L-stepholidine reduced L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) remains a challenge in Parkinson's disease (PD) drug therapy. In the present study, we examined the effect of L-stepholidine (L-SPD), a known dual dopamine receptor agent, on LID in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model. Daily administration of L-DOPA to PD rats for 22 days induced steady expression of LID, co-administration of L-SPD with L-DOPA significantly ameliorated LID without compromising the therapeutic potency of L-DOPA, indicating that L-SPD attenuated LID development. L-SPD alone elicited stable contralateral rotational behavior without inducing significant dyskinesia. Acute administration of L-SPD to rats with established LID produced significant relief of dyskinesia; this effect was mimicked by D(2) receptor antagonist haloperidol, but blunted by 5-HT(1A) receptor antagonist WAY100635. Furthermore, the mRNA level of 5-HT(1A) decreased significantly on 6-OHDA-lesioned striata, whereas chronic L-SPD treatment restored 5-HT(1A) receptor mRNA level on the lesioned striata. The present data demonstrated that L-SPD elicited antidyskinesia effects via both dopamine (D(2) receptor antagonistic activity) and nondopamine (5-HT(1A) agonistic activity) mechanisms.     

Functional neuroimaging of the 6-OHDA lesion rat model of Parkinson's disease

We characterized the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat, a well-known acute model of Parkinson's disease (PD), with [(18)F]-fluoro-2-deoxy-d-glucose (FDG) small-animal positron emission tomography (PET), which we compared with a drug-induced rotation behavioral test. In the 6-OHDA model, significant glucose hypometabolism was present in the primary motor cortex, substantia nigra, and pedunculopontine tegmental nucleus on the ipsilateral side. In contrast, neuronal activations were observed in the primary somatosensory cortex and ventral caudate-putamen area after lesioning. Correlation analysis revealed a significant relationship between the behavioral results and the degree of glucose metabolism impairment in the primary motor cortex, substantia nigra, and pedunculopontine tegmental nucleus. In addition, the pedunculopontine tegmental nucleus correlated significantly with the primary somatosensory cortex, the ventral caudate-putamen, the substantia nigra, and the primary motor cortex. Furthermore, the primary motor cortex also showed significant correlations with the substantia nigra. In conclusion, In vivo cerebral mapping of the 6-OHDA-lesioned rats using [(18)F]-FDG PET showed correspondence at the functional levels to the cortico-subcortical network impairment observed in PD patients.     

L-DOPA-induced air-stepping in the preweanling rat: electromyographic and kinematic analyses

Ontogenetic changes in intralimb coordination may result from maturation of the central pattern for locomotion, maturation of peripheral efferents, changes in afferent modulation of the centrally generated pattern, interactions with the substrate, biomechanical changes within the limb itself, or a combination of these. Electromyograms obtained from three hindlimb extensors of rats on Postnatal Days (PND) 5, 10, 15, or 20, during episodes of coordinated L-DOPA-induced air-stepping, showed that muscle activation preceded extension of the corresponding joints at all ages. The delay between the onset of extensor activity and the onset of joint extension increased during ontogeny and was greatest at PND 20. Ontogenetic changes in the relative timing of muscle activity and corresponding joint movements probably resulted from changes in biomechanical factors, changes in afferent modulation of central motor output, or both.     

Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia

L-DOPA-induced dyskinesia, the rate-limiting side effect in the therapy of Parkinson's disease, is mediated by activation of mammalian target of rapamycin (mTOR) signaling in the striatum. We found that Ras homolog enriched in striatum (Rhes), a striatal-specific protein, binds to and activates mTOR. Moreover, Rhes(-/-) mice showed reduced striatal mTOR signaling and diminished dyskinesia, but maintained motor improvement on L-DOPA treatment, suggesting a therapeutic benefit for Rhes-binding drugs.     

Comparison of adrenal and foetal nigral grafts on drug-induced rotation in rats with 6-OHDA lesions

Summary Separate groups of rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received intrastriatal foetal (E14) substantia nigra suspension grafts, intrastriatal postnatal (P22–25) adrenal medulla suspension grafts using either collagenaseor trypsin-based dissociation procedures, intraventricular adrenal medulla grafts, or remained with lesions alone. Rats with nigral or adrenal suspension grafts, but not rats with adrenal solid grafts, showed reduced apomorphine-induced rotation in comparison with lesion rats. The nigral graft group alone showed substantial reduction of amphetamine-induced rotation, and this was the only group manifesting good long-term graft survival. These results indicate that nigral and adrenal grafts do not have comparable mechanisms of functional action, and suggest that adrenal grafts can ameliorate apomorphine-induced rotation by a non-specific mechanism.     

