K OPIOIDS AND DOPAMINE--MECHANISMS OF STIMULANT ABUSE

Project: Research project

Project Details

Description

DESCRIPTION: (Applicant's Abstract)

Psychostimulant abuse is a considerable problem in society. Both cocaine
and amphetamine are widely used, and the use of methamphetamine on the rise.
These psychostimulant drugs produce their reinforcing effects via
interactions with the dopamine transporter, cocaine by inhibiting dopamine
uptake (the inward flow of dopamine into the neuron), and amphetamines by
stimulating dopamine release via reversal of the transporter. These actions
result in an increase in extracellular dopamine, which then interacts with
dopamine receptors to increase dopaminergic transmission. In order to
develop a treatment for the abuse of these substances, it is necessary to
find a mechanism by which the activity of the dopamine transporter and
dopamine receptors can be regulated. Repeated administration of a selective
kappa-opioid agonist produces a down-regulation of the dopamine transporter,
and of dopamine D: receptors, suggesting that the kappa-opioid regulation
of dopamine neurotransmission might provide a mechanism by which to alter
the effects of psychostimulants such as cocaine and amphetamine. The
specific hypothesis of this proposal is that the dopamine transporter can be
regulated via manipulations of kappa-opioid receptors, and that this will
alter the neurochemical, and hence the behavioral effects of psychostimulant
drugs such as cocaine and amphetamine. Specifically, the anatomical and
pharmacological alterations in the dopamine transporter and dopamine
receptors, as well as the associated behavioral changes, will be measured
following chronic administration of kappa-opioid receptor agonists. We will
measure receptor binding using in vitro autoradiography and homogenate
binding. Dopamine transporter function will be measured using dopamine
uptake and release assays, and dopamine receptor function will be evaluated
using adenylyl cyclase and GTPgammaS binding assays. Behavior will be
measured using locomotor activity studies. Understanding of the regulation
of dopamine neurotransmission by kappa-opioid receptor agonists will provide
leads to the development of a therapeutic agent for treating abuse of
psychostimulant drugs. Altered dopamine receptor function has been
implicated in numerous neurological disorders including schizophrenia,
Parkinson's disease, Tourette's syndrome, and Huntington's chorea, in
addition to psychostimulant drug abuse. Treatments for most of these
syndromes involve use of agonists and antagonists at particular receptors, a
state that often leads to marked side effects. Hence, the ability to
regulate dopaminergic transmission via alterations of the dopamine
transporter would be useful in the treatment of such syndromes.
StatusFinished
Effective start/end date9/30/987/31/04

Funding

  • National Institute on Drug Abuse: $131,745.00
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse: $127,908.00

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