The partial 5-HT1A agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy

Eskow, Karen L.; Gupta, Vikas; Alam, Salmahn; Park, John Y.; Bishop, Christopher

doi:10.1016/j.pbb.2007.05.002

Cited by 136 publications

(125 citation statements)

References 48 publications

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“…The present study supported previous experimental findings on animal models of PD (12)(13)(14)(15)(16)(17)(18)(19) and translated them to humans. Using a series of PET imaging assessments with radioligand markers of serotonergic ( 11 C-DASB) and dopaminergic ( 11 C-raclopride) function (Figure 6), we showed that striatal serotonergic terminals contributed to abnormal levodopa-induced short-term increases in synaptic dopamine levels in PD patients with LIDs and that the dampening of the activity of these serotonergic terminals via a 5-HT 1A agonist restored synaptic dopamine to levels similar to those observed in PD stable patients and improved LIDs.…”

Section: Discussionsupporting

confidence: 90%

“…Striatal dopamine synaptic levels after levodopa administration were not influenced by buspirone pretreatment in the PD stable patient group. Our results are in line with experimental studies showing that 5-HT 1A agonists, including buspirone, are able to reduce or prevent the development of levodopa-induced abnormal involuntary movements in animal models of PD (12)(13)(14)(15)(16)(17)(18)(19). Studies using dyskinetic rats have shown that levodopa-induced abnormal involuntary movements in rats positively correlate with levels of SERT, but not with levels of dopamine transporter, in the striatum (22).…”

Section: Discussionsupporting

confidence: 90%

“…Removing striatal serotonin (5-HT) afferents, or dampening serotonergic activity with 5-HT receptor type 1A (5-HT 1A ) receptor agonists (including buspirone) or 5-HT receptor type 1B (5-HT 1B ) receptor agonists, attenuated abnormal involuntary movements without increasing parkinsonism (12)(13)(14)(15)(16)(17)(18)(19). However, this mechanism has not been investigated in vivo in PD patients.…”

Section: Introductionmentioning

confidence: 99%

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Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Politis¹,

Wu²,

Loane³

et al. 2014

J. Clin. Invest.

212

183

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Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11 C-DASB PET to evaluate serotonin terminal function and 11 C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopaevoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Politis¹,

Wu²,

Loane³

et al. 2014

J. Clin. Invest.

212

183

View full text Add to dashboard Cite

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“…Chronic DMI can reduce NET expression in other CNS regions such as amygdala, striatum (Jeannotte et al, 2009), and hippocampus (Kitayama et al, 2006). We also point out that the serotonin terminals or transporter (SERT) can affect LID severity in preclinical models Eskow et al, 2007;Bishop et al, 2012). However, chronic DMI is not reported to alter SERT expression or function (Hyttel, 1994;Mantovani et al, 2009), thus making it unlikely that changes in SERT expression or SERT-mediated uptake are associated with our behavioral observations.…”

Section: Norepinephrine Transporter and L-dopa Dyskinesiamentioning

confidence: 71%

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

2014

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Pharmacological dopamine (DA) replacement with Levodopa [L-dihydroxyphenylalanine (L-DOPA)] is the gold standard treatment of Parkinson's disease (PD). However, long-term L-DOPA treatment is complicated by eventual debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesia (LID), a clinically significant obstacle for the majority of patients who rely on L-DOPA to alleviate PD-related motor symptoms. The manifestation of LID may in part be driven by excessive extracellular DA derived from L-DOPA, but potential involvement of DA reuptake in LID severity or expression is unknown. We recently reported that in 6-hydroxydopamine (6-OHDA)-lesioned striatum, norepinephrine transporter (NET) expression increases and may play a significant role in DA transport. Furthermore, L-DOPA preferentially inhibits DA uptake in lesioned striatum. Therefore, we hypothesized that desipramine (DMI), a NET antagonist, could affect the severity of LID in an established LID model. Whereas DMI alone elicited no dyskinetic effects in lesioned rats, DMI 1 L-DOPA-treated rats gradually expressed more severe dyskinesia compared with L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and norepinephrine-mediated inhibition of DA uptake in the DMI 1 L-DOPA group compared with L-DOPA-alone group in lesioned striatum. LID severity positively correlated with striatal extracellular signal-regulated protein kinase phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI 1 L-DOPA group compared with the L-DOPA-and DMI-alone groups. Taken together, these results indicate that the combination of chronic L-DOPA and NET-mediated DA reuptake in lesioned nigrostriatal terminals may have a role in LID severity in experimental Parkinsonism.

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“…This idea is based on work showing that L-DOPA-induced dyskinesias are reduced with serotonergic denervation of the raphe nuclei or by treatment with selective serotonergic antagonists (Carta et al, , 2008bEskow et al, 2007Eskow et al, , 2009Muñ oz et al, 2008). Serotonergic inputs from the raphe to SN, and to a lesser extent to the striatum, the globus pallidus and the subthalamus are most likely involved (Di Matteo et al, 2008).…”

Section: Quik and Wonnacottmentioning

confidence: 99%

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

Quik

Wonnacott²

2011

Pharmacol Rev

175

185

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The partial 5-HT1A agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy

Cited by 136 publications

References 48 publications

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

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