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Dopamine receptor 'supersensitivity' occurring without receptor up-regulation.
B E Mileson1, M H Lewis, R B Mailman
1Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill 27599.
Brain Research
|October 4, 1991
Summary
6-hydroxydopamine (6-OHDA) lesions in rats reveal that functional supersensitivity does not require increased dopamine receptor density or cAMP changes. This challenges the utility of unilateral models for screening antiparkinsonian drugs.
Area of Science:
- Neuroscience
- Pharmacology
- Dopamine Neurobiology
Background:
- Unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra are standard models for studying dopamine neurobiology and screening antiparkinsonian drugs.
- Pharmacological supersensitivity develops following dopamine pathway lesions, but the underlying mechanisms, particularly receptor alterations, require clarification.
Purpose of the Study:
- To investigate the role of receptor alterations in pharmacological supersensitivity induced by different 6-OHDA lesioning methods (intracisternal, bilateral, unilateral).
- To assess the necessity of receptor density changes and dopamine-sensitive adenylate cyclase activity for functional supersensitivity.
Main Methods:
- Induction of 6-hydroxydopamine (6-OHDA) lesions via intracisternal (IC), bilateral (BIL), or unilateral (UNI) administration into the substantia nigra in rats.
- Behavioral testing with apomorphine challenge to assess functional supersensitivity.
- Scatchard analysis of D1 and D2 dopamine receptor binding sites in the striatum.
- Measurement of dopamine-sensitive adenylate cyclase activity.
Main Results:
- IC and BIL lesions caused permanent dopamine depletion but did not alter D1 or D2 receptor density or affinity in the striatum.
- UNI lesions increased D2 receptor density on the lesioned side.
- Functional supersensitivity (locomotion, grooming, gnawing) was observed in IC and BIL lesioned rats without receptor density changes.
- Dopamine-sensitive adenylate cyclase activity was unchanged in IC-lesioned rats but showed a leftward shift in BIL-lesioned rats.
Conclusions:
- Functional supersensitivity following 6-OHDA lesions does not necessitate increases in dopamine receptor density or altered cAMP systems.
- The unilateral lesion model, while showing receptor changes, may not accurately reflect the mechanisms of functional supersensitivity seen in other models.
- Alternative cellular mechanisms, such as receptor interactions, may contribute to the development of pharmacological supersensitivity.