In vivo microdialysis to investigate serotonin and dopamine neurotransmission in mouse models of psychiatric and degenerative disease.

摘要

The principle focus of this thesis was the investigation of alterations in neurochemistry using microdialysis in a number of strains of genetically engineered mice. The lines of mice selected for study model various aspects of human mood and anxiety disorders or Parkinson's disease (PD). Neurochemistry was investigated in serotonin transporter (SERT) knockout mice, brain-derived neurotrophic factor (BDNF) knockout mice and mutant human A53T α-synuclein (A53T-tg) transgenic mice to understand how each of these single gene alterations influence the function of the serotonin (5-HT) and dopamine (DA) neurotransmitter systems.; The first objective was to investigate alterations in basal and stimulated extracellular 5-HT or DA levels in specific brain regions, and to interpret these in light of the behavioral phenotypes of the mutant mouse models. In addition, SERT knockout mice were employed as tools to examine the neurochemical mechanisms of action underlying the locomotor-stimulating properties of the substituted amphetamines, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH). The overarching objective of this thesis was to determine the ability of in vivo microdialysis to detect moderate, but biologically relevant changes in extracellular neurotransmitter levels occurring in response to alterations in the expression of proteins thought to directly or indirectly modulate neurotransmission.; In a second set of experiments, brain-derived neurotrophic factor knockout mice were studied to investigate an indirect modulatory role of BDNF in serotonergic neurotransmission. Mice with a 50% decrease in BDNF expression (BDNF+/−) show the following adaptations suggestive of changes in serotonergic signaling: a blunted c-fos response after d-fenfluramine (a selective 5-HT releasing amphetamine), accelerated age-dependent serotonergic neurodegeneration and brain region-specific changes in 5-HT receptor expression.; In addition, in vivo microdialysis was used to examine the effect of overexpression of mutant human A53T α-synuclein on DA neurotransmission.; In vivo microdialysis also was utilized to explore the relationship between MDMA- and METH-induced 5-HT and DA release in SERT knockout mice in an attempt to better understand the mechanisms by which these substituted amphetamines stimulate locomotor behavior. (Abstract shortened by UMI.)