Electrophysiological methods will be used to study the actions of opioids, cocaine and nicotine on individual rat brain neurons in vitro. Adult rats will be anesthetized and then killed; thin slices of brain tissue will be maintained at 37 degrees C in a physiological solution to which drugs and other substances can be added. The purpose of these experiments is to determine the effects of these drugs of abuse of single neurons of the rat brain and thus to make inferences about their actions in man. Studies will be performed on cells of the ventral tegmental area (VTA), nucleus accumbens, and locus coeruleus . Six main types of experiment are proposed. First, calcium currents will be recorded using the whole-cell configuration of the patch clamp method from neurons of the rat locus coeruleus neurons; the actions of opioids selective for mu, delta and kappa receptors will be studied. Second, the role of G-proteins and kinases in coupling opioid receptor to potassium and calcium channels in locus coeruleus neurons will be studied by introducing antibodies, toxins and other molecules into the cell from the patch clamp electrode. Third, the actions of opioids will be measured on potassium and calcium currents in locus coeruleus neurons that have been continuously or intermittently exposed to morphine in vitro during 24 - 48 hr. These experiments on the rat locus coeruleus are a continuation of present work and seek to determine the molecular events that immediately follow opioid receptor activation, and the changes that occur as a result of long term agonist exposure. Fourth, using intracellular recording methods principal (dopamine-containing) and secondary cells of the VTA will be distinguished, and the actions of opioids selective for mu, delta and kappa receptors will be studied on ion conductances of both types of cell, as well as on GABA-mediated and glutamate-mediated synaptic potentials. Fifth, the effectiveness of cocaine to inhibit dopamine uptake under physiological circumstances uptake will be studied by recording dopamine-mediated synaptic potentials in the VTA and the nucleus accumbens. Sixth, the action of nicotine on neurons of the VTA and nucleus accumbens will be studied both by intracellular microelectrode recording and by patch-clamp recording, particularly with respect to the receptor type and differences between principal and secondary cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003161-12
Application #
3207736
Study Section
Special Emphasis Panel (SRCD (24))
Project Start
1991-01-01
Project End
1995-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
12
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Pessia, M; Jiang, Z G; North, R A et al. (1994) Actions of 5-hydroxytryptamine on ventral tegmental area neurons of the rat in vitro. Brain Res 654:324-30
Seutin, V; Johnson, S W; North, R A (1994) Effect of dopamine and baclofen on N-methyl-D-aspartate-induced burst firing in rat ventral tegmental neurons. Neuroscience 58:201-6
Jiang, Z G; Pessia, M; North, R A (1994) Neurotensin excitation of rat ventral tegmental neurones. J Physiol 474:119-29
Tanaka, E; North, R A (1994) Opioid actions on rat anterior cingulate cortex neurons in vitro. J Neurosci 14:1106-13
Shen, K Z; North, R A (1993) Excitation of rat locus coeruleus neurons by adenosine 5'-triphosphate: ionic mechanism and receptor characterization. J Neurosci 13:894-9
Sugita, S; Tanaka, E; North, R A (1993) Membrane properties and synaptic potentials of three types of neurone in rat lateral amygdala. J Physiol 460:705-18
Seutin, V; Johnson, S W; North, R A (1993) Apamin increases NMDA-induced burst-firing of rat mesencephalic dopamine neurons. Brain Res 630:341-4
Piguet, P; North, R A (1993) Opioid actions at mu and delta receptors in the rat dentate gyrus in vitro. J Pharmacol Exp Ther 266:1139-49
Piguet, P (1993) GABAA- and GABAB-mediated inhibition in the rat dentate gyrus in vitro. Epilepsy Res 16:111-22
Sugita, S; North, R A (1993) Opioid actions on neurons of rat lateral amygdala in vitro. Brain Res 612:151-5

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