Pathogenesis Of Levodopa-induced Dyskinesia Research Articles

AMPK-mediated autophagy pathway activation promotes ΔFosB degradation to improve levodopa-induced dyskinesia

BackgroundParkinson's disease patients on chronic levodopa often suffer from motor complications, which tend to reduce their quality of life. Levodopa-induced dyskinesia (LID) is one of the most prevalent motor complications, often characterized by abnormal involuntary movements, and the pathogenesis of LID is still unclear but recent studies have suggested the involvement of autophagy. MethodsThe onset of LID was mimicked by chronic levodopa treatment in a unilateral 6-hydroxydopamine (6-OHDA) -lesion rat model. Overexpression of ΔFosB in HEK293 cells to mimic the state of ΔFosB accumulation. The modulation of the AMP-activated protein kinase (AMPK)-mediated autophagy pathway using by metformin, AICAR (an AMPK activator), Compound C (an AMPK inhibitor) and chloroquine (an autophagy pathway inhibitor). The severity of LID was assessed by axial, limb, and orofacial (ALO) abnormal involuntary movements (AIMs) score and in vivo electrophysiology. The activity of AMPK pathway as well as autophagy markers and FosB-ΔFosB levels were detected by western blotting. RT-qPCR was performed to detect the transcription level of FosB-ΔFosB. The mechanism of autophagy dysfunction was further explored by immunofluorescence and transmission electron microscopy. ResultsIn vivo experiments demonstrated that chronic levodopa treatment reduced AMPK phosphorylation, impaired autophagosome-lysosomal fusion and caused FosB-ΔFosB accumulation in the striatum of PD rats. Long-term metformin intervention improved ALO AIMs scores as well as reduced the mean power of high gamma (hγ) oscillations and the proportion of striatal projection neurons unstable in response to dopamine for LID rats. Moreover, the intervention of metformin promoted AMPK phosphorylation, ameliorated the impairment of autophagosome-lysosomal fusion, thus, promoting FosB-ΔFosB degradation to attenuate its accumulation in the striatum of LID rats. However, the aforementioned roles of metformin were reversed by Compound C and chloroquine. The results of in vitro studies demonstrated the ability of metformin and AICAR to attenuate ΔFosB levels by promoting its degradation, while Compound C and chloroquine could block this effect. ConclusionsIn conclusion, our results suggest that long-term metformin treatment could promote ΔFosB degradation and thus attenuate the development of LID through activating the AMPK-mediated autophagy pathway. Overall, our results support the AMPK-mediated autophagy pathway as a novel therapeutic target for LID and also indicate that metformin is a promising therapeutic candidate for LID.

The NONRATT023402.2/rno-miR-3065-5p/NGFR axis affects levodopa-induced dyskinesia in a rat model of Parkinson’s disease

Levodopa-induced dyskinesia (LID) is a common motor complication in Parkinson’s disease. However, few studies have focused on the pathogenesis of LID at the transcriptional level. NONRATT023402.2, a long non-coding RNA (lncRNA) that may be related to LID was discovered in our previous study and characterized in rat models of LID. In the present study, NONRATT023402.2 was overexpressed by injection of adeno-associated virus (AAV) in striatum of LID rats, and 48 potential target genes, including nerve growth factor receptor (NGFR) were screened using next-generation sequencing and target gene predictions. The NONRATT023402.2/rno-miR-3065-5p/NGFR axis was verified using a dual luciferase reporter gene. Overexpression of NONRATT023402.2 significantly increased the abnormal involuntary movements (AIM) score of LID rats, activated the PI3K/Akt signaling pathway, and up-regulated c-Fos in the striatum. NGFR knockdown by injection of ShNGFR-AAV into the striatum of LID rats resulted in a significant decrease in the PI3K/Akt signaling pathway and c-Fos expression. The AIM score of LID rats was positively correlated with the expressions of NONRATT023402.2 and NGFR. A dual luciferase reporter assay showed that c-Fos, as a transcription factor, bound to the NONRATT023402.2 promoter and activated its expression. Together, the results showed that NONRATT023402.2 regulated NGFR expression via a competing endogenous RNA mechanism, which then activated the PI3K/Akt pathway and promoted c-Fos expression. This suggested that c-Fos acted as a transcription factor to activate NONRATT023402.2 expression, and form a positive feedback regulation loop in LID rats, thus, aggravating LID symptoms. NONRATT023402.2 is therefore a possible novel therapeutic target for LID.

