Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning

Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark.
Journal of Neurochemistry (Impact Factor: 4.28). 11/2011; 120(5):806-17. DOI: 10.1111/j.1471-4159.2011.07598.x
Source: PubMed


J. Neurochem (2012) 120, 806–817.
Recent studies suggest that l-3,4 dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a severe complication of conventional l-DOPA therapy of Parkinson’s disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT1A agonist [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the l-DOPA-induced increase in extracellular DA and decrease in [11C]raclopride binding in an animal model of advanced Parkinson’s disease and LID, we measured extracellular DA in response to l-DOPA or a combination of l-DOPA and the 5-HT1A agonist, 8-OHDPAT, with microdialysis, and determined [11C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [11C]raclopride at baseline and after two pharmacological challenges with l-DOPA + benserazide with or without 8-OHDPAT co-treatment. Identical challenge regimens were used with the subsequent microdialysis concomitant with ratings of LID severity. The baseline increase of [11C]raclopride-binding potential (BPND) in lesioned striatum was eliminated by the l-DOPA challenge, while the concurrent administration of 8-OHDPAT prevented this l-DOPA-induced displacement of [11C]raclopride significantly in lesioned ventral striatum and near significantly in the dorsal striatum. With microdialysis, the l-DOPA challenge raised the extracellular DA in parallel with the emergence of strong LID. Co-treatment with 8-OHDPAT significantly attenuated the release of extracellular DA and LID. The 8-OHDPAT co-treatment reversed the l-DOPA-induced decrease of [11C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of l-DOPA on [11C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons.

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Available from: Steen Jakobsen, Sep 15, 2014
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    • "Indeed, as previously stated, the use of clinically comparable technology (MRI) to conduct parallel assessments in experimental animals and humans is likely to accelerate translation of basic findings to the clinic. Neuroimaging tools may therefore play a critical role in future studies evaluating not only target engagement, but also drug efficacy in models of LID, as evidenced by recent studies using PET (143, 144, 146). No studies as yet have employed MRI methods, but the potential for application of this technology is apparent. "
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    ABSTRACT: Dopamine replacement therapy in the form of levodopa results in a significant proportion of patients with Parkinson's disease developing debilitating dyskinesia. This significantly complicates further treatment and negatively impacts patient quality of life. A greater under-standing of the neurobiological mechanisms underlying levodopa-induced dyskinesia (LID) is therefore crucial to develop new treatments to prevent or mitigate LID. Such investiga-tions in humans are largely confined to assessment of neurochemical and cerebrovascular blood flow changes using positron emission tomography and functional magnetic reso-nance imaging. However, recent evidence suggests that LID is associated with specific morphological changes in the frontal cortex and midbrain, detectable by structural MRI and voxel-based morphometry. Current human neuroimaging methods however lack sufficient resolution to reveal the biological mechanism driving these morphological changes at the cellular level. In contrast, there is a wealth of literature from well-established rodent mod-els of LID documenting detailed post-mortem cellular and molecular measurements. The combination therefore of advanced neuroimaging methods and rodent LID models offers an exciting opportunity to bridge these currently disparate areas of research. To highlight this opportunity, in this mini-review, we provide an overview of the current clinical evidence for morphological changes in the brain associated with LID and identify potential cellular mechanisms as suggested from human and animal studies. We then suggest a framework for combining small animal MRI imaging with rodent models of LID, which may provide important mechanistic insights into the neurobiology of LID.
    Full-text · Article · Jun 2014 · Frontiers in Neurology
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    • "The involvement of the serotonin neurons in the appearance of LID has also been demonstrated in a rat PET-imaging study; in fact, Nahimi and co-workers have shown that administration of 8-OH-DPAT could reverse l-DOPA-induced decrease of [(11) C]raclopride binding and increase of extracellular DA in 6-OHDA-lesioned rats (30). "
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    ABSTRACT: In the recent years, the serotonin system has emerged as a key player in the induction of l-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease. In fact, serotonin neurons possess the enzymatic machinery able to convert exogenous l-DOPA to dopamine (DA), and mediate its vesicular storage and release. However, serotonin neurons lack a feedback control mechanism able to regulate synaptic DA levels. While in a situation of partial DA depletion spared DA terminals can buffer DA released from serotonin neurons, the progression of DA neuron degeneration impairs this protective mechanism, causing swings in synaptic DA levels and pulsatile stimulation of post-synaptic DA receptors. In line with this view, removal of serotonin neurons by selective toxin, or pharmacological silencing of their activity, produced complete suppression of LID in animal models of Parkinson's disease. In this article, we will revise the experimental evidence pointing to the important role of serotonin neurons in dyskinesia, and we will discuss the clinical implications.
    Full-text · Article · May 2014 · Frontiers in Neurology
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    • "In 6-OHDA-lesioned rats and MPTP monkeys chronically treated with L-DOPA, 5-HT1A/1C receptor agonists reduce expression of LID without impairing L-DOPA improvement in motor performance (Bibbiani et al., 2001; Ba et al., 2007; Dupre et al., 2007). Furthermore, administration of the 5-HT1A agonist, 8-OH-DPAT, also prevents L-DOPA-induced increment of extracellular dopamine (Nahimi et al., 2012). Other drugs that modulate 5-HT neurotransmission have shown efficacy over LID. "
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    ABSTRACT: The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.
    Full-text · Article · Mar 2014 · Frontiers in Neural Circuits
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