Project Details


A number of psychoactive agents adversely affect brain development.
However, underlying molecular mechanisms remain to due, in part,
to the complexity and inaccessibility of the brain, particularly
in developing animals. We, however, are now able to approach
questions of molecular mechanisms governing toxicity in the central
nervous system (CNS). We have succeeded in growing the brain
nonadrenergic nucleus locus coeruleus in an accessible tissue
culture system for prolonged periods. Electrophysiological studies
indicate that the locus is responsive to a variety of psychoactive
substances, including caffeine, ethanol, amphetamines and tricyclic
antidepressants. Moreover, the locus exhibits sensitive and
specific phenotypic characters by which ontogeny and toxicity may
be monitored at defined molecular loci. In the proposed
work, we will evaluate the influence of caffeine, ethanol,locus
amphetamines and the tricyclic antidepressant, desmethylimipramine,
on ontogeny. Effects of these agents will be assessed by
monitoring the noradrenergic traits, tyrosine hydroxylase,
dopamine-8-hydroxylase and the specific uptake of norepinephrine,
sensitive and specific markers of locus function Specific
antagonists will be used to define receptor sites involved in any
observed drug action. In addition, agents will be tested on locus
cells of varying maturities and critical developmental periods will
be defined. Finally, mechanisms underlying ontogeny of drug
dependency and tolerance will begin to be evaluated by examining
coeruleal traits after prolonged exposure to the psychoactive
agents. These experiments promise to identify the molecular loci
of action of drugs of abuse in the brain.
Effective start/end date9/30/888/31/92


  • National Institutes of Health: $108,037.00
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)

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