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nac8 Electronic Thesis Document.pdf (3.83 MB)

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Mechanisms of Autoreceptor-Mediated Inhibition in Central Monoamine Neurons

Courtney, Nicholas A
http://rave.ohiolink.edu/etdc/view?acc_num=case1447955036

Abstract Details

2016, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
This thesis examined the mechanisms of neurotransmission underlying feedback inhibition mediated by somatodendritic G-protein coupled dopamine D2-autoreceptors in the ventral tegmental area (VTA), noradrenaline ¿2-autoreceptors in the locus coeruleus (LC), and serotonin 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN). Local feedback inhibition mediated by these GI-coupled monoamine receptors had been speculated to ubiquitously occur via extended transmitter spillover and obligatory extracellular transmitter pooling. Collectively termed volume transmission, these mechanisms of transmission are presumed to result in a tonic, inhibitory tone that modulates the firing rates of monoaminergic neurons in response to slowly changing extracellular concentrations of monoamines. However, evidence for the volume transmission hypothesis is indirect and relies on measuring bulk extracellular monoamine concentrations and predicting receptor activation based on steady-state affinities and mathematical diffusion modeling. In monoamine neurons, autoreceptors couple to G-protein coupled, inwardly rectifying potassium channels (GIRKs) through the ¿¿-subunits of trimetric G-proteins. Activation of somatodendritic autoreceptors by locally released monoamines generates potassium currents that inhibit neuronal excitability. In this thesis, I directly investigated the synaptic mechanisms controlling autoreceptor activity by using electrophysiological methods to measure GIRK-mediated currents in response to evoked transmitter release in rodent brain slices. After characterizing the calcium dependence and clearance of midbrain dopamine transmission to demonstrate species-dependent differences in dopamine transmission, I tested the contributions of spillover and pooling to shaping autoreceptor activation in the dopamine, noradrenaline, and serotonin systems. While both spillover and transmitter pooling contributed to noradrenergic ¿2-autoreceptor activation, dopamine reuptake transporters prevented both spillover and pooling in D2-autoreceptor mediated dopamine transmission. In the dorsal raphe nucleus, transmitter spillover contributed to 5-HT1A autoreceptor activation while serotonin reuptake transporters prevented serotonin pooling and synaptic crosstalk. This thesis concludes that autoreceptor-mediated inhibitory feedback transmission encoded by locally released dopamine, noradrenaline, and serotonin occurs via distinct synaptic mechanisms. While the volume transmission hypothesis may accurately describe noradrenergic transmission in the LC, dopaminergic transmission in the VTA and serotonergic transmission in the DRN likely occur in a point-to-point fashion that is inconsistent with volume transmission. These findings provide insight into how these regions may differentially encode and influence behavior.
Christopher Ford (Advisor)
254 p.
Biophysics; Neurosciences; Physiology
Monoamine; dopamine; noradrenaline; serotonin; neurotransmission; GPCR; volume transmission

Recommended Citations

Citations

  • Courtney, N. A. (2016). Mechanisms of Autoreceptor-Mediated Inhibition in Central Monoamine Neurons [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1447955036

    APA Style (7th edition)

  • Courtney, Nicholas. Mechanisms of Autoreceptor-Mediated Inhibition in Central Monoamine Neurons. 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1447955036.

    MLA Style (8th edition)

  • Courtney, Nicholas. "Mechanisms of Autoreceptor-Mediated Inhibition in Central Monoamine Neurons." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1447955036

    Chicago Manual of Style (17th edition)

case1447955036
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© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12