Inhibition of striatal dopamine D5 receptor attenuates levodopa-induced dyskinesia in a rat model of Parkinson’s disease

Levodopa-induced dyskinesia (LID) is experienced by most patients of Parkinson’s disease (PD) upon the long-term use of the dopamine precursor levodopa. Striatal dopaminergic signaling plays a critical role in the pathogenesis of LID through its interactions with dopamine receptors. The specific roles of striatal dopaminergic D5 receptors in the pathophysiological process of LID are still poorly established. In the study, we investigated the role of striatal dopamine D5 receptor in LID by using PD rats with or without dyskinetic symptoms after chronic levodopa administration. The experimental results showed that the expression level of D5 receptors in the sensorimotor striatum of dyskinetic rats is significantly higher than that of the non-dyskinetic controls. The administration of levodopa increased c-Fos expression in a subpopulation of sensorimotor striatum neurons of dyskinetic rats, but not in non-dyskinetic rats. The majority of the c-Fos+ neurons activated by levodopa in the striatum are positive for D5 receptor staining. Intrastriatal injection of D1-like (D1 and D5) dopamine receptor antagonist, SCH-23390, significantly inhibited dyskinetic behavior in dyskinetic rats after the injection of levodopa, meanwhile, intrastriatal administration of SKF-83959, a partial D5 receptor agonist, yielded significant dyskinetic movements in dyskinetic rats without levodopa. In contrast, intrastriatal perfusion of small interfering RNA directed against DRD5 downregulated D5 receptors expression and moderately inhibited dyskinetic behavior of dyskinetic animals. Our data suggested that the striatal dopamine D5 receptor might play a novel role in the pathophysiology of LID.

Levodopa-induced Dyskinesia: Clinical Features, Pathophysiology, and Medical Management.

Levodopa-induced dyskinesia (LID) is commonly seen in Parkinson's disease patients treated with levodopa. This side effect is usually encountered after long duration of treatment, but occasionally, this may be seen even after few days or months of treatment. LID is broadly classified as peak-dose dyskinesia, wearing-off or off-period dyskinesia, and diphasic dyskinesia. Pathogenesis of LID is complex, and different neurotransmitters such as dopamine, glutamine, adenosine, and gamma-aminobutyric acid play important role altering the normal physiology of direct and indirect pathway of cortico-basal ganglia-thalamic loop responsible for fine motor control. Treatment of LID requires careful history taking and clinical examination to find the type of dyskinesia as different approach is required for different types. Changes in dopaminergic medication including continuous dopaminergic stimulation are very helpful in the management of peak-dose dyskinesia. Different types of surgical approaches including unilateral pallidotomy and deep brain stimulation have given very good result in patients, who cannot be managed by medications alone. The surgical management of LID is dealt with in detail in another review in this series.

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson's disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects. To explore this possibility, we used dual-tracer positron emission tomography to quantify regional cerebral blood flow and metabolic activity in 28 PD subjects (14 LID, 14 non-LID), scanned before and during intravenous levodopa infusion. Levodopa-mediated dissociation was most prominent in the posterior putamen (P < 0.0001) and greater in LID than in non-LID and test-retest subjects. Strikingly, LID subjects also showed increased sensorimotor cortex (SMC) activity in the baseline, unmedicated state. Imaging data from an independent PD sample (106 subjects) linked these differences to loss of mesocortical dopamine terminals in advanced patients. In aggregate, the data suggest that LID results from an overactive vasomotor response to levodopa in the putamen on a background of disease-related increases in SMC activity. LID may thus be amenable to treatment that modulates the function of these 2 regions.

