Smith, Y and Villalba, R. Striatal and extrastriatal dopamine in the basal ganglia: an overview of its anatomical organization in normal and Parkinsonian brains. Mov Disord 23 Suppl 3: S534-S547

Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, Georgia, USA.
Movement Disorders (Impact Factor: 5.68). 01/2008; 23 Suppl 3(S3):S534-47. DOI: 10.1002/mds.22027
Source: PubMed


Degeneration of the nigrostriatal dopaminergic system is the characteristic neuropathological feature of Parkinson's disease and therapy is primarily based on a dopamine replacement strategy. Dopamine has long been recognized to be a key neuromodulator of basal ganglia function, essential for normal motor activity. The recent years have witnessed significant advances in our knowledge of dopamine function in the basal ganglia. Although the striatum remains the main functional target of dopamine, it is now appreciated that there is dopaminergic innervation of the pallidum, subthalamic nucleus, and substantia nigra. A new dopaminergic- thalamic system has also been uncovered, setting the stage for a direct dopamine action on thalamocortical activity. The differential distribution of D1 and D2 receptors on neurons in the direct and indirect striato-pallidal pathways has been re-emphasized, and cholinergic interneurons are recognized as an intermediary mediator of dopamine-mediated communication between the two pathways. The importance and specificity of dopamine in regulating morphological changes in striatal projection neurons provides further evidence for the complex and multifarious mechanisms through which dopamine mediates its functional effects in the basal ganglia. In this review, the role of basal ganglia dopamine and its functional relevance in normal and pathological conditions will be discussed.

