Striatal 5-HT1A receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat

Dupre, Kristin B.; Eskow, Karen L.; Barnum, Christopher J.; Bishop, Christopher

doi:10.1016/j.neuropharm.2008.08.031

Cited by 80 publications

(79 citation statements)

References 56 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%

See 2 more Smart Citations

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

Politis¹,

Wu²,

Loane³

et al. 2014

J. Clin. Invest.

217

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.

217

183

View full text Add to dashboard Cite

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“…Rats in experiment 4 had a 15-mm guide cannula (22 gauge, C313/G/SPC; Plastics One Inc., Roanoke, VA) inserted into the dorsal striatum coincident with lesion surgery, using a procedure from Dupre et al (2008). The following coordinates were used relative to bregma: AP, ϩ0.4 mm; ML, ϩ2.9 mm; DV, Ϫ3.6 mm.…”

Section: Methodsmentioning

confidence: 99%

Behavioral and Cellular Modulation of l-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat

Lindenbach¹,

Ostock²,

Jaunarajs³

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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Chronic dopamine replacement therapy in Parkinson's disease (PD) leads to deleterious motor sequelae known as L-DOPAinduced dyskinesia (LID). No known therapeutic can eliminate LID, but preliminary evidence suggests that dl-1-isopropylamino-3-(1-naphthyloxy)-2-propanol [(Ϯ)propranolol], a nonselective ␤-adrenergic receptor (␤AR) antagonist, may reduce LID. The present study used the rat unilateral 6-hydroxydopamine model of PD to characterize and localize the efficacy of (Ϯ)propranolol as an adjunct to therapy with L-DOPA. We first determined whether (Ϯ)propranolol was capable of reducing the development and expression of LID without impairing motor performance ON and OFF L-DOPA. Coincident to this investigation, we used reverse-transcription polymerase chain reaction techniques to analyze the effects of chronic (Ϯ)propranolol on markers of striatal activity known to be involved in LID. To determine whether (Ϯ)propranolol reduces LID through ␤AR blockade, we subsequently examined each enantiomer separately because only the (Ϫ)enantiomer has significant ␤AR affinity. We next investigated the effects of a localized striatal ␤AR blockade on LID by cannulating the region and microinfusing (Ϯ)propranolol before systemic L-DOPA injections. Results showed that a dose range of (Ϯ)propranolol reduced LID without deleteriously affecting motor activity. Pharmacologically, only (Ϫ)propranolol had anti-LID properties indicating ␤AR-specific effects. Aberrant striatal signaling associated with LID was normalized with (Ϯ)propranolol cotreatment, and intrastriatal (Ϯ)propranolol was acutely able to reduce LID. This research confirms previous work suggesting that (Ϯ)propranolol reduces LID through ␤AR antagonism and presents novel evidence indicating a potential striatal locus of pharmacological action.

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“…Although the involvement of D 1 , D 2 , and D 3 receptors in dyskinesia has been extensively studied (Gold et al, 2007;Guigoni et al, 2007;Dupre et al, 2008;Jenner, 2008;Visanji et al, 2009a), D 4 receptors have been relatively neglected, even though they are present within the basal ganglia, which are key structures involved in both parkinsonism and dyskinesia (DeLong, 1990;DeLong and Wichmann, 2007). Thus D 4 receptors are encountered within the striatum (Rivera et al, 2002), pallidum (Mauger et al, 1998), and subthalamic nucleus (Flores et al, 1999) and therefore could play an important role in basal ganglia signaling.…”

Section: Introductionmentioning

confidence: 99%

L-745,870 Reduces l-DOPA-Induced Dyskinesia in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

Johnston¹,

Koprich²,

Aman³

et al. 2012

The Journal of Pharmacology and Experimental Therapeutics

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L-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3- ([4-(4-chlorophenyl) -745,870), a potent and selective dopamine D 4 receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of L-745,870 in combination with L-DOPA. To guarantee D 4 selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of L-745,870. Coadministration of L-745,870 (1 mg/kg) and L-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with L-DOPA alone (P Ͻ 0.01). L-745,870 had no effect on the duration of antiparkinsonian benefit (ONtime) (P Ͼ 0.05). However, L-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (ϩ204%; P Ͻ 0.001) and decreased duration of ON-time with disabling dyskinesia compared with L-DOPA alone (Ϫ56%; P Ͻ 0.01). Brain levels of L-745,870 (ϳ600 ng/g) were within the range at which L-745,870 provides selective D 4 receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D 4 receptor antagonists represent a potential therapeutic approach for L-DOPA-induced dyskinesia. It is noteworthy that L-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD.

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Striatal 5-HT1A receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat

Cited by 80 publications

References 56 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

Behavioral and Cellular Modulation of l-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat

L-745,870 Reduces l-DOPA-Induced Dyskinesia in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

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