SIGNATURE OF DOPAMINE SYNAPSE IN COCAINE FATALITY

  • Mash, Deborah C, (PI)

Project: Research project

Description

The incidence of cocaine-related sudden deaths has reached epidemic
proportions in many metropolitan areas around the United States.
Widespread cocaine abuse is associated with significant neuropsychiatric
and CNS complications. Epidemiological analysis of cocaine-related deaths
in Dade County, Florida, has revealed a number of important findings
regarding the temporal trends and associated risk factors. The
epidemiological findings indicate that only 6 to 11 % of the cocaine
overdose cases had significant underlying coronary artery disease or
ventricular hypertrophy, suggesting that these cardiovascular risk factors
may account for only a subgroup of the cocaine-related sudden deaths. High
dose cocaine toxicity is associated with seizures. However, the percentage
of cocaine-related deaths with seizures has declined during the epidemic.
This observation is consistent with toxicology findings which demonstrate
that median plasma concentrations of cocaine associated with sudden death
have declined annually. In contrast, an increased incidence of cocaine
psychosis and sudden death-has been reported which closely follows the
epidemic curve for cocaine-related deaths in Dade County. The
epidemiological analysis of all cocaine overdose deaths (1971 to the
present) provides a basis for assigning cocaine overdose deaths into three
subgroups: high dose acute toxicity (seizures); low dose toxicity without
significant underlying cardiac pathology; and cocaine-related death in
subjects exhibiting preterminal excited delirium. Guided by this analysis,
an extensive catalogue of well-characterized postmortem neuropathological
specimens is available for the proposed study of the morphological and
neurochemical consequences of cocaine abuse in the human brain. Cocaine
has prominent reinforcing and subjective effects that contribute to its
pattern of abuse. An increase in CNS dopamine neurotransmission, resulting
from the blockade of dopamine uptake and mediated by the activation of
dopamine receptors, is a primary determinant of the reinforcing effects of
cocaine. Recent advances in molecular biology have allowed the cloning and
characterization of the main molecular components involved in dopaminergic
synaptic transmission. By combining immunological and molecular biological
techniques, highly specific antibodies to the dopa:nine transporter and
receptor subtypes have been made available using fusion proteins as
antigens. We plan to use these monospecific antibody probes to
characterize changes in the molecularly-defined proteins of the
dopaminergic synapse in the human brain postmortem from cocaine overdose
deaths. Defining the adaptive responses of dopaminergic synaptic proteins
to repeated cocaine use may help to pinpoint the pharmacological sites in
human brain which mediate behavioral tolerance and sensitization and to
identify the neural substrates that play a role in dose escalation and
subsequent toxicity.
StatusFinished
Effective start/end date9/30/948/31/99

Funding

  • National Institutes of Health
  • National Institutes of Health: $264,035.00
  • National Institutes of Health
  • National Institutes of Health: $273,599.00

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Cocaine
Synapses
Dopamine
Sudden Death
Cocaine-Related Disorders
Seizures
Brain
Synaptic Transmission
Dihydroxyphenylalanine
Delirium
Antibodies
Incidence
Proteins
Toxicology
Hypertrophy
Organism Cloning
Coronary Artery Disease
Molecular Biology
Pharmacology
Pathology

ASJC

  • Medicine(all)