Dopamine containing nerve cells in the mammalian brain appear to be involved in the manifestations, and probably the etiology, of a number of mental illnesses. One pathway of particular importance has cell bodies in the ventral tegmental area (VTA) and target cells in the limbic cortex, including the nucleus accumbens.
The aim of the proposed research is to study the detailed properties of individual neurones in this pathway - both the cells of the VTA and their targets in the nucleus accumben. The experimental work will be carried out on slices of brain tissue removed from laboratory rats, and the principal methods will be intracellular recording of membrane potentials and membrane currents. Receptors on the cell surface will be characterized by using known concentrations of selective agonists and by determining the dissociation equilibrium constants for antagonists. The effects of activating D1 and D2 dopamine receptors sigma receptors, and amino acid receptors will be studied. The association of receptors with given sets of ion channels will be established and where appropriate the intracellular processes that couple channel to receptor will be investigated. Synaptic inputs will be excited by focal stimulation of the brain slice, and the action of agonists will be examined on presynaptic fibres - using the amplitude of the synaptic potential as a measure of transmitter release. The mechanism of action of amphetamine will be studied by measuring its effects on the membrane properties and determining whether they result from dopamine release. The avidity of amine uptake mechanism in the intact tissue slice will be measured by quantitative pharmacological studies using uptake blockers, particularly cocaine. The long term objectives of this work are an increased understanding of the function of individual cells in those regions thought to be critically involved in certain mental illnesses. The experimental results will provide information regarding the actions of certain neuroleptic drugs (eg. haloperidol, sulpiride) at known concentrations on living brain cells. Taken together with the behavioral effects of such drugs in animals, and their therapeutic effects in some aspects of human psychosis, the results are expected to increase our knowledge of the psychotic process itself.
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