Current treatment and future prospects of dopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are one of the main issues in the management of Parkinson's disease (PD); once these dyskinesias are established treatment becomes difficult, so preventive strategies should be first evaluated. Although levodopa (LD) treatment has recently been related as risk factor for LID, the main strategy to delay LID is to start PD treatment with dopamine agonists, adding LD at low doses. After LID onset, approaches include reducing single LD doses, reducing or discontinuing monoamine oxidase type B/catechol O-methyltransferase (MAO-B/COMT) inhibitors and extended-release (ER) LD. Amantadine represents the best antidyskinetic tool, and ER amantadine is the most promising upcoming antidyskinetic drug. New LD formulations such as IPX-066 (able to provide continuous dopaminergic stimulation) also represent promising new approaches. The involvement of a nondopaminergic system in the pathogenesis of LID suggests that the modulation of glutamate, serotonin and adenosine could have potential as new upcoming drug targets, but the role of such drugs will still need to be confirmed in randomized controlled trials.

Evidence of an association between sleep and levodopa-induced dyskinesia in an animal model of Parkinson's disease

Levodopa-induced dyskinesia (LID) represents a major challenge for clinicians treating patients affected by Parkinson's disease (PD). Although levodopa is the most effective treatment for PD, the remodeling effects induced by disease progression and the pharmacologic treatment itself cause a narrowing of the therapeutic window because of the development of LID. Although animal models of PD provide strong evidence that striatal plasticity underlies the development of dyskinetic movements, the pathogenesis of LID is not entirely understood. In recent years, slow homeostatic adjustment of intrinsic excitability occurring during sleep has been considered fundamental for network stabilization by gradually modifying plasticity thresholds. So far, how sleep affects on LID has not been investigated. Therefore, we measured synaptic downscaling across sleep episodes in a parkinsonian animal model showing dyskinetic movements similar to LID. Our electrophysiological, molecular, and behavioral results are consistent with an impaired synaptic homeostasis during sleep in animals showing dyskinesia. Accordingly, sleep deprivation causes an anticipation and worsening of LID supporting a link between sleep and the development of LID.

Abnormal expression of connexin 36 plays a role in the pathogenesis of levodopa induced dyskinesia in rat model of Parkinson’ s disease

Objective To explore whether gap junction disturbances are involved in the pathogenesis of levodopa-induced dyskinesia (LID). Methods The hemi-parkinsonian (PD) rat was treated intraperitoneally with L-dopa methylester (20 mg/kg) and benserazid (10 mg/kg) for 21 days and abnormal involuntary movement was evaluated to establish LID rat model. The experimental animals were divided into three groups: LID group, PD group and normal control group，respectively．The behavior responses of intraperitoneal injection of different doses of carbenoxolon and intracerebroventricular injection of quinine were observed to estimate the effects of gap junctional blockade on the abnormal involuntary movement (AIM) in the rat model of LID. Double immunofluorescence labeling was used to analyze the expression of connexin 36 (Cx36) in enkephalin positive medium spiny neurons and parvalbumin (PV) positive interneurons in the striatum. Western blottings was used to observe the expression of Cx36 in the striatum and moter cortex. Results Behavioral characteristics indicated that high dose of carbenoxolone (>60 mg/kg) intraperitoneal injection and intracerebroventricular injection of quinine (0.5，1.0，2.0 μmol/L, >2.5 μmol/L) could decrease the AIM score of LID rats. Western blotting indicated that expression of Cx36 in lesioned striatum and motor cortex of LID rat model was 219.56%±18.12% and 226.03%±16.33%, respectively, which induced a significant upregulation in comparison with the normal control group (104.05%±3.82%, t=15.389, P<0.01; 105.27%±2.82%，t=8.074, P<0.01) and untreated PD group (119.31%±8.92%, t=13.356, P<0.01; 138.20%±17.88%, t=5.872, P<0.01). Double immunofluorescence labeling staining revealed that Cx36 expression was increased in Enk-positive striatum neurons in LID model (57.59%±5.36%) compared with that in normal control group (32.67%±4.22%) and PD group (37.24%±0.86%, F=78.060, P<0.01). The expression of Cx36 in PV-positive interneurons was also elevated in LID group (68.49%±11.60%) in comparison with normal control group (40.43%±2.30%) and PD group (31.92%±5.68%, F=39.567, P<0.01). Conclusions The Cx36 expression is generally increased in lesioned striatum and motor cortex of LID rat model. In the striatum, the up-regulation of Cx36 is specifically observed in Enk-positive striatum neurons and in PV-positive interneurons. The dyskinesia behavior of LID rats can be significantly reduced by treatment with gap junction blockade. All these results suggest that gap junction dysfunction may play an important role in the pathogenesis of LID. Key words: Parkinson disease; Dyskinesias; Connexins; Gap junctions; Disease models, animal

