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.