Neuroleptic Induced Dyskinesia and Increase of 5HT2C Receptor Function

Classical antipsychotics like haloperidol cause motor side effects including acute parkinsonims and dystonia (often referred to as extrapyramidal side effects, or EPS) and late-emerging tardive dyskinesias (Janno et al. 2004; Tarsy and Baldessarini 1984; Tarsy et al. 2002). Despite the advent of newer antipsychotic drugs with reduced liability to induce EPS, these side effects remain a clinical concern, especially in vulnerable patient populations such as the elderly. Numerous reports demonstrate that a variety of haloperidol treatment paradigms induce vacuous chewing movements in rats (Rupniak et al. 1985; Waddington 1990). The emergence of vacuous chewing movements (VCMs) within days to weeks of initiating haloperi-dol treatment has been called early onset VCMs and appears to be associated with mechanisms related to EPS (Egan et al. 1996; Steinpreis et al. 1993). Late-emerging VCMs that are associated with weeks to months of treatment can persist for months after the drug is withdrawn and have been considered to model tardive dyskinesias (Waddington 1990). The precise mechanisms underlying VCMs after long-term treatment with antipsychotics is likely related to a primary mechanism of action of all antipsychotic drugs at the D2 receptor (Wadenberg et al. 2001).

Chronic treatment with haloperidol increases oral responses to mCPP (Wolf et al. 2005; Ikram et al. 2007). Furthermore, the dyskinesia measured after weeks of treatment with haloperidol are reduced by the nonselective 5-HT2 antagonists ritanserin, seganserin, or ketanserin (Naidu and Kulkarni 2001). In another study, oral dyskine-sia induced by haloperidol were reduced by concomitant daily administration of ritanserin, and the dyskinesias persisting after haloperidol withdrawal were also reduced by ritanserin administration (Marchese et al. 2004). The finding that the 5-HT1A agonists 8-OH-DPAT and buspirone also lower oral dyskinesia induced by long-term haloperidol suggests that 5-HT tone is altered by the neuroleptic (Haleem et al. 2007a, b). Indeed, these authors found that classical responses dependent on somatodendritic 5-HT1A receptors such as the control of 5-HT metabolism or locomotor responses to 8-OH-DPAT were enhanced by the neuroleptic (Samad et al. 2007). Using chronic administration of buspirone concomitantly to haloperidol, they reported a progressive suppression of oral dyskinesia induced by the neuroleptic. However, Wolf et al. (2005) have reported a slight increase in mCPP-induced inositol phosphate accumulation in striatal tissue of rats chronically treated by haloperidol. Moreover, Ikram and colleagues (2007) have shown a higher increase in 5-HIAA tissue? content induced by mCPP in the dorsolateral striatum of chronically halo-peridol-treated rats (Ikram et al. 2007). It is obvious that haloperidol affects central 5-HT transmission, perhaps by modifying both the responses of 5-HT neurons, leading to alteration in 5-HT release, and the responses of 5-HT2C receptors, as suggested by modification of coupling efficiency of the receptor with intracellular second messenger pathways.

To the best of our knowledge, no data are available regarding the responses to 5-HT in the other basal ganglia regions in animals chronically treated with halo-peridol. These studies would be important to provide a comprehensive explanation of the greater responsiveness to 5-HT2C agonists in these conditions. For instance, the blockade of 5-HT2A/2C receptors is thought to underline the inhibitory influence of clozapine and risperidone, two antipsychotic drugs that minimally induce oral dyskinesia in rats and tardive dyskinesia in humans, on the discharge of SNr neurons (Bruggeman et al. 2000). Indeed, these authors have reported that concurrent 5-HT2A/2C and moderate DA D2 receptor antagonism reproduce the in vivo effects of these atypical antipsychotics on the firing rate of SNr neurons. Therefore, it is possible that clozapine and risperidone, by blocking the excitatory response exerted by 5-HT2C receptors on SNr neurons activity, favor inhibitory effects. These data support the idea that alteration in 5-HT2C receptor transmission may occur in brain areas other than the striatum. Studies in animal models of Parkinson's disease are in fact supporting this hypothesis.

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