Chapter Five - Adenosine Receptors and Dyskinesia in Pathophysiology

First, the recent progress in the pathogenesis of levodopa-induced dyskinesia was described. Serotonin neurons play an important role in conversion from levodopa to dopamine and in the release of converted dopamine into the striatum in the Parkinsonian state. Since serotonin neurons lack buffering effects on synaptic dopamine concentration, the synaptic dopamine markedly fluctuates depending on the fluctuating levodopa concentration in the serum after taking levodopa. The resultant pulsatile stimulation makes the striatal direct-pathway neurons get potential that releases excessive GABA into the output nuclei of the basal ganglia. When levodopa is administered, the stored GABA is released, the output nuclei become hypoactive, and then dyskinesias emerge. Second, effects of adenosine A2A receptor antagonists on dyskinesia were described. It has been demonstrated that the expression of adenosine A2A receptors is increased in Parkinson's disease (PD) patients with dyskinesias, suggesting that blockade of A2A receptors is beneficial for dyskinesias. Preclinical studies have shown that A2A receptor antagonists reduce liability of dyskinesias in PD models. Clinical trials have demonstrated that A2A antagonists increase functional ON-time (ON without troublesome dyskinesia) in PD patients suffering from wearing-off phenomenon, although they may increase dyskinesia in patients with advanced PD.

Ranitidine reduced levodopa-induced dyskinesia in a rat model of Parkinson&amp;rsquo;s disease

BackgroundChronic administration of levodopa in Parkinson’s disease leads to debilitating involuntary movements, termed levodopa-induced dyskinesia (LID). The pathogenesis of LID is poorly understood. Previous research has shown that histamine H2 receptors are highly expressed in the input (striatum) and output (globus pallidus, substantia nigra) regions of the basal ganglia, particularly in the GABAergic striatopallidal and striatonigral pathways. Therefore, a histamine H2 receptor antagonist could be used to reduce LID. In the present work, we investigated whether ranitidine has the potential to diminish LID in rats with dyskinesia and explored the underlying mechanisms involved.MethodsA rat model of PD was induced by 6-hydroxydopamine. Valid PD rats were then treated with levodopa (25 mg/kg, intraperitoneally) and benserazide (12.5 mg/kg, intraperitoneally) for 21 days to induce a rat model of LID. The acute and chronic effects of administration of ranitidine at different doses (5 mg/kg, 10 mg/kg, and 20 mg/kg) on abnormal involuntary movements, levodopa-induced rotations, and the forelimb adjusting steps test were investigated in LID rats. The chronic effect of ranitidine (10 mg/kg) on the expression of Arc and proenkephalin was also evaluated.ResultsLevodopa elicited increased dyskinesia in PD rats. Acute ranitidine treatment had no effect on LID, but chronic ranitidine administration (10 mg/kg, 20 mg/kg) reduced LID in rats with dyskinesia. Importantly, levodopa-induced rotations were not affected by chronic treatment with ranitidine. In addition, chronic ranitidine (10 mg/kg, 20 mg/kg) significantly improved stepping of the lesioned forepaw. Real-time polymerase chain reaction showed that Arc and proenkephalin levels were reduced by chronic ranitidine (10 mg/kg) in dyskinetic rats.ConclusionThese data indicate that ranitidine is a good adjunct for reducing LID in rats with dyskinesia. Inhibition of dopamine D1-mediated activation in the medium spiny neurons may account for the antidyskinetic effects of ranitidine in rats with dyskinesia.

