Parkinson Disease

Another interesting application of the data regarding the functional role of 5-HT2C receptors in the basal ganglia is the possible use of 5-HT2C receptor antagonists in the treatment of Parkinson disease (Fox and Brotchie 1999;

Nicholson and Brotchie 2002; Di Giovanni et al. 2006). The neural mechanisms underlying the generation of Parkinsonian symptoms are thought to involve reduced activation of primary motor and premotor cortex and supplementary motor areas, secondary to overactivation of the output regions of the basal ganglia, i.e., SNr and globus pallidus internus (GPi) (Albin et al. 1989), largely because of excessive excitatory drive from the subthalamic nucleus (STN), consequent to DA loss in the striatum (Nicholson and Brotchie 2002; Utter and Basso 2008). Hence, it is theoretically possible that antagonists at the 5-HT2C, which act directly to reduce STN neural activity, may have positive therapeutic benefits in acronymus Parkinson disease (PD).

Therapy of Parkinson disease consists mainly of amelioration of the symptoms with classical dopaminomimetics (Hagan et al. 1997). This treatment, however, is characterized by declining efficacy and occurrence of disabling side effects (Agid 1998). Functional inhibition of GPi or STN has provided an alternative to lesion-ing, by deep brain stimulation associated with modest side effects (Rodriguez et al. 1998). As already mentioned, 5-HT2C receptors are located in the SNr and medial segment of the pallidal complex in the rat and human brain (Azmitia and Segal 1978; Pasqualetti et al. 1999), and enhanced 5-HT2C receptor-mediated transmission within the output regions of the basal ganglia in parkinsonism appears to contribute to their overactivity (Fox and Brotchie 1999). In addition, 5-HT2C-like receptor binding is increased in a rat model of Parkinsonism (Radja et al. 1993) and in human Parkinsonian patients (Fox and Brotchie 2000a). Interestingly, systemic administration of SB 206553 enhanced the anti-Parkinso-nian action of the DA D1 and D2 agonists in the 6-hydroxydopamine-lesioned rats (Fox et al. 1998; Fox and Brotchie 2000b), suggesting that the use of a 5-HT2C receptor antagonist in combination with a DA receptor agonist may reduce the reliance upon dopamine replacement therapies and may thus reduce the problems associated with long term use of currently available antiparkinsonian agents (Fox and Brotchie 1999).

On the other hand, there is also evidence that 5-HT increases the firing rate of STN neurons by acting, in part, through 5-HT2C receptors (Stanford et al. 2005; Xiang et al. 2005). In this respect, a recent in vivo study showed an increase in the percentage of subthalamic neurons exhibiting burst-firing pattern with no change in firing rate after unilateral lesion of the nigrostriatal pathway compared with normal rats. Moreover, the systemic and local administration of m-CPP increased the firing rate of subthalamic neurons in the lesioned and sham-operated rats, reversed by the subsequent administration of SB242084 (Zhang et al. 2009). Recently, De Deur waerdere et al. (2010) showed that from a functional point of view, 5-HT2C receptors exert a tonic control in basal ganglia that impacts cellular activity only in the two brain areas receiving cortical inputs, i.e., striatum and nucleus subthalamic. This suggests that the 5-HT2C receptors may functionally contribute to the regional organization of the basal ganglia network and its main afferents. Therefore, these data further support the view that 5-HT2C receptor antagonists may be useful as an adjuvant treatment to dopamine agonists to treat motor complications of PD (Di Giovanni et al. 2006).

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