The first aim of this proposal is to determine the direct action of cocaine on the membrane properties of neurons (locus coeruleus (LC), substantia nigra (SN) and dorsal raphe (DR)) in dissociated cell culture. With isolated cells the direct action of cocaine on membrane properties and exogenously applied transmitters can be studied quantitatively since diffusion barriers and endogenous transmitters will be limited. Agonists can be applied in known concentration close to the cell. The effect that cocaine has on the kinetics of ligand activated conductances will be studied to determine if cocaine changes the affinity of the receptor for the transmitter. In addition the use of cultured cells permits whole cell recording with patch electrodes such that more control of the intracellular ion content and second messengers is gained. The proposed experiments are a natural progression of previous experiments in brain slices. The knowledge and experience gained by the work from LC and DR neurons in slices over the past 8 years will be directly applicable to work on isolated cells.
The second aim i s to determine the changes induced in monoamine neurons recorded in brain slices taken from animals previously treated with repeated injections of cocaine. Chronic cocaine is known to cause long term changes in behavior. The brain slice is particularly will suited for the study of these changes at the single cell level since synaptic connections are left intact and quantitative pharmacological methods can be applied to determine any changes in receptor sensitivity. The long term goal is to use the strengths of each; the brain slice and isolated cell preparations to study action of drugs of abuse at the cellular level. The acute and chronic effects of cocaine will first be studied in cells from relatively homogenous nuclei (LC, SN and DR). Knowledge gained from those relatively simple nuclei will be applied to more complex areas such as the ventral tegmental area, nucleus accumbens and prefrontal cortex. Studies from cells taken from animals which have self-administered cocaine may lead to an understanding of the changes that cause and result from cocaine abuse. Whole cell recordings will also eventually be used to study the changes that occur with other drugs of abuse such as opioids. For example, such recordings from LC neurons with patch electrodes are vital to determine the nature of the reduction in the opioid 'spare-receptor' population following chronic opioid treatment.
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| Robinson, Brooks G; Condon, Alec F; Radl, Daniela et al. (2017) Cocaine-induced adaptation of dopamine D2S, but not D2L autoreceptors. Elife 6: |
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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 |
| Gantz, Stephanie C; Levitt, Erica S; Llamosas, Nerea et al. (2015) Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA. Cell Rep 12:944-54 |
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