Investigation of the antidyskinetic site of action of metabotropic and ionotropic glutamate receptor antagonists. Intracerebral infusions in 6-hydroxydopamine-lesioned rats with levodopa-induced dyskinesia

Long-term levodopa replacement therapy in Parkinson's disease is confounded by abnormal involuntary movements, known as levodopa induced dyskinesia (LID). Dysfunctional glutamatergic neurotransmission has been implicated in the pathogenesis of LID making metabotropic and ionotropic glutamate receptors attractive novel therapeutic targets. The objective of the present study was to investigate the antidyskinetic site of action of different glutamate receptor antagonists in the brain. For that purpose, metabotropic glutamate subtype 5 (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride, MTEP), NMDA NR2B selective ((aR,bS)-a-(4-Hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate, Ro 25-6981) and AMPA (2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, NBQX) receptor antagonists or saline were administered by intracerebral infusion in the caudate–putamen (CPu), the substantia nigra zona reticulata (SNr) or the subthalamic nucleus (STN) of 6-hydroxydopamine-lesioned rats exhibiting LID. Dyskinesia was assessed with the modified version of the rat Abnormal Involuntary Movements scale (AIMS). Ro 25-6981 and to a lesser extent NBQX improved dyskinesia (82% and 19% reduction in AIM score respectively) after infusion in the caudate–putamen. None of the three drugs managed to noticeably reduce AIM score after infusion in the SNr. MTEP was the only drug that produced a reduction in AIM score (48%) when infused in STN. In conclusion, while the striatum proved important in the antidyskinetic action of NMDA and AMPA receptor antagonists, the results of this study highlight also the importance of the metabotropic glutamate receptors that reside in the STN as therapeutic targets in the treatment of LID.

An Autoradiographic Study on the Pathogenesis of Levodopa-Induced Dyskinesia: Regulation of Dopamine Transporter by Levodopa in a Rat Model of Parkinson’s Disease

Background: The development of abnormal involuntary movements or dyskinesia is a serious complication of L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson’s disease (PD). Objective: To evaluate the correlation between dopamine transporter (DAT) regulated by L-DOPA and the pathogenesis of dyskinesia in PD rats. Methods: Thirty rats were used to establish the PD model by injecting 6-hydroxydopamine into the right medial forebrain bundle. The sham surgery rats (n = 4) received 4 µl of physiological saline. Then, 19 rats in which PD has been successfully induced were randomly assigned to the L-DOPA (20 mg/kg/day; n = 15) or model (saline; n = 4) group. After 4 weeks of treatment, ¹³¹I-N-(3-fluoropropyl)-2β-carbomethoxy-3 β-(4-iodophenyl)nortropane was injected into the rats, and images of DAT in the brain were acquired using a storage phosphor plate. The levels of DAT-specific radioactivity uptake in the bilateral corpora striata (left/right) were compared. Results: There was no difference in DAT-specific radioactivity uptake between the bilateral corpora striata in the sham surgery rats. The images were clear and symmetrically distributed in the corpora striata. In PD model rats, the DAT-specific radioactivity uptake decreased on the lesioned side and the ratios of uptake between the corpora striata were increased. Accumulation of the radioligand on the lesioned side was sparse. In the L-DOPA group, the average ratio values were significantly increased in dyskinetic rats and reduced in nondyskinetic rats. In addition, the differences between the bilateral corpora striata were reduced in nondyskinetic rats. Conclusion: L-DOPA was shown to downregulate DAT in some PD model rats. That process may be involved in the pathogenesis of dyskinesia.

