Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias

Delfino, Marina; Stefano, Andrea V.; Ferrario, Juan E.; Taravini, Irene Rita Eloisa; Murer, Mario Gustavo; Gershanik, Oscar S.

doi:10.1016/j.bbr.2003.10.009

Cited by 66 publications

(60 citation statements)

References 33 publications

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“…Previous reports indicated that the non-selective agonist apomorphine is a more potent inductor of AIMs than D2 family agonists (Lundblad et al, 2002;Delfino et al, 2004). In good agreement with these findings, apomorphine induced strong FD and AD, whereas the D2 agonist quinpirole produced a lower number of AIMs (Figure 2).…”

Section: Aims Induced By Dopamine Receptor Agonistssupporting

confidence: 86%

“…were found in pilot studies to induce comparable rates of contraversive turning behavior (data not shown; see also Delfino et al, 2004). Dosage was balanced according to rotational behavior because contraversive turning is an index of severe nigrostriatal damage and postsynaptic supersensitivity (Ungerstedt, 1976), which in turn have been linked to dyskinesia (Nutt, 2000).…”

Section: Experimental Designmentioning

confidence: 99%

“…In rodents, the susceptibility to develop dyskinesia is related to the extent of dopamine axon terminal loss in the striatum and to the nature of drug treatment in a way that closely resembles the situation in patients. Repeated exposure to dopamine agonists increases the likelihood of developing dyskinesia, and unselective dopamine agonists (apomorphine, levodopa) are more likely to induce dyskinesia than selective D2 family receptor agonists (bromocriptine, quinpirole) in severely lesioned rats (Lundblad et al, 2002;Winkler et al, 2002;Delfino et al, 2004). Taken together, data from patients and animal models suggest that sensitization of striatal neurons to D1 and/or combined D1 and D2 receptor stimulation contribute to drug-induced dyskinesia.…”

Section: Introductionmentioning

confidence: 94%

“…Behavioral evaluation of AIMs was performed after the first and seventh drug challenges. This repeated pre-exposure schedule maximizes behavioral sensitization to drugs (Morelli et al, 1989; see also Delfino et al, 2004). An eighth drug challenge was then given 3 days after finishing the sensitization protocol, whereas BOLD was measured using phMRI (groups apomorphine-eighth, n ¼ 6; quinpiroleeighth, n ¼ 6; SKF-81297-eighth, n ¼ 6; vehicle-eighth , n ¼ 3).…”

Section: Experimental Designmentioning

confidence: 99%

“…AIMs (Cenci et al, 1998;Lundblad et al, 2002;Delfino et al, 2004) were evaluated after the first and seventh drug injections of the sensitization schedule, during 2 min every 30 min, for 2 h post-injection. Forelimb dyskinesia (FD), axial dystonia (AD) and masticatory dyskinesia (MD) were scored separately.…”

Section: Behavioral Testingmentioning

confidence: 99%

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Mapping the Effects of Three Dopamine Agonists with Different Dyskinetogenic Potential and Receptor Selectivity Using Pharmacological Functional Magnetic Resonance Imaging

Delfino

Kalisch

Czisch

et al. 2007

Neuropsychopharmacol

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The mechanisms underlying dopamine agonist-induced dyskinesia in Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by 6-hydroxydopamine are more likely to show dyskinesia during chronic treatment with unselective dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing dyskinesia. As a first step towards disclosing drug-induced brain activation in dyskinesia, we examined the effects of dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions. Rats were rendered dyskinetic before pharmacologic functional magnetic resonance imaging by means of a repeated treatment regime with dopamine agonists. The unselective agonist apomorphine and the selective D1/D5 agonist SKF-81297 induced strong forelimb dyskinesia (FD) and axial dystonia and increased BOLD signal in the denervated striatum. Besides, SKF-81297 produced a significant but smaller BOLD increase in the intact striatum and a symmetric bilateral increase in the motor cortex. The D2 family agonist quinpirole, which induced mild dyskinesia on chronic treatment, did not produce BOLD changes in the striatum or motor cortex. Further evidence to support an association between BOLD changes and dyskinesia comes from a direct correlation between scores of FD and magnitude of drug-induced BOLD increases in the denervated striatum and motor cortex. Our results suggest that striatal and cortical activation induced by stimulation of D1/D5 receptors has a primary role in the induction of peak dose dyskinesia in parkinsonism.

