Abstract
Background and Purpose l‐DOPA‐induced dyskinesia (LID) is considered a major complication in the treatment of Parkinson's disease (PD). Buspirone (5‐HT1A partial agonist) have shown promising results in the treatment of PD and LID, however no 5‐HT‐based treatment has been approved in PD. The present study was aimed to investigate how the substantia nigra pars reticulata (SNr) is affected by buspirone and whether it is a good target to study 5‐HT antidyskinetic treatments.Experimental ApproachBuspirone was studied using in vivo single‐unit, electrocorticogram, local field potential recordings along with microdialysis and immunohistochemistry in naïve/sham, 6‐hydroxydopamine (6‐OHDA)‐lesioned or 6‐OHDA‐lesioned and l‐DOPA‐treated (6‐OHDA/l‐DOPA) rats.Key ResultsLocal buspirone inhibited SNr neuron activity in all groups. However, systemic buspirone reduced burst activity in 6‐OHDA‐lesioned rats (with or without l‐DOPA treatment), whereas 8‐OH‐DPAT, a full 5‐HT1A agonist induced larger inhibitory effects in sham animals. Neither buspirone nor 8‐OH‐DPAT markedly modified the low‐frequency oscillatory activity in the SNr or synchronization within the SNr with the cortex. In addition, local perfusion of buspirone increased GABA and glutamate release in the SNr of naïve and 6‐OHDA‐lesioned rats but no effect in 6‐OHDA/l‐DOPA rats. In the 6‐OHDA/l‐DOPA group, increased 5‐HT transporter and decreased 5‐HT1A receptor expression was found.Conclusions and ImplicationsThe effects of buspirone in SNr are influenced by dopamine loss and l‐DOPA treatment. The present results suggest that the regulation of burst activity of the SNr induced by DA loss may be a good target to test new drugs for the treatment of PD and LID.
Highlights
Parkinson's disease (PD) pathophysiology involves the progressive loss of different peripheral and central neuronal populations
In this study, using microdialysis approaches we found no significant changes in GABA and glutamate basal levels after DA loss with or without prolonged L-DOPA treatment
The relevance of the substantia nigra pars reticulata (SNr) in Parkinson's disease and L-DOPA-induced dyskinesia is evidenced by aberrant changes of nigral neuron activity observed after DA depletion and L-DOPA treatment in animal models, as well as the symptomatic efficacy of therapeutic interventions that normalize nigral activity in both animal models and patients with Parkinson's disease
Summary
Parkinson's disease (PD) pathophysiology involves the progressive loss of different peripheral and central neuronal populations. When investigating the possible effect of antidyskinetic drugs, it is important to take into account the results collected in animal models of Parkinson's disease that reveal the structural and functional changes in the 5-HT system induced by DA depletion and/or chronic administration of L-DOPA (see review Vegas-Suarez et al, 2019) In this regard, we have observed that buspirone, a 5-HT1A receptor partial agonist, inhibits neuronal activity in the subthalamic nucleus in control rats but has no effect after DA depletion (Sagarduy et al, 2016). The present study aimed at defining whether the SNr is involved in the effects of buspirone and that it might be a good target to investigate antidyskinetic drugs For this purpose, electrophysiological, immunohistochemical and neurochemical approaches were applied in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without prolonged treatment with L-DOPA
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