The “motor complication syndrome” in rats with 6-OHDA lesions treated chronically with l-DOPA: Relation to dose and route of administration

Lindgren, Hanna; Rylander, Daniella; Ohlin, Karin; Lundblad, Martin; Cenci, M. Angela

doi:10.1016/j.bbr.2006.09.019

Cited by 96 publications

(69 citation statements)

References 53 publications

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“…But other studies have reported that virtually all rats with sufficient levels of dopamine depletion develop signs of LID as measured by elevated AIM scores. However, the high incidence of LID in some studies might be attributed to the use of supratherapeutic doses of levodopa that are given for longer than the 15-day period used in our present study Lindgren et al, 2007). Furthermore, others have reported that severe dopamine depletion as measured by Ͼ95% loss of TH-positive cells in the SNC allows LID to appear in all rats Paillé et al, 2004).…”

Section: Discussionmentioning

confidence: 58%

“…Using unilateral 6-OHDA-lesioned rats, levodopa-induced abnormal involuntary movements (AIMs) are rated on a scale of 0 to 4 for each of four categories: 1) limb dyskinesia, 2) axial dystonia, 3) orolingual movements, and 4) rotational behavior. However, a review of published studies using the AIM rating scale produces a confusing picture of the incidence of LID in hemi-parkinsonian rats, with some studies reporting that virtually all rats show significant dyskinesia after chronic levodopa treatment Konitsiotis and Tsironis, 2006;Lindgren et al, 2007), whereas others report that approximately half either do or do not develop LID in an all-or-nothing fashion (Cenci et al, 1998;Picconi et al, 2003;Taylor et al, 2005;Carta et al, 2006). The reason for these different outcomes is not clear, but the dose of levodopa and magnitude of dopamine depletion are important variables in LID that have not been adequately characterized thus far.…”

Section: Abbreviationsmentioning

confidence: 99%

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Evaluation of Levodopa Dose and Magnitude of Dopamine Depletion as Risk Factors for Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease

Putterman

Munhall

Kozell

et al. 2007

J Pharmacol Exp Ther

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Levodopa dose and severity of Parkinson's disease (PD) are recognized risk factors for levodopa-induced dyskinesia (LID) in humans. The purpose of the present study was to evaluate the ability of these variables to predict severity of LID in a rat model of PD. Varied concentrations of 6-hydroxydopamine were injected into the midbrain to produce wide ranges of dopamine depletion in striatum. Three weeks later, rats were given daily injections of levodopa (2-10 mg/kg i.p.) plus benserazide (12.5 mg/kg i.p.) for 15 days. Abnormal involuntary movements (AIMs) were measured for limb, axial, orolingual, and rotatory movements. Dose-response analysis for total AIM scores yielded a levodopa ED 50 value of 3.2 mg/kg on treatment day 15. There were strong interrelated correlations between individual AIM categories ( Ͼ 0.7) and for each AIM category in regard to total AIM score ( Ͼ 0.7). In rats that received levodopa doses that were greater than the ED 50 , rates of amphetamine-induced rotation were significantly correlated with total AIM scores ( ϭ 0.413). However, of those rotating Ͼ5 times/min, 34% had relatively low AIM scores (Ͻ8). Likewise, there was a significant correlation between percentages of tyrosine hydroxylase (TH) loss and total AIM scores ( ϭ 0.388). However, in those rats that had Ͼ85% TH loss, 30% had AIM scores Ͻ8. Our results show that given an adequate dose and magnitude of striatal dopamine depletion, levodopa produces dyskinesia with a continuous spectrum of severity. Although levodopa dose and level of dopamine depletion are significant risk factors for LID, we conclude that other factors must contribute to LID susceptibility.The tremor, rigidity, and akinesia of Parkinson's disease (PD) are caused by progressive loss of dopamine innervation in the basal ganglia. Symptoms of PD can be largely alleviated by treatment with the dopamine precursor levodopa. However, chronic treatment is often complicated by the emergence of levodopa-induced dyskinesia (LID), which is characterized by involuntary choreiform or dystonic movements of the face, trunk, or limbs. After 1 year of levodopa treatment, more than 60% of PD patients reportedly show signs of LID, and new cases occur at an incidence of 10% per year (Grandas et al., 1999). Risk factors for LID include young age of PD onset, duration and dose of levodopa treatment, severity and duration of PD symptoms, and female gender (Nutt, 1992;Schrag and Quinn, 2000;Zappia et al., 2005). However, it is also clear that not all PD patients develop LID despite the presence of multiple risk factors. Because LID can severely limit the usefulness of levodopa treatment (Hurtig, 1997), this has prompted much research aimed at discovering mechanisms that underlie the development of LID in PD.In the last few decades, there has been steady advancement in using the hemi-parkinsonian rat to investigate LID. In this model of PD, rats receive a unilateral intracerebral injection of 6-hydroxydopamine (6-OHDA) that causes ipsilateral destruction of dopamine-containing ne...

