Role of the primary motor cortex in l-DOPA-induced dyskinesia and its modulation by 5-HT1A receptor stimulation

doi:10.1016/j.neuropharm.2011.05.021

Neuropharmacology

Volume 61, Issue 4, September 2011, Pages 753-760

https://doi.org/10.1016/j.neuropharm.2011.05.021 Get rights and content

Abstract

While serotonin 5-HT1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesias (LID) by normalizing activity in the basal ganglia neurocircuitry, recent evidence suggests putative 5-HT1AR within the primary motor cortex (M1) may also contribute. To better characterize this possible mechanism, c-fos immunohistochemistry was first used to determine the effects of systemic administration of the full 5-HT1AR agonist ±8–OH–DPAT on l-DOPA-induced immediate early gene expression within M1 and the prefrontal cortex (PFC) of rats with unilateral medial forebrain bundle (MFB) dopamine (DA) lesions. Next, in order to determine if direct stimulation of 5-HT1AR within M1 attenuates the onset of LID, rats with MFB lesions were tested for l-DOPA-induced abnormal involuntary movements (AIMs) and rotations following M1 microinfusions of ±8–OH–DPAT with or without coadministration of the 5-HT1AR antagonist WAY100635. Finally, ±8–OH–DPAT was infused into M1 at peak dyskinesia to determine if 5-HT1AR stimulation attenuates established l-DOPA-induced AIMs and rotations. While no treatment effects were seen within the PFC, systemic ±8–OH–DPAT suppressed l-DOPA-induced c-fos within M1. Intra-M1 5-HT1AR stimulation diminished the onset of AIMs and this effect was reversed by WAY100635 indicating receptor specific effects. Finally, continuous infusion of ±8–OH–DPAT into M1 at peak dyskinesia alleviated l-DOPA-induced AIMs. Collectively, these findings support an integral role for M1 in LID and its modulation by local 5-HT1AR.

Highlights

► 5-HT1AR agonism with ±8–OH–DPAT reduced l-DOPA-induced AIMs and c-fos in M1. ► Site-specific microinjection of ±8–OH–DPAT into M1 reduced the onset of dyskinesia. ► Continuous infusion of ±8–OH–DPAT into M1 reduced established dyskinesia.

Introduction

Chronic dopamine (DA) replacement therapy with l-DOPA for the treatment of Parkinson’s disease (PD) often leads to the development of l-DOPA-induced dyskinesias (LID) which are characterized by abnormal involuntary movements (AIMs; Jankovic, 2005). One possible mechanism underlying the development of LID involves the dysregulation of DA release from serotonin (5-HT) neurons (Carta et al., 2007). Indeed, following DA depletion, 5-HT neurons from the raphe nucleus convert exogenous l-DOPA to DA and release it into the striatum (Arai et al., 1994, Navailles et al., 2010). In line with these findings, serotonin 1A receptor (5-HT1AR) agonists likely reduce LID in both experimental and clinical populations by tempering supraphysiological striatal DA levels through stimulation of inhibitory somatodendritic 5-HT1A autoreceptors (Bara-Jimenez et al., 2005, Bibbiani et al., 2001, Carta et al., 2007, Eskow et al., 2009, Lindgren et al., 2010).

While evidence has implicated the dorsal raphe nucleus (Carta et al., 2007, Eskow et al., 2009) as a target for 5-HT1AR agonists, additional research suggests that extra-raphe 5-HT1AR within the basal ganglia circuitry may also modulate the expression of LID (Dupre et al., 2007, Iravani et al., 2006). For example, direct stimulation of 5-HT1AR within the subthalamic nucleus (STN; Marin et al., 2009) and the striatum has been shown to decrease l-DOPA (Bishop et al., 2009) and DA agonist (Dupre et al., 2008a, Dupre et al., 2008b) induced dyskinesias without adversely affecting anti-parkinsonian efficacy. Interestingly, a population of post-synaptic cortical 5-HT1AR known to influence corticostriatal signaling is upregulated following MPTP lesions in macaques and persists throughout l-DOPA treatment (Huot et al., 2010). Furthermore, functional imaging studies have revealed overactivity in the primary motor cortex (M1) in humans during the expression of LID (Rascol et al., 1998). Therefore, it is possible that stimulation of 5-HT1AR within M1 may diminish the onset and expression of LID.

In order to characterize the cellular, functional, and anatomical specificity of 5-HT1AR effects in the cortex, we investigated the effects of systemic ±8–OH–DPAT following l-DOPA administration on c-fos expression within M1 and the prefrontal cortex (PFC) of unilateral 6-OHDA lesioned rats. Next, the effects of intra-cortical 5-HT1AR stimulation in M1 on both the onset and peak expression of LID were examined using microinfusion and microdialysis techniques, respectively. The present results suggest the importance of M1 in LID and implicate its modulation through 5-HT1AR stimulation as a therapeutic target for the attenuation of LID.

