Objective/Rationale:
Levodopa remains the gold-standard treatment for Parkinson’s disease, unfortunately chronic treatment leads to abnormal involuntary movements known as dyskinesia. In recent years, compelling evidence has suggested that serotonin neurons play an integral role in expression of levodopa-induced dyskinesia. Preclinical studies of the current project will test whether modulation of serotonin/levodopa interactions with selective serotonin reuptake inhibitors (SSRIs) reduces dyskinesia, while maintaining levodopa efficacy implicating a novel therapeutic avenue for the Parkinson’s disease patient.
Project Description:
In order to validate the serotonin reuptake inhibition as a viable therapeutic approach, we will employ a hemi-parkinsonian pre-clinical model of dyskinesia for 3 distinct but inter-related experiments:
- Experiment 1 will examine the long-term anti-dyskinetic efficacy of the SSRIs Citalopram and Paroxetine in pre-clinical models previously expressing levodopa-induced dyskinesia. The maintenance of levodopa efficacy will also be studied.
- Experiment 2 will determine whether SSRIs reduce the development of dyskinesia while maintaining levodopa’s anti-parkinsonian effects. Brain serotonin transporter protein will also be measured as an indication as to how these compounds may be working.
- Experiment 3 will employ in vivo microdialysis to examine whether SSRIs normalize levodopa-induced striatal dopamine levels, implicating a possible mechanism of action for this class of compounds.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Within 10 years of commencing levodopa treatment, nearly 90% of Parkinson’s disease patients experience dyskinesia. Despite the ubiquity of this potentially debilitating side effect, few long term therapeutic options are currently available. If our central premise is proven correct, it will support the repositioning of FDA-approved SSRIs for use as levodopa adjuncts thereby improving treatment for the Parkinson’s disease patient.
Anticipated Outcome:
By accomplishing the goals of our project we expect to demonstrate clear preclinical evidence for the long-term anti-dyskinetic properties of serotonin transporter inhibition, compelling translational support for the repositioning of SSRIs for dyskinesia treatment and novel neurobiological mechanisms of action by which these compounds act.
Progress Report
Preliminary findings from our laboratory had suggested that the FDA-approved anti-depressants and selective serotonin reuptake inhibitors (SSRIs) citalopram and paroxetine acutely reduced L-DOPA-induced dyskinesia (LID) in a pre-clinical model of Parkinson’s disease (PD). In the first year of support through The Michael J. Fox Foundation’s Dyskinesia Challenge Program, we have been able to significantly extend these findings. Our first recently completed experiment demonstrated that the potent anti-dyskinetic effects of SSRIs, given as an interventional strategy, were maintained over several weeks and did not come at the expense of L-DOPA’s anti-parkinsonian efficacy. Preliminary findings from our second experiment, examining the protective effects of SSRIs on the development of LID are yielding complimentary results; that administering SSRIs prior to LID development delays or attenuates its expression. Collectively, our pre-clinical findings thus far implicate the translational potential of SSRIs for the treatment of LID for the PD patient.
Final Outcome
Initial findings from our laboratory suggested that citalopram and paroxetine—FDA-approved antidepressants and selective serotonin reuptake inhibitors (SSRIs)—acutely reduce levodopa-induced dyskinesia in a pre-clinical model of Parkinson’s disease (PD). In the past two years, with the support of The Michael J. Fox Foundation, we have been able to significantly extend these findings by demonstrating that the potent anti-dyskinetic effects of SSRIs, given as an interventional strategy, were maintained over several weeks. Furthermore, these effects were not the expense of levodopa’s anti-parkinsonian efficacy. We also found that administering SSRIs prior to dyskinesia development significantly prevents its expression. Finally, we have gathered significant neurochemical evidence to suggest that SSRI treatment acts to optimize dopamine neurotransmission in brain to both improve levodopa’s anti-parkinsonian efficacy and reduce dyskinesia. Collectively, our preclinical findings thus far implicate the translational potential of SSRIs for the treatment of dyskinesia for PD patients.
Presentations & Publications
Peer-Reviewed Research Articles:
Bishop, C., George, J.A., Buchta, W., Goldenberg, A.A., Mohamed, M., Dickinson, S.O., Eissa, S. and Eskow-Jaunarajs, K.L. (2012). Serotonin transporter inhibition attenuates L-DOPA-induced dyskinesia without compromising L-DOPA efficacy in hemi-parkinsonian rats. European Journal of Neuroscience 36(6):2839-2848.
Conti, M.M., Ostock, C.Y., Lindenbach, D.L., Goldenberg, A.A., Kampton, E., Dell’Isola, R., Katzman, A. and Bishop C. (2013). Effects of chronic selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemiparkinsonian rats. (Submitted)
Invited Lectures:
“Serotonin neuroplasticity in Parkinson’s Disease: implications for movement and mood”, Invited Lecture, Emory University School of Medicine, Atlanta, GA, February, 2012.
“Serotonin neuroplasticity in Parkinson’s disease: novel targets for the treatment of L-DOPA-induced dyskinesia”, Invited Lecture, Monitoring Molecules in Neuroscience, London, UK, September, 2012.
“Behavioral sciences: from mind to matter”, Invited Lecture, Panel Moderator, Binghamton University Health Care Innovation Day, Binghamton, NY, April, 2013.
Abstracts:
Katzman, A., Goldenberg, A. and Bishop C. (2012). Acute and chronic serotonin transporter inhibition attenuates L-DOPA-induced dyskinesia without compromising L-DOPA efficacy in hemi-parkinsonian rats. SUNY undergraduate research day, Albany, NY.
Goldenberg, A.A., Katzman, A., Kampton, E., Conti, M., Lindenbach, D.L. and Bishop, C. (2012). Selective serotonin reuptake inhibitors prevent expression and emergence of L-DOPA-induced dyskinesia in the hemiparkinsonian rat. Society of Neuroscience, New Orleans, LA.
Kampton, E., Gold, J., Meadows, S., Ostock, C.Y., Lindenbach, D.L. and Bishop, C. (2013) Inhibition of the serotonin transporter reduces L-DOPA-induced dyskinesia in part via modulation of dorsal raphe nucleus activity. Department of Psychology Research Colloquia, Binghamton University Binghamton, NY.