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Section: Aims Induced By Dopamine Receptor Agonistssupporting

confidence: 86%

Section: Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Experimental Designmentioning

confidence: 99%

Section: Behavioral Testingmentioning

confidence: 99%

See 3 more Smart Citations

Mapping the Effects of Three Dopamine Agonists with Different Dyskinetogenic Potential and Receptor Selectivity Using Pharmacological Functional Magnetic Resonance Imaging

Delfino

Kalisch

Czisch

et al. 2007

Neuropsychopharmacol

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Ratings of L‐DOPA‐Induced Dyskinesia in the Unilateral 6‐OHDA Lesion Model of Parkinson's Disease in Rats and Mice

2007

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This unit provides detailed protocols for establishing rodent models of L-DOPA-induced dyskinesia. The 6-hydroxydopamine (6-OHDA) lesion procedure is described in more detail for mice than for rats since the lesioning procedure in rats has been described extensively in previous work and is less difficult to perform. Unlike primate models, rodent models of L-DOPA-induced dyskinesia are relatively simple and fast to set up, thus being affordable to most laboratories. These models allow for studying the dyskinetic complications of L-DOPA treatment on large groups of animals under strictly controlled experimental conditions. Along with information and structured protocols for the practical execution of the test, this unit provides a detailed description of the rating scale and the phenomenology of rodent abnormal involuntary movements, and suggestions for beginners.

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Behavioral and biochemical correlates of the dyskinetic potential of dopaminergic agonists in the 6‐OHDA lesioned rat

Carta

Frau

Pinna³

et al. 2008

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Prolonged treatment with L-DOPA induces highly disabling dyskinesia in Parkinson's disease (PD) patients. In contrast, dopaminergic agonists display variably dyskinetic outcome, depending on pharmacokinetic/pharmacodynamic profile. The present study was aimed at assessing behavioral and biochemical correlates of intense or mild dyskinesia displayed by the different dopamine (DA) receptors stimulation in a rat model of PD. The effect of subchronic stimulation of the D(1) receptor by SKF38393, and the D(2)/D(3) receptor by ropinirole was evaluated in unilaterally 6-hydroxyDA-lesioned rats. Sensitization of contralateral turning (SCT) behavior and abnormal involuntary movements (AIMs) were assessed as behavioral correlates of dyskinetic responses. Opioid peptides mRNA in the dorsolateral striatum (dlStr) and glutamic acid decarboxylase (GAD67) mRNA content in globus pallidus (GP), were evaluated as an index of neuroadaptive changes occurring in the direct and indirect basal ganglia pathways. Subchronic SKF38393 caused AIMs and SCT whereas ropinirole elicited SCT only, indicating that both drugs induced some dyskinetic response, albeit of different type. Peptides mRNA evaluation in dlStr, showed that SKF38393 subchronic treatment was associated to an overexpression of both dynorphin (DYN) and enkephalin (ENK) mRNAs, in the direct and indirect striatal pathway respectively. In contrast, a decrease in DYN mRNA levels only was observed after treatment with ropinirole. Analysis of GAD67 mRNA levels in the GP showed an increase after both D(1) and D(2)/D(3) agonist treatments. Results suggest that presence of SCT alone or SCT plus AIMs might represent correlates of the differential severity of dyskinetic movements induced by treatment with low (ropinirole) or high (SKF38393) dyskinetic potential. Neuroadaptive increases in opioid peptide expression in both direct and indirect striatal pathways were associated to the appearance of AIMs alone. In contrast, increase of GAD67 mRNA in the GP was associated to both behavioral responses (SCT and AIMs), suggesting that neuroadaptive changes in this area were unrelated to the difference in dyskinetic potential of drugs.

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Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias

Cited by 66 publications

References 33 publications

Mapping the Effects of Three Dopamine Agonists with Different Dyskinetogenic Potential and Receptor Selectivity Using Pharmacological Functional Magnetic Resonance Imaging

Mapping the Effects of Three Dopamine Agonists with Different Dyskinetogenic Potential and Receptor Selectivity Using Pharmacological Functional Magnetic Resonance Imaging

Ratings of L‐DOPA‐Induced Dyskinesia in the Unilateral 6‐OHDA Lesion Model of Parkinson's Disease in Rats and Mice

Behavioral and biochemical correlates of the dyskinetic potential of dopaminergic agonists in the 6‐OHDA lesioned rat

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