Section snippets

Animals

Adult male Sprague-Dawley rats were used (N = 44; 225–250 g upon arrival; Taconic Farms, Hudson, NY, USA). Animals were housed in plastic cages (22 cm high, 45 cm deep, and 23 cm wide) and had free access to water and standard lab chow (Rodent Diet 5001; Lab Diet, Brentwood, MO, USA). The colony room was maintained on a 12/12 h light/dark cycle (lights on at 0700 hs) at a temperature of 22–23 °C. Animals were treated in accordance with the guidelines of the Institutional Animal Care and Use

Experiment 1: systemic ±8–OH–DPAT reduces l-DOPA-induced ALO AIMs and M1 c-fos expression

5-HT1AR agonist treatment has previously been shown to reduce LID (Bishop et al., 2009, Eskow et al., 2007, Lindgren et al., 2010). In the current study, behavioral analyses of LID also revealed a main effect of treatment for ALO AIMs (H₂ = 8.2663, p < 0.05; Fig. 1 B). l-DOPA treatment increased ALO AIMs compared to vehicle treatment while systemic adjunct treatment with the 5-HT1AR agonist, ±8–OH–DPAT attenuated ALO AIMs in l-DOPA-treated, DA-depleted rats (all p < 0.05). However, it is

Discussion

Multiple basal ganglia sites have been associated with the expression and treatment of LID. More recently, evidence has accumulated implicating a more primary role for M1. In the current investigation we provide cellular and functional confirmation of the link between M1 and LID, while further demonstrating that 5-HT1AR agonists convey their anti-dyskinetic efficacy in part via this structure. For the first time we show that l-DOPA-induced ALO AIMs were associated with an increase in c-fos

Conclusions

The current study provides strong evidence for the role of M1 in LID. Furthermore, we demonstrate that selective stimulation of 5-HT1AR within the motor cortex can attenuate both the onset and expression of peak AIMs. While the anti-dyskinetic effects of cortical 5-HT1AR stimulation likely involves the modulation of the corticostriatal pathway, further studies are necessary in order to elucidate this potential mechanism. In conclusion, the current research highlights a motor cortex-mediated

Acknowledgments

This work was supported by funds from R01-NS059600 (CB) and the Center for Development and Behavioral Neuroscience at Binghamton University (CB).

