Serotoninergic modulation of exogenous L-DOPA-derived dopamine release in rats with unilateral 6-OHDA lesions revealed with microPET imaging

Abstract

Serotoninergic modulation of exogenous L-DOPA-derived dopamine release in rats with unilateral 6OHDA lesions revealed with microPET imaging

 

Adjmal Nahimi^1,2, Mette Hølzermann^1,2, Mette Simonsen²,  Kim Vang, Steen Jakobsen², Anne Landau^1,2, Arne Møller^1,2, Gregers Wegener ³, Albert Gjedde^1,2 and Doris Doudet^1,2

^ 

¹ Centre of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark

²PET-Center, Aarhus University Hospitals, Denmark

³ Center of Psychiatric Research, Aarhus University Hospital, Denmark

Introduction: L-DOPA induced dyskinesias, a severe complication of parkinsonian therapy, occur in response to administration of therapeutic doses of L-DOPA and are modulated by rapid changes in extracellular DA. Recently, the use of 5-HT agonists and antagonists as potential adjuncts to L-DOPA to modulate extracellular DA without loss of therapeutic benefits, has started to be actively investigated. We used raclopride, a tracer of the D₂/D₃ receptors which can be used as a surrogate marker of DA-release to evaluate in-vivo the effect of 8-OH-DPAT, a 5-HT agonist, on the L-DOPA induced release of DA in 6-OHDA lesioned rats.

Methods: Rats (N=6) with unilateral 6-OHDA lesions of the DA nigro-striatal pathways received 3 [¹¹C] raclopride micro-PET scans over several days in 3 conditions. A baseline scan was followed by two pharmacological challenges with either L-DOPA+Benzeraside (50/25 mg/kg S.C.) or L-DOPA+Benzeraside+8-OH-DPAT (0,6mg/kg/S.C.) administered 30-45 minutes prior to the raclopride injection.

Results:  There was little change in raclopride binding in the unlesioned striatum in the challenge scans compared to baseline. In the 6-OHDA lesioned striata, there was a decrease in raclopride binding after L-DOPA administration, in agreement with increased release of DA. Concurrent administration of 8-OH-DPAT reduced the L-DOPA induced release of DA in the compared to L-DOPA alone. Conclusion: This study 1) demonstrated the feasibility of using micro-PET studies to assess the effect of pharmacological challenges in rats 2) supported the continued evaluation of drugs that modulate the serotonin system as possible therapeutic agents in PD and L-DOPA induced dyskinesia.