LIMBIC &MEDULLARY MECH. IN COCAINE-RELATED SUDDEN DEATH

  • 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 from 1978 - 1985 has revealed a number of important findings regarding
the temporal trends and risk factors surrounding cocaine-related sudden
death. The epidemiological findings indicate that in Dade County only 6 to
11% of the cases had significant underlying coronary artery disease or
ventricular hypertrophy, suggesting that these risk factors may account for
only a subgroup of the cocaine-related deaths. In addition, polydrug abuse
does not appear to be a significant risk factor in Dade County. High dose
cocaine toxicity is associated with seizures. However, the percentage of
cocaine-related deaths with seizures has declined during the epidemic.
This pattern is consistent with toxicology findings which demonstrate that
median plasma concentration of cocaine associated with sudden death also
appear to be declining annually. In contrast, an increased incidence of
preterminal excited delirium and sudden death has been reported which
closely follows the epidemic curve for cocaine-related deaths in Dade
County. These observations suggest that the causes of cocaine-related
death in decedents with comparatively low concentrations of blood cocaine
may be different from the high dose toxicity group. The precise
pathophysiological mechanisms leading to cocaine-related sudden death are
not well defined and, at present, all known mechanisms fail to explain why
cocaine abuse may have divergent effects on the heart. Our hypothesis is
that cocaine abuse results in abnormal neuronal activity in limbic and
brainstem centers comprising the neural substrates which mediate central
autonomic functions. Abnormal neurochemical transmission in these pathways
may, in addition to the direct cardiotoxic effects of cocaine, lead to the
pathogenesis of cocaine-related sudden death. The present proposal seeks
funds for systematic post mortem studies of the chemo- and
pathoarchitecture in brains from victims of cocaine-related death. Using
rigorous inclusion criteria for cocaine exposure, the cases selected for
neuroanatomical studies will be classified into the following subgroups :
high dose toxicity (seizures); low dose toxicity without significant
underlying cardiac pathology; and cocaine-related death in subjects
exhibiting preterminal excited delirium. We propose to characterize post
mortem neurochemical alteration in brains from victims of cocaine-related
sudden death using in vitro autoradiography on whole-brain sections. The
distribution and status of norepinephrine and dopamine terminals will be
visualized in whole-brain sections by receptor subtypes and sigma receptors
will be correlated with limbic and medullary pathoarchitecture and whenever
possible with the pattern of use and drug and metabolite levels in plasma
and brains. The proposed anatomical studies may disclose the toxic effects
of an neural sites for the action of cocaine in the human brain. These
studies may provide a basis for pharmacologically targeting multiple,
interactive dysfunctions in the brain in order to halt cocaine abuse in
chronic users.
StatusFinished
Effective start/end date4/1/904/30/15

Funding

  • National Institutes of Health: $260,105.00
  • National Institutes of Health: $257,139.00
  • National Institutes of Health: $378,675.00
  • National Institutes of Health: $272,700.00
  • National Institutes of Health
  • National Institutes of Health: $252,768.00
  • National Institutes of Health: $217,083.00
  • National Institutes of Health: $133,494.00
  • National Institutes of Health: $286,520.00
  • National Institutes of Health: $266,292.00
  • National Institutes of Health: $382,500.00
  • National Institutes of Health: $436,091.00
  • National Institutes of Health: $238,541.00
  • National Institutes of Health: $267,905.00
  • National Institutes of Health: $330,575.00
  • National Institutes of Health: $208,010.00
  • National Institutes of Health: $144,534.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $510,228.00
  • National Institutes of Health

Fingerprint

Sudden Death
Cocaine
Cocaine-Related Disorders
alpha-Synuclein
Brain
Delirium
Coroners and Medical Examiners
Parkinson Disease
Dopamine
Biogenic Amines
Seizures
Pharmaceutical Preparations
Norepinephrine
Neurons
3,4-Dihydroxyphenylacetic Acid

ASJC

  • Medicine(all)