In 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Primates, the Selective 5-Hydroxytryptamine 1a Agonist (R)-(+)-8-OHDPAT Inhibits Levodopa-Induced Dyskinesia but Only with\ Increased Motor Disability

Abstract

5-Hydroxytryptamine 1a (5-HT 1a ) receptor agonists, such as sarizotan and tandospirone, are reported to reduce levodopainduced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and in Parkinson's disease without worsening motor disability. However, these compounds are not specific for 5-HT 1a receptors and also possess dopamine antagonist actions. We now report on the effects of (2R), a selective 5-HT 1a agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets. Administration of (R)-(ϩ)-8-OHDPAT (0.2, 0.6, and 2.0 mg/kg s.c), in conjunction with levodopa/carbidopa (12.5 mg/kg each p.o.) to levodopa-primed animals, dose-dependently reduced levodopa-induced chorea but did not affect dystonic movements. However, (R)-(ϩ)-8-OHDPAT treatment also reduced locomotor activity and the reversal of motor disability. Administration of (R)-(ϩ)-8-OHDPAT alone had no effects of motor behaviors. The effects of (R)-(ϩ)-8-OHDPAT on levodopa-induced motor behaviors were antagonized by the 5-HT 1a recep-(1.0 mg/kg s.c.). Administration of (R)-(ϩ)-8-OHDPAT (0.6 mg/kg s.c.) also reduced chorea produced by the administration of the D 2 /D 3 dopamine receptor agonist pramipexole (0.06 mg/kg p.o.) to levodopa-primed MPTP-treated animals. However, again the increase in locomotor activity and reversal of motor disability produced by pramipexole were also inhibited. These data suggest that selective 5-HT 1a agonists do not provide an effective means of suppressing levodopa-induced dyskinesia, except with worsening of parkinsonism.

Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on l-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

“…Collectively, these findings show that the anti-dyskinetic actions of 5-HT 1A R agonists may be due, in part, to their impact on the corticostriatal glutamate system. The acute, chronic, and prophylactic anti-dyskinetic effects of 5-HT 1A R stimulation have been well-characterized in both preclinical (Bibbiani et al 2001;Iravani et al 2006;Carta et al 2007;Eskow et al 2007) and clinical investigations (Olanow et al 2004;Bara-Jiminez et al 2005;Goetz et al 2007). Unfortunately, a number of studies have also suggested that 5-HT 1A R agonists may worsen PD symptoms.…”

“…Unfortunately, a number of studies have also suggested that 5-HT 1A R agonists may worsen PD symptoms. For example, Iravani et al (2006) found that the more potent ±8-OH-DPAT enantiomer, +8-OH-DPAT, reduced LID but worsened motor disability. Clinically, high doses of the 5-HT 1A R agonists tandospirone and sarizotan have been reported to exacerbate parkinsonian features (Kannari et al 2002;Goetz et al 2007).…”

“…Convergent evidence also suggests that pre-and postsynaptic 5-HT 1A R within forebrain regions including the motor cortex and striatum also contribute anti-dyskinetic effects, in part by modulating DA receptor supersensitivity (Santiago et al 1998;Frechilla et al 2001;Mignon and Wolf 2005). For example, 5-HT 1A R agonists have been shown to alleviate dyskinesia induced by direct DA receptor agonists (Iravani et al 2006;Dupre et al 2007). Chronic DA replacement therapy also has profound effects on the corticostriatal glutamate system (Chase and Oh 2000).…”

Effects of 5-HT1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

“…8,9 Unfortunately, a number of studies have also shown that 5-HT 1A R agonists may, in some cases, worsen PD symptoms. For example, the more potent enantiomer +8-OH-DPAT reduced LID but worsened motor disability, 10 inducing a 5-HT-like syndrome. 11 Clinically, high doses of the 5-HT 1A R agonists tandospirone and sarizotan have been reported to exacerbate parkinsonian features.…”

Mathematical Models: Interactions Between Serotonin and Dopamine in Parkinson’s Disease

“…Many approaches to eliminating LID therefore tend to focus instead on manipulating factors that regulate serotonergic cell activity, such as serotonergic autoreceptors that participate in serotonergic homeostatic mechanisms. Simply decreasing serotonergic cell activity by administering serotonin autoreceptor agonists has the drawback of also reducing the amount of dopamine released into the extracellular space, tending to worsen PD symptoms (Iravani et al, 2006). Carta et al (2008) argue that it is reasonable to use 5-HT autoreceptor agonists especially because the DA intermixed with the 5-HT released by the serotonergic cell effectively lowers the binding of 5-HT to 5-HT autoreceptors and induces the cells to be over-active.…”