• Itzhak, Yossef, (PI)

Project: Research project

Project Details


Cocaine is a powerful rewarding and euphoric drug of abuse which has become
a major public health threat for several reasons. The drug is highly
addictive and toxic, and the risk for HIV infection increases among
intravenous poly-drug users through needle sharing and the
immunosuppressive effects of both cocaine and opiates. In addition,
simultaneous use of cocaine and alcohol is one of the most prevalent
two-way drug combination for substance abuse-related death, as perceive by
the Drug Abuse Warning Network. Recent studies have detected cocaethylene
in postmortem blood, liver and neurological tissues as a metabolic product
of concurrent cocaine and alcohol use. Since the combination of cocaine
and alcohol is associated with enhanced and prolonged euphoria, we
hypothesize that one possibility is the! formation of a neuroactive
metabolite which may be responsible for the magnified reinforcing effects
of cocaine and alcohol abuse. Neurochemical studies have suggested that
blockade of the dopamine (DA) transporter is the primary mechanism
responsible for the reinforcing properties of cocaine-related drugs,
leaving more DA available within the synapse for post-synaptic activity.
Although it is postulated that cocaethylene is a more powerful reinforcing
and euphoric drug than cocaine, the drug is equipotent to cocaine as an
inhibitor of the DA transporter. Therefore, we presume that additional
neurotransmitter systems may be associated with the rewarding properties of
these drugs. That the opioid system may be involved in the euphoric
effects induced by cocaine is supported by several studies indicating
elevated levels of endogenous opioid peptides with concomitant regulation
of opioid receptors following exposure to cocaine. In addition, cocaine
self-administration is suppressed in rhesus monkeys treated with the mixed
agonist/antagonist opiate, buprenorphine. The development of new
therapeutics to treat cocaine abuse is a fundamental issue, since several
drugs which affect the dopaminergic and serotoninergic systems have
generally failed to suppress cocaine craving. In view of the current
state, we reasoned that a definitive investigation of the neurochemical
effects of cocaine and cocaethylene on opioid neurotransmitters and
receptors may establish the role of the opioid system in the euphoric and
rewarding effects of these drugs. To establish the validity of this
hypothesis, we propose to investigate alterations in the level of opioid
peptides following acute and chronic exposure to cocaine and cocaethylene
and to determine changes in opioid receptor binding following exposure to
the drugs. Studies will also be focused to determine a possible
correlation between alterations in monoamine levels and opioid peptide
concentrations in critical brain regions following prolonged exposure to
cocaine and cocaethylene. We anticipate that these studies will further
establish the neurochemical effects of cocaine and also may elucidate the
mechanism(s) underlying cocaethylene's magnified euphoric effects.
Moreover, results of this project may provide a new approach for the
development of therapeutics to treat cocaine abuse.
Effective start/end date12/15/9111/30/94


  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)

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