Abstract
Nowadays it is assumed that besides its roles in neuronal processing, dopamine (DA) is also involved in the regulation of cerebral blood flow. However, studies on the hemodynamic actions of DA have been mainly focused on the cerebral cortex, but the possibility that vessels in deeper brain structures receive dopaminergic axons and the origin of these axons have not been investigated. Bearing in mind the evidence of changes in the blood flow of basal ganglia in Parkinson’s disease (PD), and the pivotal role of the dopaminergic mesostriatal pathway in the pathophysiology of this disease, here we studied whether striatal vessels receive inputs from midbrain dopaminergic neurons. The injection of an anterograde neuronal tracer in combination with immunohistochemistry for dopaminergic, vascular and astroglial markers, and dopaminergic lesions, revealed that midbrain dopaminergic axons are in close apposition to striatal vessels and perivascular astrocytes. These axons form dense perivascular plexuses restricted to striatal regions in rats and monkeys. Interestingly, they are intensely immunoreactive for tyrosine hydroxylase (TH) phosphorylated at Ser19 and Ser40 residues. The presence of phosphorylated TH in vessel terminals indicates they are probably the main source of basal TH activity in the striatum, and that after activation of midbrain dopaminergic neurons, DA release onto vessels precedes that onto neurons. Furthermore, the relative weight of this “vascular component” within the mesostriatal pathway suggests that it plays a relevant role in the pathophysiology of PD.
Highlights
DA is a neurotransmitter and neuromodulator involved in a wide range of brain functions including control of voluntary movements, reward-seeking behavior, cognitive processes and circuit formation during development (Schultz, 2007; Money and Stanwood, 2013; Morita et al, 2013)
While some data suggest that vascular effects of DA require activation of postsynaptic D1 DA receptors (Knutson and Gibbs, 2007), dopaminergic contacts have been described in small vessels of the monkey frontal cortex (Krimer et al, 1998), and DA receptor expression has been found in cultured endothelial cells and astrocytes (Bacic et al, 1991; Bal et al, 1994; Zanassi et al, 1999; Choi et al, 2006), suggesting a direct DA effect on vessels and surrounding astrocytes
It is noteworthy that in spite of the striatum being the main target of midbrain dopaminergic inputs, there is no evidence that striatal vessels and surrounding astrocytes
Summary
DA is a neurotransmitter and neuromodulator involved in a wide range of brain functions including control of voluntary movements, reward-seeking behavior, cognitive processes and circuit formation during development (Schultz, 2007; Money and Stanwood, 2013; Morita et al, 2013). DA exerts important actions in peripheral organs, with those being on the vascular dynamics control of particular relevance (Tayebati et al, 2011). It has been shown that DA analogs modify blood flow into discrete brain regions (Breiter et al, 1997; Marota et al, 2000), and that this effect is prevented by dopaminergic lesion (Chen et al, 1997; Nguyen et al, 2000; Jenkins et al, 2004). The involvement of DA in the regulation of regional cerebral blood flow is well-established nowadays. Most interest in cerebral blood flow regulation has been focussed on the cerebral cortex, whereas mechanisms operating in deep brain centers, including the striatum, have been less investigated. It is noteworthy that in spite of the striatum being the main target of midbrain dopaminergic inputs, there is no evidence that striatal vessels and surrounding astrocytes
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