Regional changes in type 1 cannabinoid receptor availability in Parkinson's disease in vivo

The type 1 cannabinoid receptor (CB1) is a crucial modulator of synaptic transmission in brain and has been proposed as a potential therapeutic target in Parkinson's disease (PD), especially for treatment of levodopa-induced dyskinesias (LID). Our aim was to measure CB1 levels in brains of PD patients in vivo and to investigate the relation between CB1 availability and LID. We studied 12 healthy controls and 29 PD patients (9 drug-naïve patients with early PD, 10 patients with advanced PD and LID, and 10 patients with advanced PD without LID). PD patients were examined using the Unified Parkinson's Disease Rating Scale (UPDRS) and the modified Abnormal Involuntary Movement Scale (mAIMS). All subjects underwent positron emission tomography (PET) with the CB1-selective radioligand [18F] MK-9470 and magnetic resonance imaging (MRI). PD patients showed an absolute decrease in CB1 availability in the substantia nigra. By contrast, CB1 availability was relatively increased in nigrostriatal, mesolimbic, and mesocortical dopaminergic projection areas. CB1 availability did not differ significantly between advanced PD patients with and without LID. Within the group of PD patients with LID, there was no significant correlation between CB1 availability and LID severity. These data demonstrate regional changes in CB1 availability in PD in vivo, but do not support a role for dysregulation of CB1 levels in the pathogenesis of LID.

Effect of antisense FosB and CREB on the expression of prodynorphin gene in rats with Levodopa-induced dyskinesias

The effects of antisense FosB and CREB intra-striatum injection on the expression of prodynorphin (PDyn) gene in striatal neurons of Levodopa-induced dyskinesias (LID) rats with Parkinson disease (PD) were explored. PD model in rats was established by 6-OHDA microinjection stereotaxically. The rats were treated with chronic intermittent Levodopa celiac injection for 28 days to get the LID rats. Antisense FosB and cAMP response element-binding protein (CREB) were injected into striatum of all rats respectively. In situ hybridization was used to measure the changes in the expression of PDyn mRNA in striatum and behavior changes were observed. The results showed after administration of antisense FosB, abnormal involuntary movement (AIM) was decreased and the expression of PDyn mRNA in striatum was increased in LID rats as compared with sense FosB group (P<0.01, respectively). As compared with the control group, the expression of PDyn mRNA in striatum was decreased by antisense CREB-treated LID group (P<0.01) and compared with sense CREB treated LID group, antisense CREB-treated LID group showed no changes in AIM scores and the expressions of PDyn mRNA (both P>0.05). In conclusion, FosB protein, which replaced the CREG, could regulate the expression of PDyn mRNA and play critical role in the pathogenesis of LID.

Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Taking advantage of a monkey brain bank constituted to study the pathophysiology of levodopa-induced dyskinesia, we here report the changes affecting D1, D2 and D3 dopamine receptors within the striatum of four experimental groups of non-human primates: normal, parkinsonian, parkinsonian treated with levodopa without or with dyskinesia. We also report the possible role of arrestin and G protein-coupled receptor kinases.

Topiramate reduces levodopa‐induced dyskinesia in the MPTP‐lesioned marmoset model of Parkinson's disease

Overactive AMPA receptor-mediated transmission may be involved in the pathogenesis of levodopa-induced dyskinesia. The mechanism of action of the anticonvulsant drug topiramate involves attenuation of AMPA receptor-mediated transmission. In this study, the potential antidyskinetic action of topiramate was examined in the MPTP-lesioned marmoset model of Parkinson's disease and levodopa-induced dyskinesia. Topiramate significantly reduced levodopa-induced dyskinesia, without affecting the antiparkinsonian action of levodopa. Topiramate represents an exciting potential novel therapeutic approach to levodopa-induced dyskinesia in patients with Parkinson's disease.