Effects of neostriatal 6-OHDA lesion on performance in a rat sequential reaction time task

Work in humans and monkeys has provided evidence that the basal ganglia, and the neurotransmitter dopamine therein, play an important role for sequential learning and performance. Compared to primates, experimental work in rodents is rather sparse, largely due to the fact that tasks comparable to the human ones, especially serial reaction time tasks (SRTT), had been lacking until recently. We have developed a rat model of the SRTT, which allows to study neural correlates of sequential performance and motor sequence execution. Here, we report the effects of dopaminergic neostriatal lesions, performed using bilateral 6-hydroxydopamine injections, on performance of well-trained rats tested in our SRTT. Sequential behavior was measured in two ways: for one, the effects of small violations of otherwise well trained sequences were examined as a measure of attention and automation. Secondly, sequential versus random performance was compared as a measure of sequential learning. Neurochemically, the lesions led to sub-total dopamine depletions in the neostriatum, which ranged around 60% in the lateral, and around 40% in the medial neostriatum. These lesions led to a general instrumental impairment in terms of reduced speed (response latencies) and response rate, and these deficits were correlated with the degree of striatal dopamine loss. Furthermore, the violation test indicated that the lesion group conducted less automated responses. The comparison of random versus sequential responding showed that the lesion group did not retain its superior sequential performance in terms of speed, whereas they did in terms of accuracy. Also, rats with lesions did not improve further in overall performance as compared to pre-lesion values, whereas controls did. These results support previous results that neostriatal dopamine is involved in instrumental behaviour in general. Also, these lesions are not sufficient to completely abolish sequential performance, at least when acquired before lesion as tested here.     

Behavioral effects after ibotenic acid, 6-OHDA and electrolytic lesions in the central amygdala nucleus of the rat

Selective lesions of central amygdaloid neurons with ibotenic acid and electrolytic destruction of the nucleus both led to marked increases in open field activity and activity during passive avoidance conditioning. However, electrolytic lesions of both neurons and fibers resulted in the most pronounced passive avoidance impairments and it is suggested that this lesion effect should be attributed to a combined destruction of intrinsic neurons and neurons located outside the central amygdala nucleus. The 6-OHDA lesions resulted in no significant changes in the behavioral parameters under investigation or in plasma corticosterone levels. The lack of reduced corticosterone levels in any of the lesioned groups do not indicate that general fear arousal is critically dependent on intact central amygdala neurons in the rat. The behavioral data are, however, still compatible with a hypothesis of a temporary reduction in fear arousal during the initial phase of the passive avoidance conditioning.     

Tardive dyskinesia: a 3-year follow-up study

A prospective study of tardive dyskinesia was carried out to gain information regarding the natural history of the condition and to identify risk factors. Out of an original cohort of 182 psychiatric patients receiving maintenance antipsychotic drugs 99 were available for reassessment after 3 years. In this follow-up group the point prevalence of oro-facial dyskinesia increased from 39% to 47% over the 3-year period. Twenty-two patients developed the disorder, while remission occurred in 14 others. Risk factors predicting the presence of oro-facial dyskinesia at follow-up included being over 50 years of age and the presence of akathisia. There was no convincing association between the duration of antipsychotic drug treatment and the presence or severity of oro-facial dyskinesia. Patients receiving over 1000 mg chlorpromazine equivalents of antipsychotic drug per day were unlikely to have the condition. The amount of purposeless trunk and limb movement present proved to be a relatively stable phenomenon, showing only a slight increase with age and no change over the follow-up period. The implications of these findings are discussed, with particular consideration being given to the effects of loss of patients to follow-up.     

Acquisition and performance in a rat sequential reaction time task is not affected by subtotal ventral striatal 6-OHDA lesions

Based on findings of experiments with humans, non-human primates and rodents, it is commonly accepted that dopaminergic basal ganglia processes play a crucial role in procedural and sequential learning. Primal evidence for this hypothesis came from serial reaction time tasks (SRTT) studies, demonstrating that healthy controls show increased reaction times when visual stimulus presentation switches from a previously learned sequence to random stimulus presentation. This so-called interference effect was reduced in patients with Parkinson's disease. Since ethical and methodical aspects limit neurobiological research in human subjects, we developed a rat version of the human SRTT, which can be used to study experimentally induced brain damage. In the present experiment we investigated the effects of bilateral 6-OHDA lesions of the ventral striatum on sequential learning. The lesions led to subtotal dopaminergic depletions in the ventral striatum (58–60%) and also minor depletions in the medial neostriatum (32–46%). These lesions impaired task acquisition only moderately and did not worsen sequential performance since lesion and control animals showed a comparable interference effect when the trained sequence was tested against random stimulus presentation or violated sequences. In contrast, in an earlier SRTT experiment with medial neostriatal dopaminergic lesions (58–66%), the lesion animals were clearly impaired in their sequential learning as compared to controls. Therefore, we assume that subtotal dopamine loss in the medial neostriatum, rather than the ventral striatum, has a substantial effect on sequential learning.     

