Objective/Rationale:
Although Parkinson's disease (PD) is primarily caused by dopamine dysfunction, function of serotonin (another neurotransmitter) is also affected. This suggests that serotonergic drugs may address some of the symptoms of PD. The serotonin 5-HT1A receptor is an attractive target because 5-HT1A agonists (chemicals that activate a receptor) are capable of reducing levodopa-induced dyskinesias. However, current 5-HT1A agonists are poorly selective, metabolically unstable and/or insufficiently active at appropriate 5-HT1A receptor subpopulations. The project will examine the effects of novel, highly selective and efficacious “biased agonists” targeting subpopulations of 5-HT1A receptors.
Project Description:
The target of this project is the subpopulation of serotonin 5-HT1A receptors that is expressed in the cortex region of the brain. These receptors mediate reductions in dyskinesia, depression and cognitive effects in pre-clinical models and increase the anti-parkinsonian effects of levodopa. This project will compare the actions of an older 5-HT1A agonist with that of new, highly selective “biased agonists." Drugs will be tested in pre-clinical models in order to determine whether brain region-preferential targeting increases the separation between therapeutic-like and side-effect responses.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
5-HT1A receptors are widely expressed in brain regions that control mood, cognition and movement; many of these functions are affected in PD. Appropriate activation of 5-HT1A receptors, therefore, holds the potential to treat diverse symptoms of Parkinson's. In particular, preferential targeting of 5-HT1A receptor subpopulations in the frontal cortex could improve control of motor symptoms and simultaneously avoid dyskinesias. Such a strategy may also improve the mood deficits that are frequently observed in PD patients.
Anticipated Outcome:
The project is designed to test the hypothesis that preferential activation of cortical 5-HT1A receptors should widen the “therapeutic window” between the anti-parkinsonian effects of levodopa and its induction of dyskinesia. If this hypothesis is confirmed, then the project will have generated compelling data to pursue the identification and clinical development of biased agonists that preferentially target cortical 5-HT1A receptors.