Noradrenergic modulation of the motor response induced by long-term levodopa administration in Parkinsonian rats

A decrease in noradrenergic activity in Parkinson's disease might play a critical role in long-term motor complications associated with chronic dopaminergic replacement. Using the rat model of parkinsonism with an additional noradrenergic degeneration induced by the N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) toxin we evaluated whether the circling motor activity and dose-failure episodes induced by levodopa (l-DOPA) differ between single (6-OHDA) and double (6-OHDA + DSP-4) denervated animals challenged with a single daily dose of l-DOPA. While single-lesioned animals showed a sensitization-desensitization turning response with a significant increase on day 15 and a decrease on day 22, in double-lesioned animals, the turning activity was maximal from day 1 and did not decay on day 22. Double-lesioned rats exhibited significantly higher number of turns on days 15 and 22 and a significantly lower percentage of dose-failure episodes during treatment. Noradrenergic denervation appears to be associated with prolonged long-term dopaminergic sensitization. This type of response appears to be comparable to that in the clinical setting with intermittent l-DOPA administration where no desensitization occurs once the abnormal response is established.