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Title: Molecular and behavioural studies on a mouse model with impaired monoamine storage
Author: Chan, P. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
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The role of the neural specific vesicular monoamine transporter (Vmat2) in presynaptic dopamine handling and postsynaptic dopamine transmission was investigated using a Vmat2 mutant mouse. Expression studies using in situ hybridization showed that Vmat2 mRNA was absent in the dopaminergic cells of the Vmat2 homozygous mutant whereas dopamine transporter expression was unchanged. Furthermore, no Vmat2 immunopositive cells were found in the midbrain and striatum of the Vmat2 mutant. Neurochemical analysis showed that levels of dopamine and its metabolite homovanillic acid were reduced in the homozygous mice. Following MPTP treatment, the number of remaining dopaminergic cells in the midbrain was much reduced in the Vmat2 mutant as compared with the normal wild type suggesting impaired functioning of Vmat2. Presynaptic dopamine handling in the Vmat2 mutant was investigated by in vivo microdialysis which revealed much lower levels of basal an amphetamine stimulated release of dopamine in the striatum, as compared to the wild type. The consequences of this hypodopaminergic transmission on gene expression in striatal neurons was investigated. The results showed that the prolonged dopamine depletion due to impaired presynaptic vesicular monoamine storage resulted in down-regulation of the expression of substance P and dynorphin and up-regulation of enkephalin mRNA expression, consistent with loss of tonic dopamine release in the striatum. The expression of the adenosine A2a receptor which is preferentially expressed in the striatopallidal output neurons was also significantly upregulated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available