Chronic L-DOPA therapy alters central serotonergic function and L-DOPA-induced dopamine release in a region-dependent manner in a rat model of Parkinson’s disease
Neurobiology of Disease. 2011-02-01; 41(2): 585-590
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The therapeutic benefit of L-DOPA is commonly attributed to restoration of
dopamine (DA) extracellular levels in the striatum of Parkinsonian patients.
However, the loss of efficacy of L-DOPA after chronic use is paradoxically
associated with a similar or enhanced striatal DA response. Release of
L-DOPA-derived DA depends on the widespread serotonergic (5-HT) innervation in
the brain. Chronic exposure of 5-HT neurons to L-DOPA could lead to aberrant
neurochemical responses beyond the striatum. Using multi-site intracerebral
microdialysis in a rat model of Parkinson’s disease, we showed that chronic
L-DOPA treatment at a therapeutic dose (12 mg/kg/day for 10 days) homogeneously
reduced basal 5-HT release and metabolism. These effects were paralleled by a
decrease in tissue content of 5-HT and its metabolite. Chronic L-DOPA treatment
severely altered the brain pattern of 5-HT and DA release responses to L-DOPA
(3-12 mg/kg) with an overall loss of efficacy of L-DOPA to increase DA release.
Our data demonstrate for the first time in vivo that the impairment of 5-HT
neuronal function induced by chronic L-DOPA alters in a region-dependent manner
L-DOPA-induced DA release. Changes in neurochemical pattern of L-DOPA in the
brain may favour the occurrence of both motor and non-motor side effects.