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L-DOPA-induced dyskinesia (LID) is a frequent adverse side effect of L-DOPA treatment in Parkinson's disease (PD). Understanding the mechanisms underlying the development of these motor disorders is needed to reduce or prevent them. We investigated the role of TrkB receptor in LID, in hemiparkinsonian mice treated by chronic L-DOPA administration. Repeated L-DOPA treatment for 10 days specifically increased full-length TrkB receptor mRNA and protein levels in the dopamine-depleted dorsal striatum (DS) compared to the contralateral non-lesioned DS or to the DS of sham-operated animals. Dopamine depletion alone or acute L-DOPA treatment did not significantly increase TrkB protein levels. In addition to increasing TrkB protein levels, chronic L-DOPA treatment activated the TrkB receptor as evidenced by its increased tyrosine phosphorylation. Using specific agonists for the D1 or D2 receptors, we found that TrkB increase is D1 receptor-dependent. To determine the consequences of these effects, the TrkB gene was selectively deleted in striatal neurons expressing the D1 receptor. Mice with TrkB floxed gene were injected with Cre-expressing adeno-associated viruses or crossed with Drd1-Cre transgenic mice. After unilateral lesion of dopamine neurons in these mice, we found an aggravation of axial LID compared to the control groups. In contrast, no change was found when TrkB deletion was induced in the indirect pathway D2 receptor-expressing neurons. Our study suggests that BDNF/TrkB signaling plays a protective role against the development of LID and that agonists specifically activating TrkB could reduce the severity of LID.
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Activation of serotonin 5-HT1A receptors using the selective agonist 8-OH-DPAT in animals with a compromised presynaptic nigrostriatal system attenuates the increase in striatal extracellular DA derived from administration of exogenous L-DOPA (Kannari et al., 2001), suggesting that such agonists could be used to regulate the concentration of DA following L-DOPA administration. There is abundant evidence from animal model studies that serotonin receptor modulation with 5-HT1A agonists such as 8-OH-DPAT (Bishop et al., 2009; Carta et al., 2007; Eskow et al., 2009; Ostock et al., 2011), buspirone (Eskow et al., 2007; Lundblad et al., 2005), piclozotan (Tani et al., 2010), sarizotan (Grégoire et al., 2009; Marin et al., 2009) can reduce LID symptoms. Likewise, evidence from exploratory clinical trials supports anti-dyskinetic effects of the 5-HT1A agonists in PD patients on L-DOPA treatment (Bonifati et al., 1994; Kannari et al., 2002; Kleedorfer et al., 1991; Politis et al., 2014).
The gold standard for symptomatic relief of Parkinson's disease (PD) is L-DOPA. However, long-term treatment often leads to motor complications such as L-DOPA-induced dyskinesia (LID). While amantadine (Gocovri™) is the only approved therapy for dyskinesia in PD patients on the American market, it is associated with neurological side effects and limited efficacy. Thus, there remains a high unmet need for addressing LID in PD patients worldwide.
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The strong anti-dyskinetic effect found with combined 5-HT1A and 5-HT1B/D agonism renders buspirone and zolmitriptan together a meaningful treatment for LID in PD.
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Acetylcholine muscarinic receptors (mAChRs) contribute to both the facilitation and inhibition of levodopa-induced dyskinesia operated by striatal cholinergic interneurons, although the receptor subtypes involved remain elusive. Cholinergic afferents from the midbrain also innervate the substantia nigra reticulata, although the role of nigral mAChRs in levodopa-induced dyskinesia is unknown. Here, we investigate whether striatal and nigral M1 and/or M4 mAChRs modulate dyskinesia and the underlying striato-nigral GABAergic pathway activation in 6-hydroxydopamine hemilesioned rats. Reverse microdialysis allowed to deliver the mAChR antagonists telenzepine (M1 subtype preferring), PD-102807 and tropicamide (M4 subtype preferring), as well as the selective M4 mAChR positive allosteric modulator VU0152100 in striatum or substantia nigra, while levodopa was administered systemically. Dyskinetic movements were monitored along with nigral GABA (and glutamate) and striatal glutamate dialysate levels, taken as neurochemical correlates of striato-nigral pathway and cortico-basal ganglia-thalamo-cortical loop activation. We observed that intrastriatal telenzepine, PD-102807 and tropicamide alleviated dyskinesia and inhibited nigral GABA and striatal glutamate release. This was partially replicated by intrastriatal VU0152100. The M2 subtype preferring antagonist AFDX-116, used to elevate striatal acetylcholine levels, blocked the behavioral and neurochemical effects of PD-102807. Intranigral VU0152100 prevented levodopa-induced dyskinesia and its neurochemical correlates whereas PD-102807 was ineffective. These results suggest that striatal, likely postsynaptic, M1 mAChRs facilitate dyskinesia and striato-nigral pathway activation in vivo. Conversely, striatal M4 mAChRs can both facilitate and inhibit dyskinesia, possibly depending on their localization. Potentiation of striatal and nigral M4 mAChR transmission leads to powerful multilevel inhibition of striato-nigral pathway and attenuation of dyskinesia.
Dopamine receptor cooperativity synergistically drives dyskinesia, motor behavior, and striatal GABA neurotransmission in hemiparkinsonian rats
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The striatum undergoes significant neuroplasticity both in Parkinson's Disease (PD) and following dopamine (DA) replacement therapy with l-DOPA. Unfortunately, these changes also contribute to the emergence of l-DOPA-induced dyskinesia (LID). While convergent strategies have demonstrated independent roles for DA D1 -receptors (D1R) and D2-receptors (D2R) in LID, DA receptor cooperativity, either by cellular or circuit mechanisms, has also been implicated in the dyskinetic brain. How this cooperativity is substantiated is vitally important given that l-DOPA, once converted to DA, stimulates all DA receptors. The present experiments sought to characterize the effect of individual or collective stimulation of D1R and D2R-like receptors both systemically and intrastriatally. In experiment 1, hemiparkinsonian l-DOPA-primed rats received systemic doses of the D1R agonist SKF38393 and D2R-like agonist quinpirole. Dyskinesia and motor improvement were monitored using the abnormal involuntary movements scale (AIMs) and the forepaw adjustment steps test (FAS), respectively. In experiment 2, SKF38393 and quinpirole were administered intrastriatally via reverse-phase in vivo microdialysis while coincident changes in striatal glutamate and gamma-Aminobutyric acid (GABA) were monitored. SKF38393 and quinpirole dose-dependently increased AIMs. When threshold DA agonist doses were co-administered, AIMs and motor performance were synergistically enhanced. Like systemic experiments, striatal co-administration of threshold concentrations of DA agonists resulted in synergistic exacerbation of AIMs, and concurrent increases in GABA efflux. These data highlight the role of striatal DA receptor cooperativity in LID and suggest a central role for striatal GABA release in these effects.
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2018, Experimental Neurology
Citation Excerpt :
Supporting this view, several studies have demonstrated antidyskinetic effects by manipulation of serotonergic components in animal models of levodopa-induced dyskinesia (see Cenci, 2014 for review), such as serotonin reuptake inhibitors (Bishop et al., 2012; Conti et al., 2014; Fidalgo et al., 2015) and 5-HT1A agonists (Carta et al., 2007; Dupre et al., 2008; Lindgren et al., 2010). At the same time, other studies have shown that activation of 5-HT1A receptors in both motor cortex (Ostock et al., 2011) and striatum (Meadows et al., 2017; Ostock et al., 2011) can have independent antidyskinetic effects suggesting that multiple parallel mechanisms are at play following systemic 5-HT1A agonist administration. Recently, it has been demonstrated that ‘biased’ and highly selective 5-HT1A agonists are able to alleviate dyskinesia in animal models of PD while minimally interfering with levodopa antiparkinsonian effects (Huot et al., 2015; Iderberg et al., 2015a, 2015b).
Recently, the biased and highly selective 5-HT_1A agonists, NLX-112, F13714 and F15599, have been shown to alleviate dyskinesia in rodent and primate models of Parkinson's disease, while marginally interfering with antiparkinsonian effects of levodopa. To provide more detailed information on the processes underlying the alleviation of dyskinesia, we have here investigated changes in the spectral contents of local field potentials in cortico-basal ganglia-thalamic circuits following treatment with this novel group of 5-HT_1A agonists or the prototypical agonist, 8-OH-DPAT. Dyskinetic symptoms were consistently associated with 80 Hz oscillations, which were efficaciously suppressed by all 5-HT_1A agonists and reappeared upon co-administration of the antagonist, WAY100635. At the same time, the peak-frequency of fast 130 Hz gamma oscillations and their cross-frequency coupling to low-frequency delta oscillations were modified to a different extent by each of the 5-HT_1A agonists. These findings suggest that the common antidyskinetic effects of these drugs may be chiefly attributable to a reversal of the brain state characterized by 80 Hz gamma oscillations, whereas the differential effects on fast gamma oscillations may reflect differences in pharmacological properties that might be of potential relevance for non-motor symptoms.
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Because the serotonergic nervous system plays an important role in regulating diverse physiological functions including psychoemotional expression, sensorimotor integration, and cognitive functions, 5-hydroxytryptamine (5-HT) receptors are considered to be involved in the pathogenesis and treatment of various central nervous system (CNS) disorders. This article will review the diversity of 5-HT receptor functions in modulating CNS disorders and discuss the therapeutic potential of 5-HT receptors in the treatment of psychosis (e.g., schizophrenia), emotional disorders (e.g., anxiety and depression), and neurological diseases (e.g., Parkinson's disease). Existing evidence implies that stimulation of 5-HT_1A receptors or blockade of 5-HT₂, 5-HT₃, and 5-HT₆ receptors produces clinical benefits for the treatment of schizophrenia, such as an amelioration of negative symptoms, cognitive impairment, mood disturbances, and/or drug-induced extrapyramidal side effects. Stimulation of 5-HT_1A receptors and blockade of 5-HT₂ or 5-HT₃ receptors seem to be effective for the treatment of anxiety and depression. In addition, modulation of 5-HT_1A, 5-HT₂, and 5-HT₃ receptors is also considered to be useful in the treatment of Parkinson's disease (e.g., improvement of parkinsonian motor symptoms, l-DOPA-induced dyskinesia and psychosis, and mood disturbances). Thus, new drugs acting on 5-HT receptor subtypes are expected to emerge as future therapy options for neuropsychiatry disorders. These therapeutic approaches modulating serotonergic activity may resolve the limitations of the current treatment of CNS disorders by improving clinical efficacy as well as reducing drug side effects.

