**3.2 Non-motor symptoms**

532 Etiology and Pathophysiology of Parkinson's Disease

observations in PD patients that examined levels of 5-HIAA in cerebrospinal fluid and have found significant reductions when compared to control patients. Interestingly, the deficits in cerebrospinal fluid 5-HIAA levels were more pronounced in PD patients with depression in comparison to non-depressed PD patients, again supporting a relationship between decreased 5-HT function and depression in PD (Mayeux et al., 1984; Mayeux et al., 1986). Development of additional imaging technologies, like PET and SPECT, has facilitated the measurement of SERT and thus the evaluation of the integrity of the 5-HT terminal (Meyer et al., 2007). In vivo SPECT studies, using non-specific ligands for SERT, found decreased binding in the cortex and hypothalamus of PD patients (Berding et al., 2003a; Berding et al., 2003b). However, these findings have been contradicted by studies that did not find any changes in the mid-brain but rather reduction in the thalamic nuclei of PD patients (Caretti et al., 2008; Kim et al., 2003; Roselli et al., 2010). Decreased SERT binding has been observed by use of PET imaging using more specific ligands. Under these circumstances reduced SERT was observed in the striatum, frontal cortex, caudate nucleus, putamen and the mid-brain raphe region of patients with PD (Albin et al., 2008; Guttman et al., 2007; Kerenyi et al., 2003). SERT binding is also labile, changing as PD progresses. For example, in the early stages of PD, SERT binding has been shown to be reduced in only in the striatum, thalamus and cingulate cortex. In later symptomatic stages of PD these alterations appear to extend to the prefrontal cortex and the raphe nuclei (Haapaniemi et al., 2001; Politis et al., 2010). Such findings suggest that a progressive reduction in SERT binding may serve as good a bio-marker for the diagnosis

In addition to neuronal integrity, 5-HT receptors are also affected in PD. Modification of pre- and post-synaptic 5-HT receptors has been observed in various animal and human studies of PD. While it is not clear whether these compensatory changes are due to lost 5-HT input, DA innervation, or DA replacement, it is established that dopaminergic tone regulates the expression of several 5-HT receptors. 5-HT1A receptor binding is not consistently affected in the 6-OHDA model of PD; however, studies in MPTP-treated macaques suggest increases in striatal and cortical binding (Frechilla et al., 2001; Huot et al., 2010b). 5-HT1B receptor binding is significantly increased in the striatum (54%) and the globus pallidus (33%). Intranigral lesions have also been reported to increase 5-HT4 receptor density in the caudate and the globus pallidus (Di Matteo et al., 2008). Studies using in situ hybridization and autoradiographic radioligand binding have revealed few changes in 5- HT1A and 5-HT2B receptor binding (Numan et al., 1995; Zhang et al., 2008); however, 5-HT2A receptors have been shown to increase in the striatum (Zhang et al., 2008). The possibility exists that striatal 5-HT2A and 5-HT2C receptor are differentially regulated in 6-OHDAlesioned animals and the changes observed in these receptors could be a reflection of the compensatory changes in the PD-afflicted brain. Some of the changes in 5-HT receptor binding are reversible after treatment with l-DOPA, Zhang and colleagues (2008) reported a reversal of increased striatal 5-HT2A receptor mRNA in a 6-OHDA rodent model of PD after l-DOPA treatment. Interestingly, l-DOPA did not alter the changes in striatal 5-HT2C receptor mRNA levels. It appears that changes in regulation of the 5-HT2A receptor are dependent on striatal DA levels and the 5-HT2C loss could be due to nigrostriatal loss, thus reflecting a difference in regulation between the two receptor sub-types. The 5-HT receptor changes seen in PD patients are partly similar to changes in the experimental PD models. Similar increases were seen in the density of 5-HT2A and 5-HT2C receptor in the striatum as

and development of treatment strategies for PD patients.
