Pisani, A. et al. Targeting striatal cholinergic interneurons in Parkinson's disease: focus on metabotropic glutamate receptors. Neuropharmacology 45, 45-56

Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata, Rome, Italy.
Neuropharmacology (Impact Factor: 5.11). 08/2003; 45(1):45-56. DOI: 10.1016/S0028-3908(03)00137-0
Source: PubMed


In the early sixties, anticholinergic drugs were introduced in the pharmacological treatment of Parkinson's disease (PD). The rationale behind their utilisation in the treatment of the disease was based on the evidence of an imbalance between the dopaminergic inputs and the intrinsic cholinergic innervation within the striatum. Metabotropic glutamate (mGlu) receptors have been shown to play a key role in striatal function both in physiological conditions and in experimental models of diseases affecting this brain area. Indeed, compelling electrophysiological and morphological evidence shows that mGlu receptors are highly expressed at cellular level and exert a profound modulatory role on cholinergic interneurons excitability. This review will provide a brief survey of studies on the localization and function of mGlu receptors in cholinergic interneurons. The potential relevance of these findings in the control of motor function and in the treatment of PD will be discussed.

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    • "Group II mGlu receptor agonists have proven effective in animal models of PD (79). A decrease in mGlu2/3 receptor density in dyskinetic compared to non-dyskinetic MPTP-lesioned monkeys was observed (46). "
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    ABSTRACT: Anti-glutamatergic drugs can relieve Parkinson's disease (PD) symptoms and decrease l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID). This review reports relevant studies investigating glutamate receptor subtypes in relation to motor complications in PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Antagonists of the ionotropic glutamate receptors, such as N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, display antidyskinetic activity in PD patients and animal models such as the MPTP monkey. Metabotropic glutamate 5 (mGlu5) receptor antagonists were shown to reduce the severity of LID in PD patients as well as in already dyskinetic non-human primates and to prevent the development of LID in de novo treatments in non-human primates. An increase in striatal post-synaptic NMDA, AMPA, and mGlu5 receptors is documented in PD patients and MPTP monkeys with LID. This increase can be prevented in MPTP monkeys with the addition of a specific glutamate receptor antagonist to the l-DOPA treatment and also with drugs of various pharmacological specificities suggesting multiple receptor interactions. This is yet to be well documented for presynaptic mGlu4 and mGlu2/3 and offers additional new promising avenues.
    Frontiers in Neurology 08/2014; 5:144. DOI:10.3389/fneur.2014.00144
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    • "This would only be required when there is a need for a greater number of the theoretical striatal units, such as when multiple units are needed to represent perceptually dissimilar exemplars from the same category (i.e., with discontinuous and nonlinear categories). Our assumption that striatal cholinergic interneurons are dysfunctional in PD is based on animal models that demonstrate increased activity of such neurons in the presence of reduced dopamine levels (Raz et al., 2001; Pisani et al., 2003; Bonsi et al., 2011). If this over activity of striatal interneurons is sufficient, improper signaling between medium spiny neurons would be likely to occur and the linking of perceptually dissimilar stimuli to the same response would be greatly compromised. "
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    ABSTRACT: Previously we found that Parkinson's disease (PD) patients are impaired in procedural-based category learning when category membership is defined by a nonlinear relationship between stimulus dimensions, but these same patients are normal when the rule is defined by a linear relationship (Maddox and Filoteo, 2001; Filoteo et al., 2005a,b). We suggested that PD patients' impairment was due to a deficit in recruiting "striatal units" to represent complex nonlinear rules. In the present study, we further examined the nature of PD patients' procedural-based deficit in two experiments designed to examine the impact of (1) the number of categories, and (2) category discontinuity on learning. Results indicated that PD patients were impaired only under discontinuous category conditions but were normal when the number of categories was increased from two to four. The lack of impairment in the four-category condition suggests normal integrity of striatal medium spiny cells involved in procedural-based category learning. In contrast, and consistent with our previous observation of a nonlinear deficit, the finding that PD patients were impaired in the discontinuous condition suggests that these patients are impaired when they have to associate perceptually distinct exemplars with the same category. Theoretically, this deficit might be related to dysfunctional communication among medium spiny neurons within the striatum, particularly given that these are cholinergic neurons and a cholinergic deficiency could underlie some of PD patients' cognitive impairment.
    Frontiers in Systems Neuroscience 02/2014; 8:14. DOI:10.3389/fnsys.2014.00014
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    • "Parkinson's disease is one of the most common of neurological disorders, which is largely characterised by its effects on motor function, such as bradykinesia and dyskinesia; further to other non-motor symptoms, for example pain and gastrointestinal dysfunction. Parkinson's disease arises mostly due to a progressive degeneration of dopaminergic neurons in the substantia nigra, leading to excessive cholinergic neurotransmission in the striatum (Pisani et al., 2003). Subsequently, the inhibitory effect that dopamine provides in these circuits augments GABAergic firing in the striatopallidal pathway leading to excessive inhibition of GABAergic neurons in the subthalamic nucleus, in turn leading to the abnormal enhancement of glutamatergic neurons (Hirsch, 2000). "
    Pharmacology, 03/2012; , ISBN: 978-953-51-0222-9
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