Objective/Rationale:
Levodopa continues to be the gold-standard therapy for patients with Parkinson’s disease (PD). Unfortunately, effective long-term treatment is beset by abnormal involuntary movements, also known as dyskinesias. Research evidence indicates that aberrant neuroplasticity in serotonin neurons contributes significantly to the expression of dyskinesias. Studies in this project will evaluate the therapeutic potential of concomitant subthreshold stimulation of 5-HT1A receptors and blockade of 5-HT2A receptors in reducing dyskinesias while maintaining L-DOPA efficacy.
Project Description:
In order to test the validity of targeting 5-HT1A and 5-HT2A receptors as an effective therapeutic tool we will employ the hemi-parkinsonian pre-clinical model to evaluate two distinct but related experimental studies.
Experiment 1 will determine whether acute co-modulation of 5-HT1A and 5-HT2A receptors, in pre-clinical models of Parkinson's disease, reduces dyskinesias induced by L-DOPA without affecting therapeutic efficacy of L-DOPA. The receptor specificity of this approach will be evaluated using the 5-HT1A receptor antagonist WAY100635.
Experiment 2 will evaluate whether chronic combination therapy maintains anti-dyskinetic efficacy without affecting L-DOPA's positive therapeutic effects. Additionally, striatal levels of delta fos-b, a known neurobiological marker of LID, will be determined to examine the molecular effects of combination therapy.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Dyskinesias produced by chronic dopamine replacement therapy with L-DOPA, continue to be a major debilitating side-effect in patients with Parkinson's disease. Research has focused on therapies that reduce these side-effects; however, many of these have been limited due to poor efficacy or worsening of parkinsonism. If our central hypothesis is proven correct, it will support the use of drug(s) with affinity for 5-HT1A and 5-HT2A receptors as an adjunct to L-DOPA therapy.
Anticipated Outcome:
Achieving the stated objective in these key pre-clinical studies will help validate the acute anti-dyskinetic potential of concomitant targeting of 5-HT1A and 5-HT2A receptors while also provide substantial evidence for the long-term efficacy and mechanistic articulation of this combination therapy for the improved treatment of PD.
Final Outcome
Preliminary findings from our laboratory indicated that concomitant stimulation of 5-HT1A receptors and blockade of 5-HT2A receptors provided benefit against levodopa-induced dyskinesia. We have been able to significantly extend these findings over the past year. These findings are significant considering that drugs acting on these receptors, even though effective experimentally, have failed to provide relief in the clinic. Our strategy involved using sub-therapeutic doses of drugs that targeted these receptor systems to reduce levodopa-induced dyskinesias without affecting levodopa’s therapeutic efficacy. Our findings suggest that concomitant stimulation of 5-HT1A receptors and blockade of 5-HT2A receptors, in an acute manner, was able to reduce levodopa-induced dyskinesia without compromising the positive benefits of levodopa. However, this therapeutic strategy seems to be partially effective when tested for a chronic period of time. Our findings validate the strategy of targeting more than one receptor system to get anti-dyskinetic benefits. Further studies are needed to fine-tune this strategy such that it provides benefit in the long term.
Presentations & Publications
Bhide, N.S.*, Ostock, C.Y. and Bishop, C. (2013). Anti-dyskinetic concomitant targeting of 5-HT1A and 5-HT2A receptors does not affect anti-parkinsonian efficacy of L-DOPA. Society for Neuroscience, San Diego, CA.
"Pharmacological modulation of Serotonin and Norepinephrine systems as therapy for improved treatment in Parkinson’s disease", Invited Lecture, Eli Lilly and Company, October 2013
"Pharmacological modulation of Serotonin and Norepinephrine systems as therapy for improved treatment in Parkinson’s disease", Invited Lecture, Western New England University, May 2013
“Pharmacological modulation of Serotonin and Norepinephrine systems as therapy for improved treatment in Parkinson’s disease", Invited Lecture, Ohio Northern University, April 2013
January 2014