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Supersensitivity to dopamine agonists following unilateral, 6-hydroxydopamine-induced striatal lesions in mice
Abstract:
Following an injection of 6-hydroxydopamine into the left striatum, mice initially circled spontaneously in the direction of the lesion and gradually developed an ability to circle in the opposite direction when challenged with apomorphine or L-dopa. Dose-response curves for apomorphine- and L-dopa-induced circling rates shifted to the left as the duration between the time of the 6-hydroxydopamine injection and the time of testing increased from 2 to 30 days. There was a positive correlation between the rate of apomorphine-induced circling and the reduction in the dopamine concentration in the lesioned forebrain. Doses of apomorphine and L-dopa required to elicit circling responses were 1/6 to 1/10 of those required to increase locomotor activity in normal mice. These data support the concept of development of supersensitivity of postsynaptic dopaminergic receptors in the lesioned striatum.
Insights
Mice with dopamine-depleted striatum showed increased circling behavior after drug treatment. This suggests postsynaptic dopaminergic receptors become more sensitive over time following dopamine depletion.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Dopamine depletion in the striatum is a hallmark of Parkinson's disease.
- Understanding dopaminergic receptor function is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the development of postsynaptic dopaminergic receptor supersensitivity after striatal dopamine depletion.
- To characterize the behavioral responses to dopaminergic agonists in a rodent model.
Main Methods:
- Unilateral striatal injection of 6-hydroxydopamine to create dopamine-depleted lesions in mice.
- Administration of apomorphine and L-dopa to assess circling behavior at various time points post-lesion.
- Measurement of dopamine concentration in the lesioned forebrain.
Main Results:
- Lesioned mice initially circled towards the lesion but later developed contralateral circling in response to apomorphine or L-dopa.
- Dose-response curves for drug-induced circling shifted leftward with increased time post-lesion (2-30 days).
- A positive correlation was observed between circling rate and reduced dopamine levels; lower drug doses were effective compared to normal mice.
Conclusions:
- The findings support the development of postsynaptic dopaminergic receptor supersensitivity in the lesioned striatum.
- This supersensitivity may contribute to altered motor control and drug responses in dopamine-depleted states.