Serotonergic targets for the treatment of l-DOPA-induced dyskinesia

Abstract

Dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) continues to be the gold-standard treatment for Parkinson's disease (PD). Despite clear symptomatic benefit, long-term L-DOPA use often results in the development of L-DOPA-induced dyskinesia (LID), significantly reducing quality of life and increasing costs for PD patients and their caregivers. Accumulated research has demonstrated that several pre- and post-synaptic mechanisms contribute to LID development and expression. In particular, raphe-striatal hyperinnervation and unregulated DA release from 5-HT terminals is postulated to play a central role in LID manifestation. As such, manipulation of the 5-HT system has garnered considerable attention. Both pre-clinical and clinical research has supported the potential of modulating the 5-HT system for LID prevention and treatment. This review discusses the rationale for continued investigation of several potential anti-dyskinetic strategies including 5-HT stimulation of 5-HT1A and 5-HT1B receptors and blockade of 5-HT2A receptors and SERT. We present the latest findings from experimental and clinical investigations evaluating these 5-HT targets with the goal of identifying those with translational promise and the challenges associated with each.

The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease

“…Recent efforts have focused on modulating the serotonin system in an attempt to regulate abnormal dopamine release in the striatum and prevent the development of dyskinesia ([ 35 ] for a recent review). Several groups have investigated the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin (5-HT) receptor agonists in combination with L-DOPA treatment (e.g., [ 18 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]).…”

“…Of interest are especially 5-HT1A receptor agonists (e.g., [ 14 , 18 , 37 , 38 , 39 , 43 , 44 ]), which are thought to stimulate 5-HT1A autoreceptors on serotonin neurons in the dorsal raphe nucleus (DRN) and attenuate neuronal activity and, consequently, serotonin (and abnormal dopamine) release from serotonin terminals. Many of the serotonergic agents tested are indeed found to reduce dyskinesia severity in preclinical studies [ 35 ]; however, these agents can also attenuate the prokinetic effects of L-DOPA or have other undesirable side effects (e.g., [ 42 , 45 , 46 , 47 ]), limiting their clinical usefulness [ 48 ].…”

Aurrerapen terapeutikoak Parkinson gaixotasunean

“…Dosi handiagoek ez zituzten emaitza hain onuragarriak lortu; izan ere, OFF aldien emendioarekin erlazionatu ziren, efektu antidiskinetiko gehigarririk aurkeztu gabe [15]. Hala ere, iaz argitaratutako eskala handiagoan egindako bi ikerketatan, 2 mg-ko dosiak ez zuen erakutsi plazeboarekin konparatuz ezberdintasunik [16].…”

Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson’s Disease

“…The serotonin (5-HT) system has been demonstrated to play a crucial role in the pathogenesis of LID in animal models of PD [79]. Indeed, after advanced dopaminergic cell loss, remaining serotonin neurons can convert exogenous LD to DA and mediate its vesicular storage and release [38,80].…”

“…5-HT 1A R is the most studied of the 5-HT family. Indeed, several preclinical and clinical studies demonstrated that 5-HT 1A R stimulation (auto- and heteroreceptors) [49,83,84] may reduce dyskinesia through the decrease of DA release [79]. Moreover, 5-HT 1A R activation may also weaken glutamatergic transmission ameliorating motor symptoms [83].…”