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

Abstract

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.

Could the serotonin theory give rise to a treatment for levodopa-induced dyskinesia in Parkinson’s disease?

“…Although amantadine was the result of a serendipitous discovery, increasing evidence points to the serotonergic system as a key player in the induction and expression of levodopa-induced dyskinesia (LID) in both patients with Parkinson's disease (Bonifati et al, 1994;Politis et al, 2014) and animal models of the disorder (Carta et al, 2007;Muñ oz et al, 2008). Studies in rat and primate models of Parkinson's disease have demonstrated that the serotonergic system is a major source of striatal levodopa-derived dopamine release (Carta et al, 2007;Muñ oz et al, 2008).…”

“…Aberrant release of dopamine derived from serotoninergic neurons seems to be instrumental for the emergence of LID in patients with Parkinson's disease. In fact, recent PET studies have shown that patients with dyskinesia have higher synaptic dopamine levels after L-DOPA treatment compared to non-dyskinetic subjects (de la Fuente-Fernandez et al, 2004;Politis et al, 2014). Administration of buspirone (a partial 5-HT1A receptor agonist) produced significant dampening of synaptic dopamine levels in these patients and attenuated the expression of LID (Politis et al, 2014).…”

Serotonin-to-dopamine transporter ratios in Parkinson disease

“…[6][7][8][9] The above studies propose that serotonergic terminals in the degenerating striatum are responsible for mishandling exogenous levodopa and exacerbating dyskinesia in the animal model [10][11][12] and PD. 13 Accordingly, the presence of dyskinesia could be a reflection of serotonergic over dopaminergic terminals' activity. Nonetheless, the above mechanisms have not been fully understood in humans.…”

“…The LED Total , LED Ldopa , and LED Dag doses were calculated in milligrams for each individual following the formulas 13 described in table e-1 on the Neurology ® Web site at Neurology.org. DD diagn was defined as the time from the date of the PD diagnosis at the movement disorders clinic and DD onset as the time since each individual first experienced a PD motor symptom.…”

Parkinson';s Disease, Diabetes and Cognitive Impairment

“…The cardinal pathological characteristic of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta [7], however, lines of evidence from in vivo molecular imaging research has demonstrated that PD pathology involves also non-dopaminergic systems such as the serotonergic [8][9][10]. Serotonergic pathology in PD has been associated with the development of tremor [11,12], dyskinesias [13][14][15] and various non-motor symptoms [16][17][18].…”