The role of the dorsal raphe nucleus in the development, expression, and treatment of L‐dopa‐induced dyskinesia 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.

Behavioral and Cellular Modulation of l-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat

“…The AIMs test is a metric of dyskinesia, a primary side effect of L-DOPA therapy. Rats were monitored for AIMs using a procedure modified from Lundblad et al (2002) and described in Eskow et al (2009). After treatment with L-DOPA, rats were placed in plastic cylinders (22.2 cm diameter, 25.4 cm height; Thermo Fisher Scientific, Waltham, MA) and rated by trained observers blind to the experimental condition for 1 min every 10 min over a 180-min period.…”

In Vivo Evaluation of 11C-DASB for Quantitative SERT Imaging in Rats and Mice

“…where C(t) and C r (t) are regional radioactivity concentration in the target and reference regions, respectively; k 2 is the clearance rate constant from target tissue to plasma; k 9 2 is the rate constant from reference tissue to plasma; and R 1 is relative radioligand delivery (R 1 In in vivo PET, for which conditions depend on many physiologic parameters (body temperature, blood flow, receptor/transporter availability), BP is calculated as the ratio of the available receptor density (B avail ) to the apparent equilibrium dissociation rate constant (appK D ).…”

“…Ser otonergic neurons accumulate mainly in the brainstem and form the raphe nuclei (1). Although the raphe nuclei consist of only a few neurons, these nuclei innervate nearly all brain regions (1).…”

“…Although the raphe nuclei consist of only a few neurons, these nuclei innervate nearly all brain regions (1). Under normal physiologic conditions, the membranebound, sodium-chloride-dependent SERT (serotonin transporter, or 5-hydroxytryptamine transporter) is responsible for specific reuptake of released serotonin by cells (2).…”

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

“…This idea is based on work showing that L-DOPA-induced dyskinesias are reduced with serotonergic denervation of the raphe nuclei or by treatment with selective serotonergic antagonists (Carta et al, , 2008bEskow et al, 2007Eskow et al, , 2009Muñ oz et al, 2008). Serotonergic inputs from the raphe to SN, and to a lesser extent to the striatum, the globus pallidus and the subthalamus are most likely involved (Di Matteo et al, 2008).…”