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Combining the lack of chromogranins with chronic L-DOPA treatment affects motor activity in mice
Leandro Castañeyra-Ruiz1,2, Agustín Castañeyra3, Ayoze González-Santana1,2,3
1Department of Neurosurgery, School of Medicine, Washington University in Saint Louis, St. Louis, MO, USA.
Abstract:
We have tested whether the lack of chromogranins (Cgs) A and B could provoke CNS disorders when combined with an excess of dopamine. We chronically treated (over 6 months) mice lacking both chromogranins A and B (Cgs-KO) with a low oral dosage of L-DOPA/benserazide (10/2.5 mg/kg). Motor performance in the rota-rod test, open field activity, and metabolic cages indicated a progressive impairment in motor coordination in these mice, and an increase in rearing behavior, which was accompanied by an increase in DA within the substantia nigra. We conclude that mild chronic L-DOPA treatment does not produce nigro-striatal toxicity that could be associated with parkinsonism, neither in control nor Cgs-KO mice. Rather, Cgs-KO mice exhibit behaviors compatible with an amphetamine-like effect, probably caused by the excess of catecholamines in the CNS.
Insights
Mice lacking chromogranins A and B (Cgs-KO) showed impaired motor coordination and increased rearing behavior when treated with L-DOPA. This suggests an amphetamine-like effect from excess catecholamines, not parkinsonism.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Chromogranins (Cgs) are proteins involved in neurotransmitter storage and release.
- The role of Cgs in central nervous system (CNS) disorders, especially in conjunction with dopamine (DA) excess, remains unclear.
Purpose of the Study:
- To investigate if the absence of chromogranins A and B (Cgs-KO) exacerbates CNS disorders when combined with elevated dopamine levels.
- To assess the potential neurotoxicity of chronic L-DOPA treatment in mice lacking Cgs.
Main Methods:
- Chronic oral administration of a low dose of L-DOPA/benserazide (10/2.5 mg/kg) to Cgs-KO and control mice for over six months.
- Evaluation of motor performance using the rota-rod test.
- Assessment of general activity and behavior through open field tests and metabolic cages.
Main Results:
- Cgs-KO mice exhibited progressive motor coordination deficits and increased rearing behavior compared to controls.
- Elevated dopamine levels were observed in the substantia nigra of Cgs-KO mice.
- No evidence of nigro-striatal toxicity associated with parkinsonism was found in either Cgs-KO or control mice.
Conclusions:
- Mild chronic L-DOPA treatment does not induce parkinsonism-related neurotoxicity.
- Mice lacking chromogranins A and B display behaviors suggestive of an amphetamine-like effect, likely due to elevated CNS catecholamines.
