Trask, Robert B. (2009) Dopaminergic modulation of melanin-concentrating hormone expressing neurons. Masters thesis, Memorial University of Newfoundland.
- Accepted Version
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Melanin-concentrating hormone (MCH) is a neuropeptide that acts centrally as an anabolic signal, while also mediating behaviours such as reward, activity level, and anxiety. MCH expressing neurons are limited in their expression being isolated to the lateral hypothalamus (LH) and nearby zona incerta (ZI). Despite this limited area of expression the neurons project widely throughout the brain. The neurotransmitter/neuromodulator dopamine (DA), which is best known for its role in reward and locomotion, is released within the LH area. DA action within the LH area is known to influence MCH related behaviours: for example, an injection of DA into the LH will decrease food intake. Since MCH promotes food intake and DA has anorexic properties in the LH it is hypothesized that DA inhibits the activity of the MCH expressing neurons. However, DA's mechanism of action on MCH neurons is not known. This study was carried out to determine the cellular mechanisms by which DA influences MCH expressing neurons. To determine this MCH neuronal activity was monitored using whole cell patch-clamp recordings from LH/ZI containing rat brain slices. MCH neurons were identified and distinguished from nearby orexin neurons by their electrophysiological characteristics and post-hoc immunohistochemistry. All drugs were bath applied. In order to monitor DA's presynaptic influence y-aminobutyric acid (GABA) release was recorded through pharmacologically isolated miniature inhibitory postsynaptic currents (mlPSCs). Results showed that DA inhibits the activity of MCH expressing neurons through hyperpolarization and a reduction in action potential firing. Furthermore, DA induced a dose dependent outward current. This current was the result of G protein-activated inwardly rectifying K⁺ (GIRK) channel activation. Surprisingly, initiation of the GIRK current was not dependent on DA receptor activation but rather on the highly expressed adrenergic α₂ₐ receptor. Norepinephrine (NE) also produced a reversible, dose dependent outward current in MCH neurons when acting on the adrenergic receptors. The DA and NE induced outward currents were of similar magnitudes, indicating both have similar efficacies when acting on MCH neurons. Monitoring mlPSCs revealed that DA had no consistent effect on their frequency or amplitude, indicating that DA does not influence synaptic GABA transmission. Overall this study demonstrates that DA has a direct postsynaptic inhibitory influence on MCH neurons. This inhibition is accomplished though activation of adrenergic receptors and the initiation of a GIRK current. Furthermore, this study reveals a cross talk between dopaminergic and adrenergic signalling at the cellular level within the LH area.
|Item Type:||Thesis (Masters)|
|Additional Information:||Includes bibliographical references (leaves 32-41)|
|Department(s):||Medicine, Faculty of|
|Library of Congress Subject Heading:||Dopaminergic mechanisms; Hypothalamic hormones; Neuropeptides;|
|Medical Subject Heading:||Dopamine Agents; Hypothalamic Hormones; Neuropeptides|
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