**2.2 Non-motor symptoms**

#### **2.2.1 NE loss and non-motor symptoms**

Although motor symptoms of PD are widely acknowledged hallmarks of this neurodegenerative disease, there exists compelling evidence for the presence of psychiatric complications, such as depression, anxiety and psychotic symptoms (Bosboom et al., 2004). Loss of dopaminergic and noradrenergic innervation has been associated with psychiatric complications such as depression (Remy et al., 2005) and anxiety (Stein et al., 1990; Lauterbach et al., 2003). Cognitive and mood dysfunction has been reported in >50% of PD patients. In patients with early PD, depression (40%), apathy (27%), and anxiety (27%) are widely reported (Aarsland et al., 2009) and it is notable that these non-motor symptoms are identified as the most important and devastating feature contributing towards poverty of quality of life (McKinlay et al., 2008; Schrag, 2006). Moreover, the incidence of depression and anxiety in PD exceeds not only rates within the normal population but also other neurological disorders (Weintraub et al., 2003), with anxiety disorders, such as off-period panic attacks and specific phobias, have been reported in nearly 40% of PD patients (Lauterbach, 2005). Collectively these findings lead to the important observation that depression and anxiety are likely a result of neuropathological processes rather than as a result of motor impairments.

Pathophysiology of Non-Dopaminergic Monoamine

symptomatic relief for the PD patient.

by raphe neurons (Braak et al., 2003).

nuclei (Braak et al., 2003).

**3.1 CNS pathophysiology of 5-HT system in PD 3.1.1 Neuroanatomical evidence in PD patients** 

Systems in Parkinson's Disease: Implications for Mood Dysfunction 531

and ante-mortem (Miyawaki et al., 1997; Scatton et al., 1983). Since the 5-HT system ubiquitously innervates and modulates basal ganglia nuclei, 5-HT loss likely affects both motor symptoms of PD and l-DOPA related side effects. In addition, given the role of 5-HT in mood, such alterations may also correlate with the preponderance of depression and anxiety seen in PD. Therefore, various treatment strategies have been developed that modulate the 5-HT system. In the following sections, we review the neuropathology of the 5-HT system in PD, the consequences of a damaged 5-HT system on non-motor aspects, and the line of experimental and clinical treatments targeting the 5-HT system to provide

Even though degeneration of DA neurons in the SNpc remains the best identified neuropathological hallmark in PD, there exists increasing evidence suggesting PD-related pathology in the principle 5-HT cell bodies, the raphe nuclei and other regions innervated

Multiple studies have reported the presence of LB in the caudal group of raphe nuclei, like the raphe magnus and raphe pallidus, in early PD, sometimes occurring even before the onset of motor symptoms (Braak et al., 2003; Del Tredici et al., 2002; Parkkinen et al., 2008). It is interesting to note that these caudal raphe nuclei contain 5-HT neurons associated with functions like pain perception, and gastrointestinal motility that are manifest as early symptoms in PD patients prior to motor complaints (Chaudhuri and Schapira, 2009). The rostral raphe nuclei consisting of dorsal and medial raphe nuclei are equally affected in PD and according to Braak staging, are affected before the SNpc but after the caudal raphe

Despite reports of raphe LB formation, evidence for the degeneration of 5-HT neurons in the rostral raphe nuclei is variable; post-mortem analysis of PD brains by Paulus and Jellinger (1991) revealed a profound loss of 5-HT neurons, however, other studies have not (Halliday et al., 1990; Mann and Yates, 1983). Several studies have employed transcranial sonography to study the midbrain raphe nuclei. This work has revealed abnormal pathology in the form of hypoechogenicity or an absence of sonographic signals in PD vs. control subjects. Interestingly, PD patients in one study also suffered from higher incidence of depression, reflecting a direct relationship between raphe nuclei loss and PD-related depression (Becker et al., 1997; Berg and Gaenslen, 2010; Walter et al., 2007b). MRI imaging studies carried out in depressed PD patients have also demonstrated a loss of homogeneity in the midbrain