Opioid antagonists increase the dyskinetic response to dopaminergic agents in parkinsonian monkeys: interaction between dopamine and opioid systems

The pathogenesis of levodopa-induced dyskinesias (LID) still remains obscure. It has been suggested that enhanced opioidergic transmission in striatal output pathways may play a role in the induction of LID. To test this hypothesis, we have investigated the effect of different doses of the opioid receptor antagonists, naloxone and naltrexone on the dyskinetic response to a D1 agonist SKF 82958, a D2 agonist quinpirole and l-3,4-dihydroxyphenylalanine ( l-Dopa). We have used six female cynomolgus monkeys rendered parkinsonian by the toxin MPTP and presenting a stable parkinsonian syndrome. All responded to l-Dopa and had developed dyskinesias which were manifested with each dose. The parkinsonian syndrome and dyskinesias were evaluated for each animal and scored after the treatments. Locomotor activity was measured by an electronic motility monitoring system. Our results show that coadministration of naloxone or naltrexone with dopaminergic agents leads to a significant increase in the severity of dyskinesias without noticeable effect on the antiparkinsonian efficacy of the treatment. These results suggest that increased opioidergic transmission in the two major striatal output pathways in monkeys or humans with LID might be an attempt to dampen the effect of abnormal dopaminergic stimulation rather than the cause of dyskinesias.

Naloxone reduces levodopa-induced dyskinesias and apomorphine-induced rotations in primate models of parkinsonism.

Using in situ hybridization, it was found that subchronic treatment with levodopa/benserazide increased preproenkephalin-A and preproenkephalin-B mRNAs in the dopamine-depleted striatum. In order to examine whether dysfunction of the endogenous opioid system may underlie the development of levodopa-induced dyskinesias, the effect of naloxone, an opioid antagonist, on dyskinesias was investigated in two models of parkinsonism in the common marmoset. MPTP-treated monkeys were administered a daily oral dose of levodopa/benserazide which relieved the parkinsonian symptoms but induced severe and reproducible dyskinetic movements. Naloxone (0.1, 0.2 or 0.5 mg/kg) was given subcutaneously (s.c.) during peak-dose dyskinesia, which reduced the dyskinesias significantly using the highest dose, normalized the motor activity, but did not modify the antiparkinson effect. Unilaterally 6-OHDA -lesioned marmosets received apomorphine s.c., which caused a contralateral turning behavior that could be reduced up to 35 percent by concomitant administration of naloxone. Taken together the present results suggest a possible role for the endogenous opioid system in the pathogenesis of levodopa-induced dyskinesia in primates.

Rapid development of dopaminergic supersensitivity in reserpine-treated rats demonstrated with 14C-2-deoxyglucose autoradiography

Dopaminergic denervation supersensitivity has been implicated in the pathogenesis of levodopa-induced dyskinesias, the most common and limiting side effect in the drug treatment of Parkinson's disease, yet the mechanisms that mediate altered drug sensitivity remain poorly understood. In animals models, one key component of denervation supersensitivity is the enhanced efficacy of selective D1 agonists to stimulate locomotion. In rats with chronic dopamine depletion induced by 6-hydroxydopamine nigral lesion, the increased ability of D1 agonists to stimulate regional cerebral glucose utilization (RCGU) in the substantia nigra pars reticulata (SNr) has provided a metabolic correlate to the heightened motor response. In this study, we used the stimulation of RCGU in the SNr as a sensitive in vivo assay of D1 agonist effect to examine the time course of development of supersensitivity in rats following acute dopamine depletion with single doses of reserpine (5.0 mg/kg, i.p.) and alpha-methyl-p-tyrosine (AMPT; 100 mg/kg, i.p.). The stimulatory effect of the D1 agonist SKF 38393 (30 mg/kg) on RCGU in the SNr was first enhanced 6 hr after reserpine/AMPT injection and was maximally enhanced at 12-24 hr (relative 2-deoxyglucose uptake increased 32-51%; P less than 0.05). The response to SKF 38393 returned to control values 5 d after reserpine/AMPT injection. The single reserpine/AMPT injections depleted striatal dopamine to 1-2% of control values from 3-48 hr postinjection, whereas D1 and D2 dopamine receptor densities were unchanged at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)