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View Abstract
Methods for the assessment of akinesia in the unilateral rat Parkinson model have so far been lacking. The experiments reported here evaluate the usefulness of a new “stepping test” to monitor forelimb akinesia in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesencephalic dopamine (DA) system, and to assess the ability of DA- receptor agonists and fetal DA neuron transplants to reverse these deficits. The 6-OHDA lesion induced marked and long-lasting impairments in the initiation of stepping movements with the contralateral paw. Systemic injections of low doses (chosen to be subthreshold for induction of rotation) of the mixed D1 and D2 receptor agonist apomorphine, the D1-selective agonist SKF 38393, and to a lesser extent also the D2-selective agonist quinpirole were effective in reversing these deficits. Similar effects was seen after a subrotational dose of L-dopa, whereas amphetamine had no effect. Fetal nigral transplants, implanted as multiple deposits in the ipsilateral caudate-putamen and substantia nigra, restored initiation of stepping to a similar degree as the DA agonists. Nigral grafts placed in substantia nigra alone were also effective, although the improvement was less pronounced. Apomorphine, at a dose effective in the lesion-only animals, had no additive effect in the grafted rats, whereas amphetamine appeared to further improve stepping in the rats with intranigral transplants. Identical experiments were performed on skilled forelimb use in the so- called staircase test. Interestingly, neither the DA agonist drugs nor the nigral transplants had any effects on the lesion induced deficits in this more complex task. The results show that forelimb stepping is a highly useful test to monitor lesion-/and transplant-induced changes in forelimb akinesia, a behavioral parameter that may be analogous to limb akinesia and gait problems seen in patients with Parkinson's disease.
Protocol Steps
1
Create unilateral dopamine lesion
Induce unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesencephalic dopamine system in rats
Not specifiedNot specified
Note: This creates the Parkinson model with forelimb akinesia
View evidence from paper
“evaluate the usefulness of a new stepping test to monitor forelimb akinesia in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesencephalic dopamine (DA) system”
2
Perform staircase test baseline
Assess skilled forelimb use and complex motor control in lesioned rats using the staircase test apparatus
Not specifiedNot specified
Note: Establish baseline performance before drug or transplant interventions
View evidence from paper
“Identical experiments were performed on skilled forelimb use in the so-called staircase test”
3
Administer dopamine agonist drugs
Systemically inject low doses of dopamine agonists (apomorphine, SKF 38393, quinpirole) or L-dopa at subthreshold/subrotational doses
Not specifiedNot specified
Note: Doses chosen to be subthreshold for induction of rotation behavior
View evidence from paper
“Systemic injections of low doses (chosen to be subthreshold for induction of rotation) of the mixed D1 and D2 receptor agonist apomorphine, the D1-selective agonist SKF 38393”
4
Perform staircase test after drug administration
Reassess skilled forelimb use on the staircase test following dopamine agonist or L-dopa administration
Not specifiedNot specified
Note: Measure effects of pharmacological intervention on complex motor control
View evidence from paper
“Identical experiments were performed on skilled forelimb use in the so-called staircase test”
5
Implant fetal nigral transplants
Implant fetal dopamine neuron transplants as multiple deposits in the ipsilateral caudate-putamen and substantia nigra, or in substantia nigra alone
Not specifiedNot specified
Note: Two implantation strategies tested: combined caudate-putamen and substantia nigra deposits versus substantia nigra alone
View evidence from paper
“Fetal nigral transplants, implanted as multiple deposits in the ipsilateral caudate-putamen and substantia nigra, restored initiation of stepping to a similar degree as the DA agonists. Nigral grafts placed in substantia nigra alone were also effective”
6
Perform staircase test after transplantation
Reassess skilled forelimb use on the staircase test following fetal nigral transplant implantation
Not specifiedNot specified
Note: Measure effects of neural transplantation on complex motor control
View evidence from paper
“Identical experiments were performed on skilled forelimb use in the so-called staircase test”
7
Test drug effects in transplanted animals
Administer apomorphine or amphetamine to rats with nigral transplants and reassess staircase test performance
Not specifiedNot specified
Note: Apomorphine at effective dose showed no additive effect; amphetamine appeared to further improve stepping in intranigral transplant animals
View evidence from paper
“Apomorphine, at a dose effective in the lesion-only animals, had no additive effect in the grafted rats, whereas amphetamine appeared to further improve stepping in the rats with intranigral transplants”
Subjects / Specimens
Species
rat
Strain
Not specified
Age
Not specified
Sex
unknown
Weight
Not specified
Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesencephalic dopamine system