Amphetamine-induced behavioral phenotype in a hypoxanthine-guanine phosphoribosyltransferase-deficient mouse model of Lesch-Nyhan syndrome.

In humans, congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a disorder known as the Lesch-Nyhan syndrome. Patients with this disorder exhibit a prominent neurobehavioral phenotype that results in part from dysfunction of catecholaminergic systems in the striatum. HPRT-deficient mice produced as animal models for this syndrome curiously exhibit no spontaneous neurobehavioral abnormalities. However, the present study demonstrates that HPRT-deficient mice are more sensitive than their HPRT-normal littermates to the ability of amphetamine to stimulate locomotor or stereotypic behaviors. This behavioral supersensitivity to amphetamine indicates the existence of an underlying subclinical abnormality of catecholaminergic systems in the brains of HPRT-deficient mice, analogous to findings in human Lesch-Nyhan patients.     

帕金森病大鼠黑质小胶质细胞及星形胶质细胞的变化

目的探讨帕金森病(PD)发病中黑质小胶质细胞和星形胶质细胞的变化。方法采用立体定向术将神经毒素6-羟基多巴胺(6-OHDA)注入大鼠右侧黑质和内侧前脑束内,制备大鼠PD模型。将制模成功的16只PD大鼠随机分为2周和8周模型组,另6只正常大鼠作为对照组。观察各组大鼠黑质致密带内多巴胺(DA)能神经元、OX-42(小胶质细胞的特异性标志物)及神经胶质纤维酸性蛋白(GFAP,星形胶质细胞的特异性标志物)阳性细胞的分布和形态变化。结果 2周和8周模型组损毁侧黑质致密部DA能神经元较健侧显著减少(P0.01),损毁侧OX-42阳性细胞的数量较健侧明显增加(P0.01),形态呈"阿米巴状"。损毁侧GFAP阳性细胞数量较健侧明显增加(P0.01),突起变短,染色加深。2周模型组和8周模型组DA能神经元及两种胶质细胞的变化情况相似。结论 PD大鼠模型中存在着小胶质细胞和星形胶质细胞的激活,且两种胶质细胞的活化程度在PD发病过程中的不同时间无明显差别。     

Increase in the effectiveness of somatodendritic 5-HT-1A receptors in a rat model of tardive dyskinesia

The present study concerns responsiveness of pre- and postsynaptic 5-hydroxytryptamine (5-HT)-1A receptors in a rat model of tardive dyskinesia (TD). Vacuous chewing movements (VCMs) in rats are widely accepted as an animal model of TD. Results show that haloperidol injected at a dose of 1 mg/kg twice a day for 5 weeks elicited VCMs, which increased in a time dependent manner following the drug administration for 3-5 weeks. Tolerance was produced in motor coordination during the potentiation of VCMs. Exploratory activity in an open field and in an activity box decreased in haloperidol treated animals. The effects of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 0.5 mg/kg) were monitored 48-h after withdrawal from repeated administration of haloperidol. 8-OH-DPAT-induced locomotion was greater in haloperidol treated rats. 5-HT synthesis increased in haloperidol treated animals, while 8-OH-DPAT-induced decreases of 5-HT synthesis were greater in repeated haloperidol than repeated saline injected animals. The results suggest that an increase in the effectiveness of somatodendritic 5-HT-1A receptors may decrease the inhibitory influence of 5-HT on the activity of dopaminergic neurons to precipitate VCMs. The 5-HT-1A agonist may help to alleviate neuroleptic-induced TD.     

Cardiovascular effects of central 6-OHDA treatment: a comparison of indirect and direct measurements

The effect of intracerebro-ventricular treatment with 6-hydroxydopamine on blood pressure and heart rate was studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls (WKY). When measured with the indirect tail-cuff method, the development of hypertension was found to be markedly inhibited in 6-OHDA treated SHR, while blood pressure was slightly lower in treated WKY. Heart rate was lower in both strains, although the greatest effect was found in SHR. In contrast, direct measurement via an arterial cannula indicated significantly lower blood pressure in 6-OHDA treated SHR only. Heart rate was by this method found to be not different between the SHR groups, but was increased in treated WKY. These results indicate that the mild stress of indirect blood pressure determinations has a marked influence on the results found.     

