Impact of L-DOPA treatment on regional cerebral blood flow and metabolism in the basal ganglia in a rat model of Parkinson's disease

Increased putamen hypercapnic vasoreactivity in levodopa-induced dyskinesia

“…Dissociation of vasomotor and metabolic responses to levodopa has been noted as a consistent feature of acute drug administration in human PD (3,4) and in the 6-OHDA rat model (5,6). This phenomenon is closely linked to levodopa-mediated increases in local CBF, likely related to engagement of D 1 receptors on blood vessels apposed to dopamine terminals in the mammalian striatum (8,9,19).…”

“…This contrasts with the development of angiogenesis in the chronically levodopa-treated 6-OHDA rodent, wherein localized microvascular pathology is closely linked to the appearance of dyskinesia (12,13,16). Given the immaturity of angiogenic blood vessels, the increases in local CBF induced acutely by levodopa may lead to transient stretching of the endothelial lining and consequent changes in blood-brain barrier permeability (2,5). Such effects, needless to say, are unlikely to occur in areas with normally developed capillary endothelium (4).…”

“…While the mechanism of LID is not precisely known, experimental evidence from the 6-hydroxydopamine (6-OHDA) rat model has implicated neurovascular dysregulation in dopaminergically denervated brain regions as a major factor underlying the development of levodopa-mediated involuntary movements (2). Evidence for this hypothesis has been provided by recent dual-tracer PET studies conducted in human PD subjects (3,4) and in the rodent model (5,6). In brief, levodopa administration is associated with increases in local cerebral blood flow (CBF) and with simultaneous reductions in cerebral glucose metabolic rate (CMR) in the same brain regions.…”

“…In addition to human PD, levodopa-mediated dissociation has been observed in the 6-hydroxydopamine rat model (6). In both species, levodopa-mediated dissociation is most prominent in the basal ganglia, with notably greater effects in human subjects and experimental animals with druginduced dyskinesia (4,5).…”

The preferential nNOS inhibitor 7-nitroindazole and the non-selective one NG-nitro-l-arginine methyl ester administered alone or jointly with l-DOPA differentially affect motor behavior and monoamine metabolism in sham-operated and 6-OHDA-lesioned rats

“…The reason for this decline in DA content is unknown, but one can assume that L-NAMEinduced inhibition of the endothelial isoform of NOS may reduce L-DOPA bioaviability, via decreasing cerebral blood flow (CBF). It is worth to mentioning that treatment with L-DOPA evoked large increases in regional CBF in the putamen/ globus pallidus and dorsal midbrain of PD patients (Hirano et al, 2008;Ko et al, 2015) as well as in the ipsilateral striatum of dyskinetic unilaterally 6-OHDA-lesioned rats (Ohlin et al, 2012). Regarding catabolism of DA, after combined administration of L-NAME and L-DOPA metabolic index of DOPAC/DA in the ipsilateral STR as well as in the ipsi-and contralateral SN did not differ significantly from that calculated for the group receiving L-DOPA alone.…”