian motor symptoms in various animal models (e.g., MPTP-induced bradykinesia and motor disabilities, 6-OH-DA-induced catalepsy, contralateral rotation behavior in the 6-OH-DA-hemilesioned model, D₂ antagonist-induced bradykinesia and catalepsy). The efficacy of 5-HT_1A agonists in improving parkinsonian motor symptoms seems to be as good as that of currently used antiparkinsonian agents (e.g., L-DOPA, D₂ agonists and mACh antagonists). In addition, since the antiparkinsonian actions of 5-HT_1A agonists occur through non-dopaminergic mechanisms, 5-HT_1A agonists seem to exert antiparkinsonian actions in an additive fashion with currently used dopaminergic agents (Fig. 8).

Figure 8.

5-HT_1A receptors as a therapeutic target in Parkinson’s disease. 5-HT_1A receptors seem to be a favorable target for the treatment of Parkinson’s disease. 5-HT_1A agonists or 5-HT_1A partial agonists are expected to be effective for L-DOPA-induced dyskinesia, mood disorders and dopamine agonist-induced emesis as well as parkinsonian core motor symptoms. 5-HT_1A partial agonists or 5-HT_1A antagonists may also be useful for treating the cognitive impairments associated with Parkinson’s disease.

It is well documented that the activation of 5-HT_1A receptors is involved in the treatment of depression and anxiety, which are often seen in patients with Parkinson’s disease. Although further studies are required to elucidate the mechanisms involved and clinical efficacy, partial 5-HT_1A agonists or 5-HT_1A antagonists are expected to ameliorate cognitive impairments in Parkinson’s disease. It is therefore likely that 5-HT_1A receptors are an attractive target for treating non-motor symptoms (i.e., cognitive impairments and mood disorders) of Parkinson’s disease (Fig. 8). Finally, 5-HT_1A agonists seem to alleviate drug-related adverse reactions such as L-DOPA-induced dyskinesia and dopamine agonist-induced emesis. Notably, 5-HT_1A agonists exert clear efficacy against dyskinesia, one of the main side effects of L-DOPA (Fig. 8).

The present review illustrates that the activation of 5-HT_1A receptors provides multiple benefits in the treatment of Parkinson’s disease, i.e., amelioration of the core parkinsonian symptoms, cognitive impairments, mood disorders, L-DOPA-induced dyskinesia and dopamine agonist-induced emesis (Fig. 8). These findings encourage the synthesis of new 5-HT_1A agonists with favorable 5-HT_1A selectivity and pharmacodynamic properties. In addition, designing compounds which possess combined activities for both 5-HT_1A and dopamine D₂ receptors seems to be a promising approach to the treatment of Parkinson’s disease. These new ligands for 5-HT_1A receptors may overcome limitations of clinical efficacy and/or improve adverse reactions in the current treatment of Parkinson’s disease.