PD-related pathology of the 5-HT system is not limited to the cell bodies of the raphe nuclei. Convincing evidence exists for damaged 5-HT projections and terminals as well. For example, post-mortem studies in PD patients have described significant loss of 5-HT markers, such as brain 5-HT concentrations. In cortical and the basal ganglia regions 5-HT content has been reported to be reduced by as much as 50% compared to controls (Birkmayer and Birkmayer, 1987). Kish and colleagues (2008) investigated the integrity of the forebrain 5-HT system. In contrast to DA loss, which was preferential to the putamen, 5- HT loss was more prominent in the caudate for all 5-HT markers including 5-HT (-66%), the 5-HT metabolite 5-HIAA (-42%), 5-HT transporter (SERT), (-56%) and the rate limiting enzyme in 5-HT synthesis tryptophan hydroxylase (-59%). These corroborated ante-mortem

raphe consistent with neuronal compromise and/or cell loss (Berg et al., 1999).

The exact pathophysiology underlying these mood dysfunctions are unknown though given the role of NE in several of these symptoms, it is likely that NE loss in PD plays a critical role. As discussed earlier, neurodegeneration of LC neurons in PD is a well established phenomenon that precedes DA neuronal loss (Braak et al., 2003). It has been postulated that a compromised LC produces significant changes in NE receptors and transporters that may lead to the development or exacerbation of depression/anxiety (Eskow Jaunarajs et al., 2010). Additionally, Remy et al. (2005) have reported reduced binding for the DA/NE transporter, suggesting a loss of terminals, in the LC of PD patients suffering from anxiety and depression (Remy et al., 2005). In a rodent model of PD, alterations in DA and NE systems in the striatum have been reported to produce anxiety (Tadaiesky et al., 2008), consistent with findings in naïve rats that NE regulates anxiety behavior. Experimental studies have reported depression and anxiety-like behaviors in a 6-OHDA lesion model of PD (Branchi et al., 2010; Eskow Jaunarajs et al., 2010; Tadaiesky et al., 2008). Additionally, concomitant depletion of NE, 5-HT and DA in a unilateral rodent model of PD produced symptoms of depression, suggesting that loss of all three systems contribute to PD-like depression (Delaville et al., 2010). In an interesting study, Taylor et al. (2009) used a vesicular monoamine transporter-2 (VMAT-2) deficient mouse model to induce severe NE and DA loss thereby mimicking PD. VMAT-2 deficient mice exhibited severe depression and anxiety-like symptoms that worsened with advancing age (Taylor et al., 2009) highlighting a possible interplay between DA and NE. Histological studies have highlighted the fact that LC neuron morphology is more severely affected in PD with depression than in PD without depressio (Chan-Palay and Asan, 1989). While most of the evidence in clinical and experimental models correlating NE deficit with mood dysfunction is indirect, there exists evidence that noradrenergic drugs might provide relief in the treatment of these mood disorders.

#### **2.2.2 Treatment of non-motor symptoms with NE drugs**

The role for the NE system in affective disorders such as anxiety and depression has been partially implicated by the effectiveness of drugs that enhance NE levels. Reboxetine, a NET inhibitor, has been proven to be effective in the treatment of depression associated with PD (Pintor et al., 2006). In one of the largest Randomized Clinical Trials (RCT) to date Menza and colleagues (2009) found that Nortryptaline, a tricyclic antidepressant (TCA), with preferential actions as a NET inhibitor, was proven to be more effective in treating depression in PD patients compared to selective 5-HT reuptake inhibitors (SSRIs: Menza et al., 2009). In a similar placebo controlled study in PD patients, Desipramine, a NET inhibitor, was found to be effective in treating depression; however, these improvements were accompanied with mild adverse side effects (Devos et al., 2008). These therapeutic findings suggest a more prominent role for NE in the development of depression in PD. The few drugs that seem to be effective in treating depression likely act to elevate extracellular NE levels in the brain, by blocking NET (Dziedzicka-Wasylewska et al., 2006). Therefore, it seems feasible that drugs that mimic NE or elevate NE levels in the brain would be effective in treating NE-related non-motor symptoms in PD.

