Cocaine is known to act on amine containing neurons to inhibit uptake of transmitters. The reuptake of noradrenaline, 5-HT and dopamine is inhibited, but it is not known whether these mechanisms are equally sensitive to cocaine in intact functioning neurons. It is proposed to compare and contrast the action of cocaine at sites in brain which contain each of these neurotransmitters. Intracellular recordings from neurons in four amine containing nuclei; the locus coeruleus, dorsal raphe, substantia nigra and ventral tegmental area will be made in submerged brain slices in vitro at 37 degrees C. The choice of these nuclei is based on the compact structure, biochemical homogeneity and the presence of amine receptors on the cell bodies of the neurons contained in each of the nuclei. Neurons in each of the four nuclei are similar in that they possess receptors for the same transmitter which they produce, 'autoreceptors'. These nuclei differ however in the type of 'autoreceptor', the number of other amine receptor subtypes and the afferent innervation from other amine containing nuclei. The effects of cocaine on the membrane properties, the actions of exogenously applied substances (noradrenaline, 5-hydroxytryptamine and dopamine) and synaptically released transmitters (noradrenaline, 5-hydroxytryptamine and dopamine) will be determined in these major amine containing nuclei. By investigating the action of cocaine of neurons in four amine containing nuclei the proposed studies will significantly increase our understanding of cocaine actions in the central nervous system. From these studies it should be possible to determine the cellular mechanisms and sites which are involved in the psychotomimetic actions of cocaine, and perhaps in the dependence liability which cocaine is now recognized to possess.
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| Kramer, Paul F; Williams, John T (2016) Calcium Release from Stores Inhibits GIRK. Cell Rep 17:3246-3255 |
| Gantz, Stephanie C; Robinson, Brooks G; Buck, David C et al. (2015) Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium. Elife 4: |
| Kramer, Paul F; Williams, John T (2015) Cocaine Decreases Metabotropic Glutamate Receptor mGluR1 Currents in Dopamine Neurons by Activating mGluR5. Neuropsychopharmacology 40:2418-24 |
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