Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

Abstract

L-DOPA remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT 1A ) receptor agonists and serotonergic type 2A (5-HT 2A ) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair L-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT 1A and 5-HT 2A receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT 1A -and 5-HT 2A -modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT 1A and 5-HT 2A receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively.

2.12.2 the Serotonin System: A Potential Target for Anti-Dyskinetic Treatments and Biomarker Discovery

“…In line with this, recent data points to a role of 5-HT1A receptors expressed in primary motor cortex in the modulation of LID [17]. An effective alleviation of LID can also be achieved by antagonising 5-HT2A receptors, most probably attenuating corticostriatal glutamate or nigrostriatal dopamine release [4].…”

“…through a postsynaptic mechanism. Cortical expression of 5-HT2A receptors has shown to be enhanced in dyskinetic monkeys [4], probably contributing to the corticostriatal overactivity and the excessive striatal glutamate release that has been associated to LID. Likewise, there is an increased expression of 5-HT1B proteins on striatonigral neurons in dyskinetic mice [13].…”

“…However, the selectivity seems not to be the solely problem since the lack of anti-parkinsonian effect persists also with highly specific substances. Instead, stimulation of anatomically distinct subpopulations of receptors has been postulated as a better way of treating dyskinesia without compromising the anti-parkinsonian efficacy [4]. To exclusively target e.g.…”

“…The receptors can also be found on non-serotonergic neurons, such as medium-sized spiny neurons (5-HT1B) and corticostriatal neurons (5-HT1A), where receptor stimulation reduces pallidal GABA-or striatal glutamate release, respectively. The corticostriatal neurons also express the 5-HT2A receptor, which regulates striatal glutamate release (See Figure 1) [4].…”

Mechanisms underlying cortical resonant states: implications for levodopa-induced dyskinesia

“…Levetiracetam is indicated for the treatment of refractory partial epilepsy and can reduce neuronal synchronization in animal models of epilepsy, in part through interference with synaptic release mechanisms (Klitgaard et al, 2003). Finally, understanding the differential actions of drugs in different central nervous system structures may provide important clues on how to tailor compounds to achieve more specific actions (Huot et al, 2011;Ostock et al, 2011).…”