Decreased striatal opiate delta-receptors in the rat model of persistent dyskinesia induced by iminodipropionitrile

Chronic administration of iminodipropionitrile (IDPN) causes a persistent behavioral syndrome which consists of hyperactivity, vertical neck dyskinesias and lateral head twitches. D-Ala-D-Leu-enkephalin binding revealed a 26% decrease in the number but no change in the affinity of delta-opiate receptors in the striata of IDPN-treated rats. These findings are similar to those seen in the brains of patients with Huntington's disease. Further studies are needed to clarify the relationship of these findings to the phenomenology of the IDPN-induced dyskinetic abnormalities.     

Ibotenic acid lesions of the striatum reduce drug-induced rotation in the 6-hydroxydopamine-lesioned rat

Lesions of the dopaminergic nigrostriatal tract produce a range of motor and sensorimotor deficits. One of the simplest and most reliable is the rotational response of the animal following activation with drugs that stimulate the dopaminergic network, most notably amphetamine and apomorphine. Consequently, the rotation test has been extensively used in assessing the success of treatments designed to restore dopaminergic function, including neural transplants. The present study investigates whether rotation induced by 6-hydroxydopamine lesions of the nigrostriatal bundle in rats is modified by additional lesions in the neostriatum. It was found that apomorphine-induced rotation can be reduced by ibotenic acid lesions of the dopamine-deafferented striatum, and that the extent of the reduction was proportional to the size of the lesions. In contrast, such lesions produced a non-significant reduction in amphetamine-induced rotation, although the correlation between the extent of the reduction and the size of the lesion was again apparent. Since the pattern of change was similar in direction, albeit smaller in magnitude, than the previously reported effects of intrastriatal transplantation in rats with similar nigrostriatal lesions, rotation tests alone do not provide an unequivocal test of graft survival and function.     

Alterations of Hrd1 expression in various encephalic regional neurons in 6-OHDA model of Parkinson's disease

The ubiquitin-proteasome system plays a central role in regulated degradation of cellular proteins under different physiological conditions. Accumulation of misfolded proteins is involved in the pathogenesis of many neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD). Hrd1 is a newly identified ubiquitin ligase involved in degradation of misfolded proteins from the endoplasmic reticulum (ER), thereby protecting cells against ER stress. Increasing evidence has linked ER stress to PD pathogenesis. However, the expression of Hrd1 in PD brain remains elusive. In the present study, the expression of Hrd1 in different encephalic regions was studied in 6-OHDA model of Parkinson's disease by immunohistochemistry. The results showed that Hrd1 was up-regulated in 6-OHDA-treated mice in various encephalic regional neurons, especially those in hippocampus, substantia nigra (SN), subthalamic nucleus (STN), striatum and frontal lobe. It suggested that Hrd1 up-regulation may represent a protective response against neurodegeneration in PD.     

环孢菌素A结合神经干细胞移植对6-OHDA大鼠PD模型的作用

目的:观察环孢菌素A(cyclosporine A,CsA)结合神经干细胞(neural stem cells,NSCs)移植对于6-OHDA大鼠PD模型的作用。方法:SD大鼠随机分为四组:(1)正常组;(2)模型组;(3)NSCs组;(4)NSCs+CsA组。APO诱导旋转测试、悬挂实验、自发实验观察行为学改变,高效液相色谱(HPLC)检测纹状体多巴胺(dopamine,DA)含量。移植术后1、2、4周,ELISA检测纹状体TNF-α、IL-1β、IFN-γ、IL-4的含量,免疫组化观察移植部位细胞的变化。结果:与模型组相比,移植组大鼠的旋转次数减少(P0.05),悬挂评分提高(P0.05),自发总活动度增加(P0.05),纹状体DA含量升高(P0.05),且NSCs+CsA组优于NSCs组(P0.05)。移植组的TNF-α、IL-1β三个时间点均低于模型组,且NSCs+CsA组抑制TNF-α、IL-1β的作用强于NSCs组(P0.05);移植组的IL-4、IFN-γ三个时间点均高于模型组(P0.05),但NSCs+CsA组的IFN-γ低于NSCs组(P0.05)。细胞的存活增殖迁移状态在2周时较好,4周时较差。与NSCs组相比,NSCs+CsA组的迁移细胞形态瘦长,4周时EGFP活细胞较多(P0.05)。GFAP+细胞数:NSCs+CsA组NSCs组;小胶质细胞数:模型组NSCs组NSCs+CsA组。结论:NSCs移植可改善PD大鼠行为障碍,增加纹状体DA含量,有利于营造良好的脑内微环境,加用CsA可提高其疗效。