Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression
| Autor: | Francesca M. Coppelli, Anne M. Andrews, Amy M. Avila, Tiffany A. Mathews, Dennis L. Murphy, Denise E. Fedele |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Serotonin medicine.medical_specialty Microdialysis 3 4-Dihydroxyphenylacetic acid Dopamine Gene Dosage Down-Regulation Nerve Tissue Proteins Striatum Serotonergic Synaptic Transmission Mice chemistry.chemical_compound Internal medicine medicine Animals Monoamine Oxidase Serotonin transporter Brain Chemistry Mice Knockout Neurons Serotonin Plasma Membrane Transport Proteins Membrane Glycoproteins biology General Neuroscience Brain Membrane Transport Proteins Extracellular Fluid Hydroxyindoleacetic Acid Corpus Striatum Endocrinology chemistry Potassium biology.protein 3 4-Dihydroxyphenylacetic Acid medicine.drug |
| Zdroj: | Journal of Neuroscience Methods. 140:169-181 |
| ISSN: | 0165-0270 |
| Popis: | Serotonin (5-HT) plays an integral regulatory role in mood, anxiety, cognition, appetite and aggressive behavior. Many therapeutic and illicit drugs that modulate these functions act at the serotonin transporter (SERT), thus a mouse model with reduced transporter expression was created to further investigate the effects of differential serotonin reuptake. In the present study, in vivo microdialysis was used to determine homeostatic alterations in extracellular 5-HT levels in unanesthetized SERT knockout mice. SERT(-/-) mice had significantly higher levels of basal dialysate 5-HT than SERT(+/+) mice in striatum and frontal cortex. In addition, although gene-specific increases in 5-HT were evident, neuroadaptive alterations in dialysate dopamine levels were not detected in striatum. Zero net flux microdialysis was utilized to further investigate alterations in extracellular 5-HT. Using this method, a gene dose-dependent increase in extraneuronal 5-HT was observed in striatum (2.8 +/- 1, 9.4 +/- 1 and 18 +/- 3 nM) and frontal cortex (1.4 +/- 0.4, 3.5 +/- 0.9 and 14 +/- 1 nM) in SERT(+/+), SERT(+/-) and SERT(-/-) mice, respectively. Potassium stimulation revealed greater depolarization-induced increases in striatal 5-HT but not dopamine in SERT(-/-) mice. Furthermore, dialysate 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in striatum in a gene dose-dependent manner, while DOPAC was unchanged in SERT knockout mice. Finally, determination of monoamine oxidase (MAO) activity revealed no significant differences in KM or Vmax of type-A or type-B isozymes indicating that alterations in SERT expression do not cause adaptive changes in the activities of these key catabolic enzymes. Overall, these results demonstrate that constitutive reductions in SERT are associated with increases in 5-HT in the extracellular signaling space in the absence of changes in dopamine neurochemistry. Furthermore, use of zero net flux microdialysis appears warranted in investigations of serotonergic synaptic function where modest changes in extracellular 5-HT are thought to occur in response to altered uptake. |
| Databáze: | OpenAIRE |
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