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Role of the primary motor cortex in l-DOPA-induced dyskinesia and its modulation by 5-HT1A receptor stimulation

Abstract

Highlights

Introduction

Section snippets

Animals

Experiment 1: systemic ±8–OH–DPAT reduces l-DOPA-induced ALO AIMs and M1 c-fos expression

Discussion

Conclusions

Acknowledgments

Neuropharmacology

Neurobiol. Dis.

Brain Res.

Trends Neurosci.

Brain Res.

Exp. Neurol

Pharmacol. Biochem. Behav.

Prog. Neurobiol.

Brain Res.

Neuroscience

Neuroscience

Exp. Neurol.

Neurobiol. Dis.

Brain Res.

Neuron

Eur. Neuropsychopharmacol.

Glutamate NMDA receptor dysregulation in Parkinson’s disease with dyskinesias

Brain

Effects of Sarizotan on the corticostriatal glutamate pathways

Synapse

Effects of serotonin 5-HT1A agonist in advanced Parkinson’s disease

Mov. Disord.

Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models

Neurology

MDMA and fenfluramine reduce l-DOPA-induced dyskinesia via indirect 5-HT1A receptor stimulation

Eur. J. Neurosci.

Contribution of the striatum to the effects of 5-HT1A receptor stimulation in l-DOPA-treated hemiparkinsonian rats

J. Neurosci. Res.