PSYCHOACTIVE DRUG EFFECTS ON SINGLE BRAIN NEURONES

Project: Research project

Description

Brain amines have become increasingly implicated in several types of mental
illness, either the amine-containing cells themselves or discrete
populations of target cells which bear receptors for amines. The proposed
studies take advantage of two properties of these amine-containing cells to
investigate the cellular consequences of activation of the various amine
receptors in mammalian brain. First, the cell bodies of the neurones are
densely clustered. Second, the cells themselves bear receptors for the
amines which they release (autoreceptors). This enables a study to be made
of the actions of the amine transmitters on the membrane of the same cells
that produce them. Intracellular recordings will be made from single neurones in slices of rat
midbrain superfused at 37 degrees C. Three series of experiments will be
conducted - involving the 5-hydroxytryptamine (5-HT) cells of the dorsal
raphe, the noradrenaline (NA) containing cells of the locus coeruleus and
the dopamine (DA) cells of the substantia nigra. First, the ion channels
affected by the natural agonists 5-HT, NA and DA will be determined by
single-electrode voltage clamp experiments. In these experiments, stable
analogues of the natural amines which are selective for particular receptor
sub-types will be used. Second, receptors on the neurones will be
characterized by pharmacological null methods at equilibrium (antagonist
affinities by the Schild method and agonist affinities by the Furchgott
technique). Third, the intracellular second messengers (linkage) which
couple receptor activation to ion channel will be investigated. Fourth,
transmitter release will be measured from the single tissue slice in vitro
using tritium labeling techniques. The action of various agonists on
transmitter release will be correlated with their actions on membrane
conductances measured simultaneously. The proposed studies will significantly increase our understanding of
mental illness because the receptors for a variety of psychomimetic and
psychotherapeutic agents will be characterized on intact, single brain
neurones and because the consequences of receptor activation or blockade
will be determined at the level of membrane ion channel and
neurotransmitter release.
StatusFinished
Effective start/end date9/1/8511/30/04

Funding

  • National Institutes of Health: $236,681.00
  • National Institutes of Health: $243,783.00
  • National Institutes of Health: $251,095.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $202,387.00
  • National Institutes of Health: $236,439.00
  • National Institutes of Health: $196,971.00

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Dopamine
Psychotropic Drugs
Neurons
Pharmacology
Serotonin
Brain
gamma-Aminobutyric Acid
Cholecystokinin B Receptor
Receptors, Serotonin, 5-HT3
Dopaminergic Neurons
Ion Channels
Nucleus Accumbens
Cell Nucleus
Ventral Tegmental Area
Sincalide
Interneurons
Mesencephalon
Synapses
Schizophrenia
Potassium

ASJC

  • Medicine(all)