Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacologicalbased treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.

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 Approach Buspirone 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 Results Local 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 Implications The 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.

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Author contributions L.U. and C.M. conceived the study, designed the experiments, and drafted the final version of the manuscript. S.V.S. performed all the experiments, carried out data quantification and analysis, prepared the figures, and contributed to the first draft. A. A. and C. M. collaborated in the optogenetic experiments. C.R. and H.B. contributed to the immunostaining experiment design. C.M. revised the data analysis. S.V.S., C.M., J.V.L., A.S., and L.U. interpreted the results. All authors reviewed and edited the manuscript.

Graphical AbstractThe role of the liver in the metabolism of toxic compounds and in Aβ and α-synuclein clearance is related to neurological disorders such as Alzheimer’s Ddisease (AD) and Parkinson’s Disease (PD) development, although the supplementation with certain compounds may exert a protective effect. The current Western diet and alterations in the BA profile, whose homeostasis is controlled by the liver, have been also related to both AD and PD.

Cortical information is transferred to the substantia nigra pars reticulata (SNr) and the entopeduncular nucleus (EP), the output structures of the basal ganglia (BG), through three different pathways: the hyperdirect trans-subthalamic and the direct and indirect trans-striatal pathways. The nigrostriatal dopamine (DA) and the activation of 5-HT1A receptors, distributed all along the BG, may modulate cortical information transmission. We aimed to investigate the effect of buspirone (5-HT1A receptor partial agonist) and WAY-100635 (5-HT1A receptor antagonist) on cortico-nigral and cortico-entopeduncular transmission in normal and DA loss conditions. Herein, simultaneous electrical stimulation of the motor cortex and single-unit extracellular recordings of SNr or EP neurons were conducted in urethane-anesthetized sham and 6-hydroxydopamine (6-OHDA)-lesioned rats before and after drug administrations. Motor cortex stimulation evoked monophasic, biphasic, or triphasic responses, combination of an early excitation, an inhibition, and a late excitation in both the SNr and EP, while an altered pattern of evoked response was observed in the SNr after 6-OHDA lesion. Systemic buspirone potentiated the direct cortico-SNr and cortico-EP transmission in sham animals since increased duration of the inhibitory response was observed. In DA denervated animals, buspirone administration enhanced early excitation amplitude in the cortico-SNr transmission. In both cases, the observed effects were mediated via a 5-HT1A-dependent mechanism as WAY-100635 administration blocked buspirone’s effect. These findings suggest that in control condition, buspirone potentiates direct pathway transmission and DA loss modulates responses related to the hyperdirect pathway. Overall, the results may contribute to understanding the role of 5-HT1A receptors and DA in motor cortico-BG circuitry functionality.