**7. Noradrenergic agents relieve L-DOPA-induced dyskinesia**

#### **7.1 Chronic L-DOPA therapy induces dyskinesia**

In addition to the potential neuroprotective effect of the noradrenergic nervous system on dopaminergic neurons early in the progression of PD, the noradrenergic nervous system may also improve therapy of PD subjects. As indicated above, L-DOPA is the primary therapy in the treatment of PD motor symptoms. However, chronic treatment of L-DOPA in PD subjects results in permanent severe side effect, dyskinesia (abnormal involuntary movements). The incidence of dyskinesia in PD subjects increases with the length of time on L-DOPA therapy; 30% of patients experience dyskinesia after 4-6 years to 90% after 9 years (Rascol et al., 2000; Ahlskog & Muenter, 2001). The underlying mechanism behind L-DOPA-induced dyskinesia is thought to be extraphysiological DA release resulting in aberrant receptor signaling in the striatum; this enhanced dopaminergic signaling then dysregulates subsequent striatal output (Cenci, 2007, 2009; Winkler et al., 2002). Until a means of preventing the onset of PD occurs or a new treatment for PD that does not result in dyskinesia is found, adjunct pharmacological therapy with L-DOPA that prevents or reduces dyskinesia is the focus of future work in PD therapy.

#### **7.2 AR antagonists reduce L-DOPA-induced dyskinesia**

As indicated earlier, the different types of ARs (β-, α1- and α2-ARs) are localized to the striatum and AR agents can alter the activity of striatal neurons (see above). However, at the present time it is unclear if the loss of LC noradrenergic neurons early in the progression of PD contributes to the L-DOPA-induced overactivity of striatal neurons that ultimately results in dyskinesia (Marin et al., 2008) or how L-DOPA therapy affects noradrenergic neurons (Figure 2). What is known is that α2-AR agonists can facilitate movement by acting through the striatum (Hill and Brotchie, 1999). Therefore, α2-AR antagonists have been studied as a potential adjunct therapy to reduce L-DOPA-induced dyskinesia. α2-AR antagonists, yohimbine, idazoxan and fipamezole reduce L-DOPA dyskinesia in the MPTP and 6OHDA PD animal models and in Parkinsonian patients. These α2-AR antagonists reduce L-DOPA-induced side effects without affecting the anti-parkinsonian effect of L-DOPA (Brotchie, 2005; Buck et al., 2010; Colosimo and Craus, 2003; Chopin et al., 1986; Gomez-Mancilla and Bedard, 1993; Grondin et al., 2000; Henry et al., 1999; Lundblad et al., 2002; Rascol et al., 2001; Savola et al., 2003). However, the anti-dyskinetic effect of α2-AR antagonists may be limited to just L-DOPA; idazoxan did not reduce apomorphine-induced dyskinesia (Fox et al., 2001). The α2-ARs are not the only receptor capable of modulating L-DOPA-induced dyskinesia. Because β-ARs are found in large concentrations in the striatum (see above), studies are now beginning to determine if β-AR antagonists, such as propranolol, can reduce L-DOPA-induced dyskinesia. These studies indicate that propranolol also reduces L-DOPA-induced dyskinesia (Goshima et al., 1991; Reisine et al., 1982; Carpentier et al., 1996; Dekundy et al., 2007). α1-AR antagonist also reduces L-DOPAinduced dyskinesia; however, this receptor subtype has not been investigated to the same degree as α2- and β-AR antagonists (Buck and Ferbeger, 2010).

#### **8. Conclusion**

258 Etiology and Pathophysiology of Parkinson's Disease

These data indicate that administration of the noradrenergic neurotoxin 6OHDA can

These data suggest that enhanced noradrenergic function can protect dopaminergic neurons from damage, while reducing noradrenergic function enhances the susceptibility of dopaminergic neurons to damage. The number of studies examining this important question are few, but the data indicates the LC noradrenergic nervous system can modulate the viability of dopaminergic neurons to damage. It is unknown why dopaminergic neurons in PD are reduced. The loss of dopaminergic neurons and the appearance of PD symptoms occur midway in the progression of the disorder, after the loss of LC noradrenergic neurons. Therefore, determining factors that can maintain the stability of dopaminergic neurons in the early stages of the disorder is imperative in preventing the loss of dopaminergic neurons and the onset of PD symptoms. Since LC neuronal loss occurs early in the progression of PD and is a prominent neuropathologic change in PD, an animal model examining the neuroprotective effect of the noradrenergic nervous system on dopaminergic neurons must exhibit reduced LC noradrenergic neuronal number, so DSP4 may not be the best animal model of LC neuronal loss. Future work will determine if there is a particular time following the loss of LC noradrenergic neurons that renders the dopaminergic neurons more susceptible to damage, or it may be that following administration of MPTP, animals

with reduced LC function do not recover from the damage induced by MPTP.

In addition to the potential neuroprotective effect of the noradrenergic nervous system on dopaminergic neurons early in the progression of PD, the noradrenergic nervous system may also improve therapy of PD subjects. As indicated above, L-DOPA is the primary therapy in the treatment of PD motor symptoms. However, chronic treatment of L-DOPA in PD subjects results in permanent severe side effect, dyskinesia (abnormal involuntary movements). The incidence of dyskinesia in PD subjects increases with the length of time on L-DOPA therapy; 30% of patients experience dyskinesia after 4-6 years to 90% after 9 years (Rascol et al., 2000; Ahlskog & Muenter, 2001). The underlying mechanism behind L-DOPA-induced dyskinesia is thought to be extraphysiological DA release resulting in aberrant receptor signaling in the striatum; this enhanced dopaminergic signaling then dysregulates subsequent striatal output (Cenci, 2007, 2009; Winkler et al., 2002). Until a means of preventing the onset of PD occurs or a new treatment for PD that does not result in dyskinesia is found, adjunct pharmacological therapy with L-DOPA that prevents or

As indicated earlier, the different types of ARs (β-, α1- and α2-ARs) are localized to the striatum and AR agents can alter the activity of striatal neurons (see above). However, at the present time it is unclear if the loss of LC noradrenergic neurons early in the progression of PD contributes to the L-DOPA-induced overactivity of striatal neurons that ultimately results in dyskinesia (Marin et al., 2008) or how L-DOPA therapy affects noradrenergic

**7. Noradrenergic agents relieve L-DOPA-induced dyskinesia** 

**7.1 Chronic L-DOPA therapy induces dyskinesia** 

reduces dyskinesia is the focus of future work in PD therapy.

**7.2 AR antagonists reduce L-DOPA-induced dyskinesia** 

increase the susceptibility of dopaminergic neurons to damage.

**6.4 Summary** 

The dopaminergic nervous system has been the major focus of research in PD for many years, and rightly so because it is the loss of dopaminergic neurons and function that is responsible for the appearance of the motor symptoms that define PD. However, the noradrenergic nervous system appears to play an important role in the progression of PD and in the therapy of PD. LC noradrenergic neurons are reduced early in the progression of PD, even before dopaminergic neurons. Animal models suggest that the loss of LC noradrenergic neurons will enhance the susceptibility of dopaminergic neurons to damage. Understanding the relationship of LC neuronal loss to enhanced dopaminergic susceptibility to damage introduces a time window in which pharmacological intervention could *prevent* the loss of dopaminergic neurons and the appearance of motor symptoms. But until this relationship is examined, the noradrenergic nervous system can be used to reduce Dyskinesia, the severe side effects of chronic L-DOPA therapy. These data indicate the importance of examining neurotransmitter systems other than DA and determining the role of transmitters, such as NE, in affecting PD.
