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The role of the dorsal raphe nucleus in the development, expression and treatment of LID in hemiparkinsonian rats

Abstract


Convergent evidence indicates that in later stages of Parkinson's disease raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine neurons by converting and releasing dopamine derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine (L-DOPA). Because the serotonin system is not equipped with dopamine autoregulatory mechanisms, it has been postulated that raphe-mediated striatal dopamine release may fluctuate dramatically. These fluctuations may portend the development of abnormal involuntary movements called L-DOPA-induced dyskinesia (LID). As such, it has been hypothesized that reducing the activity of raphestriatal neurons could dampen supraphysiological stimulation of striatal dopamine receptors thereby alleviating LID. To directly address this, the current study employed the rodent model of LID to investigate the contribution of the rostral raphe nuclei (RRN) in the development, expression and treatment of LID. In the first study, dual serotonin/dopamine selective lesions of the RRN and medial forebrain bundle, respectively, verified that the RRN are essential for the development of LID. In a direct investigation into the neuroanatomical specificity of these effects, microinfusions of ±8-OH-DPAT into the intact dorsal raphe nucleus dose-dependently attenuated the expression of LID without affecting the anti-parkinsonian efficacy of L-DOPA. These current findings reveal the integral contribution of the RRN in the development and expression of LID and implicate a prominent role for dorsal raphe 5-HT1AR in the efficacious properties of 5-HT1AR agonists.


Keywords: Parkinson's disease, serotonin, dopamine, raphe nuclei, L-DOPA, dyskinesia


Introduction


Initial treatment with L-3,4-dihydroxyphenyl-L-alanine (L-DOPA) is exceptionally effective for patients suffering from Parkinson's disease (PD). As PD progresses, higher doses of L-DOPA become necessary and the therapeutic window for dopamine (DA) replacement therapy narrows, increasing the risk for impaired antiparkinsonian efficacy and the development of abnormal involuntary movements called L-DOPA-induced dyskinesia (LID; Jankovic, 2005). Although the mechanism(s) underlying LID are multifaceted, pulsatile supraphysiological release of L-DOPA-derived DA within the striatum leading to abnormal stimulation of supersensitized DA receptors is clearly involved (Cenci & Lundblad, 2006).


Mounting evidence argues that the serotonin (5-HT) system plays a crucial role in this exaggerated release of exogenous DA into the striatum. Serotonergic neurons of the rostral raphe nuclei (RRN), including the dorsal (DRN) and median (MRN) raphe nuclei, hyperinnervate the striatum and are thought to usurp the role of the dopaminergic system upon severe DA denervation (Arai et al., 1998; Maeda et al., 2005; Kannari et al., 2006). Recently, Carta et al. (2007) suggested that DA released from striatal 5-HT terminals acts as a “false neurotransmitter”, unfettered by a lack of DA-sensitive autoreceptors. As a consequence, excessive swings in striatal DA levels following L-DOPA treatment may lead to LID development.


5-HT1A receptor (5-HT1AR) agonists have been shown to possess antidyskinetic properties in both animal and human populations (Bonifati et al., 1994; Bibbiani et al., 2001; Eskow et al., 2007; Goetz et al., 2007). Unfortunately, their utility has been limited by reports of exacerbated parkinsonian symptoms (Iravani et al., 2006) and findings that the 5-HT1AR agonist, sarizotan provided limited antidyskinetic efficacy in phase III clinical trials (Merck KGaA, NCT00105521). Therefore, more effective development and use of these promising compounds requires knowledge of their precise underlying mechanism(s). One prominent theory suggests that 5-HT1AR agonists may be acting at densely expressed somatodendritic 5-HT1A autoreceptors within the RRN, which normally modulate neuronal excitation and consequent release of 5-HT in projection areas (Kreiss & Lucki, 1994; Riad et al., 2000). The RRN send dense serotonergic input to the striatum and previous preclinical studies have indicated that stimulation of RRN 5-HT1ARs may temper pulsatile raphestriatal DA release from 5-HT terminals following DA denervation, curtailing the expression of LID (Kannari et al., 2001; Yamato et al., 2001). However, neither the direct role of the RRN in the development of LID nor the specific neuroanatomical loci for the antidyskinetic effects of 5-HT1AR agonists have been directly investigated. To clarify this critical mechanism, the current study determined the role of the RRN in the development of abnormal involuntary movements and examined the unique contribution of DRN 5-HT1AR in the antidyskinetic effects of 5-HT1AR agonists in hemiparkinsonian rats. The results of the present investigation directly identify that the RRN and intrinsic DRN 5-HT1AR contribute to LID development and the antidyskinetic effects of 5-HT1AR agonists, respectively.


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