ELECTROPHYSIOLOGY OF CNS DOPAMINE RECEPTOR KNOCKOUT

Project Details

Description

Dopaminergic neurotransmission in the brain modulates a number of
important cognitive and behavioral functions. For example, schizophrenia
is believed to result from an imbalance in forebrain dopamine systems.
Recent advances in molecular biology have led to the identification of 5
different genes coding for dopamine receptors of 2 main families, D1 and
D2. Although agonists and antagonists that discriminate between members of
the D1 and D2 families exist, drugs do not yet exist that are selective
among family members (e.g., D2 vs. D3 vs. D4 or D1 vs. D5). This has
resulted in confusion about the sites and mechanisms of action of dopamine
in the brain, about precisely which receptor subtypes mediate which
cellular effects, and likely also contributes to the mixed therapeutic
efficacy and unwanted side effects of antischizophrenic drugs in use
today.

We have shown that in vivo infusion of specifically designed antisense
oligodeoxynucleotides complementary to the mRNA coding for different
dopamine receptors produces a highly regional- and receptor-specific pre-
or postsynaptic "knockout" of the dopamine D2 or D3 receptors as indexed
by receptor autoradiography. In vivo and in vitro electrophysiological
techniques will be used to determine the roles that D2 and D3 dopamine
receptors play in the modulation of the electrical activity of substantia
nigra dopaminergic neurons and neostriatal neurons. Subsequent experiments
will utilize similar methods to achieve knockout of the D1 and D4
receptors.

The site and receptor subtype of the dopamine receptor that mediates the
inhibitory effects of amphetamine on nigral cell firing will be
determined. In vivo extracellular and in vitro intracellular recordings
will be used to confirm the identity of the nigral somadendritic
autoreceptor and determine the role that it plays in the control of the
rate and pattern of firing of nigral dopamine neurons. In vivo and in
vitro intracellular recordings will be used to define receptor subtype-
specific actions of dopamine on neostriatal neurons, and determine the
site and subtype of the receptor that mediates dopamine's effect on
corticostriatal synaptic transmission.

This research is highly relevant to both basic and applied neuroscience.
Validating the antisense approach to selective receptor knockout in vivo
by electrophysiological means is a necessary first step towards the
application of this technique to a variety of research issues. The
identification of the particular dopamine receptor subtype(s) that
mediates a number of well-characterized physiological responses to
dopamine may provide information that will direct future research towards
the design of a new generation of antipsychotic drugs that are
simultaneously more effective and lack the often devastating side effects
of the neuroleptics in use today.
StatusFinished
Effective start/end date4/1/963/31/00

ASJC

  • Physiology
  • Neuroscience(all)

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