L-DOPA-induced dysregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson's disease.

Convergent evidence indicates that raphestriatal serotonin (5-HT) neurons can convert and release dopamine (DA) derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine (L-DOPA) as a treatment for Parkinson's disease (PD). While aspects of such neuroplasticity may be beneficial, chronic L-DOPA may also modify native 5-HT function, precipitating the appearance prevalent non-motor PD symptoms such as anxiety and depression. To examine this, male Sprague-Dawley rats were rendered parkinsonian with bilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) infusions and treated for at least 28 days with vehicle or L-DOPA. In the first experiment, striatal, hippocampal, amygdalar, and prefrontal cortex DA and 5-HT levels were examined at various post-treatment time-points. In experiment 2, L-DOPA's effects on DA and 5-HT cell bodies in the substantia nigra pars compacta and dorsal raphe, respectively, were examined. Finally, the effects of L-DOPA on affective behaviors were assessed in locomotor chambers, social interaction, forced swim, and elevated plus maze behavioral tests. Bilateral 6-OHDA lesion induced approximately 80% DA and 30% 5-HT depletion in the striatum compared to sham-lesioned controls, while monoamine levels remained largely unchanged in extrastriatal regions. Tissue levels of DA were increased at the expense of 5-HT levels in parkinsonian rats subjected to chronic L-DOPA injections in all regions sampled, though DA or 5-HT cell bodies were unaffected. Behaviorally, rats could only be tested 24h after their last L-DOPA injection due to severe dyskinesia. Despite this, prior exposure to chronic L-DOPA treatment exerted a pronounced anxiogenic phenotype. Collectively, these results suggest that chronic L-DOPA treatment may interfere with the balance of DA and 5-HT function in affect-related brain regions and could induce and/or exacerbate non-motor symptoms in PD.