Promising Outcomes of Original Grant:
Researchers investigated the effects of serotonin 5-HT1A biased agonists on rotation behavior in pre-clinical models. The scientists used a pre-synaptic (before impulse is conveyed) 5-HT1A preferential agonist. It stimulated rotation behavior by itself and, at a low dose, this effect was increased by co-administration with levodopa. The effects of the drug were abolished by a 5-HT1A receptor antagonist (chemical that blocks a response). This data suggests that preferential targeting of pre-synaptic 5‑HT1A receptors could facilitate dopamine release from dopaminergic neurons. Such activity could potentially translate to beneficial motor effects in Parkinson's disease (PD) patients.
Objectives for Supplemental Investigation:
Two objectives will be pursued in the supplemental investigation. First, a novel drug will be tested in addition to the tool drugs from the original funded grant. The new drug is a clinical phase 5-HT1A agonist. It potently activates both pre and post-synaptic 5‑HT1A receptors and is exceptionally selective. Secondly, whereas the original funded grant focused on behavioral experiments, the supplemental investigation will investigate the neurochemical effects of 5‑HT1A biased agonists by microdialysis.
Importance of This Research for the Development of a New PD Therapy:
Although serotonergic dysfunction is known to occur in PD, previous attempts to target 5‑HT1A receptors have met with only limited clinical success. Existing drugs often suffer from poor selectivity, weak partial agonism, and lack of discrimination between subpopulations of 5-HT1A receptors in different brain regions. Hence, it would be desirable to target 5-HT1A receptors in PD using highly selective full agonists. The present project is testing such drugs and providing an understanding of the mechanisms of action of 5-HT1A receptors. If the project is successful, a drug candidate will be taken forward into clinical trials.