#### **3. Serotonin system**

The 5-HT system like the NE system undergoes significant, though more variable, neurodegeneration as PD progresses; a finding documented in various studies, both post-

The exact pathophysiology underlying these mood dysfunctions are unknown though given the role of NE in several of these symptoms, it is likely that NE loss in PD plays a critical role. As discussed earlier, neurodegeneration of LC neurons in PD is a well established phenomenon that precedes DA neuronal loss (Braak et al., 2003). It has been postulated that a compromised LC produces significant changes in NE receptors and transporters that may lead to the development or exacerbation of depression/anxiety (Eskow Jaunarajs et al., 2010). Additionally, Remy et al. (2005) have reported reduced binding for the DA/NE transporter, suggesting a loss of terminals, in the LC of PD patients suffering from anxiety and depression (Remy et al., 2005). In a rodent model of PD, alterations in DA and NE systems in the striatum have been reported to produce anxiety (Tadaiesky et al., 2008), consistent with findings in naïve rats that NE regulates anxiety behavior. Experimental studies have reported depression and anxiety-like behaviors in a 6-OHDA lesion model of PD (Branchi et al., 2010; Eskow Jaunarajs et al., 2010; Tadaiesky et al., 2008). Additionally, concomitant depletion of NE, 5-HT and DA in a unilateral rodent model of PD produced symptoms of depression, suggesting that loss of all three systems contribute to PD-like depression (Delaville et al., 2010). In an interesting study, Taylor et al. (2009) used a vesicular monoamine transporter-2 (VMAT-2) deficient mouse model to induce severe NE and DA loss thereby mimicking PD. VMAT-2 deficient mice exhibited severe depression and anxiety-like symptoms that worsened with advancing age (Taylor et al., 2009) highlighting a possible interplay between DA and NE. Histological studies have highlighted the fact that LC neuron morphology is more severely affected in PD with depression than in PD without depressio (Chan-Palay and Asan, 1989). While most of the evidence in clinical and experimental models correlating NE deficit with mood dysfunction is indirect, there exists evidence that noradrenergic drugs might provide

The role for the NE system in affective disorders such as anxiety and depression has been partially implicated by the effectiveness of drugs that enhance NE levels. Reboxetine, a NET inhibitor, has been proven to be effective in the treatment of depression associated with PD (Pintor et al., 2006). In one of the largest Randomized Clinical Trials (RCT) to date Menza and colleagues (2009) found that Nortryptaline, a tricyclic antidepressant (TCA), with preferential actions as a NET inhibitor, was proven to be more effective in treating depression in PD patients compared to selective 5-HT reuptake inhibitors (SSRIs: Menza et al., 2009). In a similar placebo controlled study in PD patients, Desipramine, a NET inhibitor, was found to be effective in treating depression; however, these improvements were accompanied with mild adverse side effects (Devos et al., 2008). These therapeutic findings suggest a more prominent role for NE in the development of depression in PD. The few drugs that seem to be effective in treating depression likely act to elevate extracellular NE levels in the brain, by blocking NET (Dziedzicka-Wasylewska et al., 2006). Therefore, it seems feasible that drugs that mimic NE or elevate NE levels in the brain would be effective

The 5-HT system like the NE system undergoes significant, though more variable, neurodegeneration as PD progresses; a finding documented in various studies, both post-

relief in the treatment of these mood disorders.

in treating NE-related non-motor symptoms in PD.

**3. Serotonin system** 

**2.2.2 Treatment of non-motor symptoms with NE drugs** 

and ante-mortem (Miyawaki et al., 1997; Scatton et al., 1983). Since the 5-HT system ubiquitously innervates and modulates basal ganglia nuclei, 5-HT loss likely affects both motor symptoms of PD and l-DOPA related side effects. In addition, given the role of 5-HT in mood, such alterations may also correlate with the preponderance of depression and anxiety seen in PD. Therefore, various treatment strategies have been developed that modulate the 5-HT system. In the following sections, we review the neuropathology of the 5-HT system in PD, the consequences of a damaged 5-HT system on non-motor aspects, and the line of experimental and clinical treatments targeting the 5-HT system to provide symptomatic relief for the PD patient.
