Abstract
The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA) and the serotonergic (5-HT) system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA) and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson’s disease (PD) patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rigidity, resting tremor, postural abnormalities and gait deficits
It has been suggested that 5-HT neurons are mainly responsible for the increase in DA release induced by chronic L-DOPA treatment in the striatum (Carta et al, 2007, 2008)
The motor improvements or side effects produced by low doses of L-DOPA (3–6 mg/kg) cannot be explained only by what happens in the striatum since those doses fail to produce physiological levels of DA in that nucleus (Navailles et al, 2010b, 2011; Nevalainen et al, 2011; Porras et al, 2014; De Deurwaerdère et al, 2017)
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rigidity, resting tremor, postural abnormalities and gait deficits. After chronic treatment using L-DOPA and/or DA denervation, the inhibitory control exerted by 5-HT1A receptors over the electrical activity of 5-HT neurons is maintained (Miguelez et al, 2016a) In these conditions, 5-HT1A receptor agonists completely inhibit DRN neuron activity and diminish L-DOPA-induced DA release at the terminal sites (Kannari et al, 2001; Iderberg et al, 2015). Extracellular levels of 5-HT in the presence of L-DOPA can be impacted in different ways by: (1) decreased exocytosis, which non-exocytotic release can compensate for to a limited extent; (2) the loss of extracellular clearance by the SERT (competition with DA); and (3) the loss of other clearance mechanisms such as the noradrenaline transporter (Navailles et al, 2014). The release of L-DOPA-derived DA from 5-HT neurons is a complicated mechanism involving 5-HT receptors and transporters in a region-dependent manner
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