Effect of tricyclic antidepressants on L-DOPA-induced dyskinesia and motor improvement in hemi-parkinsonian rats

• Serotonin and norepinephrine transporters contribute to L-DOPA's motor effects.
• Serotonin transporter inhibition reduced dyskinesia while preserving L-DOPA benefits.
• Norepinephrine transporter blockade shifted the dyskinetic window to the right.
• Monoamine transporters serve different roles in L-DOPA-induced motor behaviors.
• Monoamine transporters may serve as therapeutic adjuncts with L-DOPA.

Although dopamine replacement therapy with L-DOPA in Parkinson's disease initially reduces motor symptoms, its chronic use often leads to the development of abnormal involuntary movements known as L-DOPA-induced dyskinesia. Increasingly, research has indicated that non-dopaminergic neurons gain function in the parkinsonian brain, taking up and converting L-DOPA to dopamine and releasing it as a “false neurotransmitter”. Although less explored, promiscuity between monoamine transporters may also modulate these processes. Therefore, in order to examine the differential roles of monoamine transporters in L-DOPA's behavioral effects, three tricyclic antidepressants (TCA) with graded affinity for serotonin (SERT) vs. norepinephrine (NET) transporters were tested in hemi-parkinsonian rats: clomipramine (SERT > NET), amitriptyline (SERT = NET), and desipramine (SERT < NET). Rats received 6-hydroxydopamine lesions and were primed with L-DOPA (12 mg/kg, s.c.) to develop stable dyskinesia (N = 19 of 26). In a series of studies, rats were administered TCAs (0, 7.5, 15 or 30 mg/kg, i.p.) followed by L-DOPA (6 mg/kg, s.c.) and were measured for dyskinesia using the abnormal involuntary movements scale as well as motor performance and activity using the forepaw adjusting steps test and locomotor chambers, respectively. Clomipramine, the compound with the highest affinity for SERT was most effective in attenuating L-DOPA-induced dyskinesia without altering L-DOPA's stimulatory effects. In contrast, desipramine, the TCA with the highest NET affinity deferred L-DOPA's effects to later time points in testing. The current results indicate divergent roles for non-dopaminergic neuronal transporters in L-DOPA's mechanisms of action and point to novel targets for improving Parkinson's disease treatment.