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    • "There are also data supporting the presence of D 2 or D 1 receptors expressed postsynaptically by GPe or GPi neurons (see Smith and Villalba, 2008; Rommelfanger and Wichmann, 2010). Moreover, ultrastructural investigations have reported the existence of synaptic contacts between DA axon terminals and pallidal dendrites in the rat (Rodrigo et al., 1998) and monkey (Smith and Kieval, 2000), providing further support of a direct DA modulation of pallidal activity. "
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    ABSTRACT: The external (GPe) and internal (GPi) segments of the primate globus pallidus receive dopamine (DA) axonal projections arising mainly from the substantia nigra pars compacta and this innervation is here described based on tyrosine hydroxylase (TH) immunohistochemical observations gathered in the squirrel monkey (Saimiri sciureus). At the light microscopic level, unbiased stereological quantification of TH positive (+) axon varicosities reveals a similar density of innervation in the GPe (0.19 ± 0.02 × 10 6 axon varicosities/mm 3 of tissue) and GPi (0.17 ± 0.01 × 10 6), but regional variations occur in the anteroposterior and dorsoventral axes in both GPe and GPi and along the mediolateral plane in the GPe. Estimation of the neuronal population in the GPe (3.47 ± 0.15 × 10 3 neurons/mm 3) and GPi (2.69 ± 0.18 × 10 6) yields a mean ratio of, respectively, 28 ± 3 and 68 ± 15 TH+ axon varicosities/pallidal neuron. At the electron microscopic level, TH+ axon varicosities in the GPe appear significantly smaller than those in the GPi and very few TH+ axon varicosities are engaged in synaptic contacts in the GPe (17 ± 3%) and the GPi (15 ± 4%) compared to their unlabeled counterparts (77 ± 6 and 50 ± 12%, respectively). Genuine synaptic contacts made by TH+ axon varicosities in the GPe and GPi are of the symmetrical and asymmetrical type. Such synaptic contacts together with the presence of numerous synaptic vesicles in all TH+ axon varicosities observed in the GPe and GPi support the functionality of the DA pallidal innervation. By virtue of its predominantly volumic mode of action, DA appears to exert a key modulatory effect upon pallidal neurons in concert with the more direct GABAergic inhibitory and glutamatergic excitatory actions of the striatum and subthalamic nucleus. We argue that the DA pallidal innervation plays a major role in the functional organization of the primate basal ganglia under both normal and pathological conditions.
    Frontiers in Neuroanatomy 08/2015; 9(111):1-14. DOI:10.3389/fnana.2015.00111 · 3.54 Impact Factor
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    • "In addition, extrastriatal dopaminergic regions such as the prefrontal cortex may be negatively affected by Mn intoxication (Guilarte, 2013) as in iPD (Smith and Villalba, 2008). Nigral neurons that contain either neuromelanin or calbindin (Fig. 1) have been shown to be resistant or susceptible to particular neurotoxic insults and disease processes, including dystonia and parkinsonism (Smith and Villalba, 2008; Zecca et al., 2003). Thus, neuromelanin-containing dopaminergic neurons have demonstrated a resistance to Mn toxicity in occupationally exposed humans (Perl and Olanow, 2007), whereas depigmentation occurred in intact dopaminergic neurons in the brains of individuals with SLC30A10 mutations (Lechpammer, 2014). "
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    ABSTRACT: Movement abnormalities caused by chronic manganese (Mn) intoxication clinically resemble but are not identical to those in idiopathic Parkinson's disease. In fact, the most successful parkinsonian drug treatment, the dopamine precursor levodopa, is ineffective in alleviating Mn-induced motor symptoms, implying that parkinsonism in Mn-exposed individuals may not be linked to midbrain dopaminergic neuron cell loss. Over the last decade, supporting evidence from human and nonhuman primates has emerged that Mn-induced parkinsonism partially results from damage to basal ganglia nuclei of the striatal "direct pathway" (ie, the caudate/putamen, internal globus pallidus, and substantia nigra pars reticulata) and a marked inhibition of striatal dopamine release in the absence of nigrostriatal dopamine terminal degeneration. Recent neuroimaging studies have revealed similar findings in a particular group of young drug users intravenously injecting the Mn-containing psychostimulant ephedron and in individuals with inherited mutations of the Mn transporter gene SLC30A10. This review will provide a detailed discussion about the aforementioned studies, followed by a comparison with their rodent analogs and idiopathic parkinsonism. Together, these findings in combination with a limited knowledge about the underlying neuropathology of Mn-induced parkinsonism strongly support the need for a more complete understanding of the neurotoxic effects of Mn on basal ganglia function to uncover the appropriate cellular and molecular therapeutic targets for this disorder. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail:
    Toxicological Sciences 08/2015; 146(2):204-12. DOI:10.1093/toxsci/kfv099 · 3.85 Impact Factor
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    • "As mentioned above, there is solid anatomical, biochemical, physiological and pharmacological evidence that supports the idea that dopamine is the key regulatory transmitter in the control of movement exerted at the basal ganglia level (see Smith and Villalba, 2008). The activation of dopaminergic transmission in this circuitry produces hyperkinesia, whereas its inhibition results in a reduction of movement. "
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    ABSTRACT: Endocannabinoids and their receptors play a modulatory role in the control of dopamine transmission at the basal ganglia. However, this influence is generally indirect and exerted through the modulation of GABA and glutamate inputs received by nigrostriatal dopaminergic neurons, which lack of CB1 receptors although may produce endocannabinoids. Additional evidence suggest that CB2 receptors may be located in nigrostriatal dopaminergic neurons, as well as that certain eicosanoid-related cannabinoids may directly activate TRPV1 receptors, which have been found in nigrostriatal dopaminergic neurons, thus allowing in both cases a direct regulation of dopamine transmission by specific cannabinoids. In addition, CB1 receptors form heteromers with dopaminergic receptors which represent another way to make possible a direct interaction between both systems, in this case at the postsynaptic level. Through these direct mechanisms or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with dopamine transmission in the basal ganglia and this likely has an important influence on dopamine-related functions in these structures (i.e. control of movement) and, particularly, on different pathologies affecting these processes, in particular, Parkinson's disease, but also dyskinesia, dystonia and other pathological conditions. The present review will address the current literature supporting these cannabinoid-dopamine interactions at the basal ganglia, with emphasis in aspects dealing with the physiopathological consequences of these interactions. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13215 · 4.84 Impact Factor
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