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Section: Discussionmentioning

confidence: 58%

Section: Abbreviationsmentioning

confidence: 99%

Evaluation of Levodopa Dose and Magnitude of Dopamine Depletion as Risk Factors for Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease

Putterman

Munhall

Kozell

et al. 2007

J Pharmacol Exp Ther

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“…Several approaches were used to evaluate the effect of nicotine treatment on motor function in rats with a unilateral nigrostriatal lesion. One of these involved measurement of dopaminergic drug-induced rotational behavior using a computerized system (ROTOMAX, AccuScan System; AccuScan Instruments, Inc.) (Mabandla et al, 2004;Howells et al, 2005;Steiner et al, 2006;Lindgren et al, 2007). This test has been extensively used for 6-OHDA-lesioned rats because it is objective, reliable, and provides a good index of dopaminergic denervation (Meredith and Kang, 2006).…”

Section: Nicotine Administration Via Minipumpmentioning

confidence: 99%

Continuous and Intermittent Nicotine Treatment Reduces l-3,4-Dihydroxyphenylalanine (l-DOPA)-Induced Dyskinesias in a Rat Model of Parkinson's Disease

Bordia

Campos²,

Huang³

et al. 2008

J Pharmacol Exp Ther

110

128

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The development of abnormal involuntary movements (AIMs) or dyskinesias is a serious complication of L-DOPA [L-3,4-dihydroxyphenylalanine] therapy for Parkinson's disease. Our previous work had shown that intermittent nicotine dosing reduced L-DOPA-induced dyskinetic-like movements in nonhuman primates. A readily available nicotine formulation is the nicotine patch, which provides a constant source of nicotine. However, constant nicotine administration more readily desensitizes nicotinic receptors, to possibly yield alternate behavioral outcomes. Therefore, we investigated whether constant nicotine administration reduced L-DOPAinduced AIMs in a rat parkinsonian model, with results compared with those with intermittent nicotine dosing. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion were exposed to either intermittent (drinking water) or constant (minipump) nicotine for Ն2 weeks at doses that yielded plasma levels of the nicotine metabolite cotinine similar to those in smokers. The rats were next treated with L-DOPA/ benserazide (8 or 12 mg/kg/15 mg/kg) for Ն3 weeks to allow for the development of AIMs, with nicotine treatment continued. Both modes of nicotine administration resulted in Ն50% decline in L-DOPA-induced AIMs. Nicotine treatment also significantly reduced AIMs in L-DOPA-primed rats using either dosing regimen, whereas nicotine removal led to an increase in AIMs. There was no effect of nicotine on various measures of motor performance in 6-OHDA-lesioned rats. In summary, nicotine provided either via the drinking water or minipump reduced L-DOPA-induced AIMs in a rat model of Parkinson's disease. These results suggest that either intermittent or constant nicotine treatment may be useful in the treatment of L-DOPA-induced dyskinesias in patients with Parkinson's disease.Dyskinesias are a complication of L-DOPA treatment that eventually develop in the majority of patients with Parkinson's disease (Fabbrini et al., 2007;Singh et al., 2007;Santini et al., 2008). These abnormal movements can be quite debilitating and represent a major drawback to continued L-DOPA therapy. A variety of drugs targeting various neurotransmitter systems in the basal ganglia have been reported to exert beneficial effects against dyskinetic-like movements in parkinsonian animal models, including the glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid systems (Brotchie, 2005;Fox et al., 2006;Fabbrini et al., 2007). However, management of L-DOPA-induced side effects in patients with Parkinson's disease continues to represent a serious therapeutic challenge.Therefore, there is a continual search for new approaches and alternative agents that may reduce this side effect associated with L-DOPA therapy. One drug that has recently been shown to attenuate L-DOPA-induced dyskinetic-like movements in nonhuman primates is nicotine (Quik et al., 2007b). Nicotine may exert this effect by acting on nicotinic acetylcholine receptors, which are present on dopaminergic terminals in the striatum and ...

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“…Stable AIMs, resembling peak dose dyskinesias in patients, were induced in the animals by daily injections of 6 mg/kg L-DOPA (Research Organics, Cleveland, OH) in combination with 15 mg/kg benserazide hydrochloride (a peripheral decarboxylase inhibitor; Sigma) for 28 d. The L-DOPA and the benserazide was mixed and dissolved in physiological saline and administered to each rat as a subcutaneous injection. This route of administration has been adopted after the findings of Lindgren et al (2007) suggesting that the subcutaneous injections gave more consistent and reliable L-DOPA response compared with the intraperitoneal route. The dyskinetic animals were allocated to one of the four experimental groups (see above), and kept on a maintenance regimen of twice-weekly L-DOPA injections for an additional 29 weeks (Lee et al, 2000).…”

Section: Behavioral Analysismentioning

confidence: 99%

Serotonin Neuron Transplants Exacerbate l-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease

Carlsson¹,

Carta²,

et al. 2007

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The “motor complication syndrome” in rats with 6-OHDA lesions treated chronically with l-DOPA: Relation to dose and route of administration

Cited by 96 publications

References 53 publications

Evaluation of Levodopa Dose and Magnitude of Dopamine Depletion as Risk Factors for Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease

Evaluation of Levodopa Dose and Magnitude of Dopamine Depletion as Risk Factors for Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease

Continuous and Intermittent Nicotine Treatment Reduces l-3,4-Dihydroxyphenylalanine (l-DOPA)-Induced Dyskinesias in a Rat Model of Parkinson's Disease

Serotonin Neuron Transplants Exacerbate l-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease

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