links Locus Coeruleus
Michael T. Hyson, Ph.D. **
in the Brain-Mind Bulletin (1989)
Currently: Research Director,
Sirius Institute, Puna, Hawai’i
like methyphenidate (ritalin), dextroamphetamine, or clonadine,
often calm hyperactive children and increase their attention
spans. Paradoxically, these same compounds usually cause increased
activity and even anxiety in adults.
Mefford and W. Potter propose a model that may resolve the
paradox. Most of the 600,000 hyperactive children receiving
drug therapy annually in the US may have chronically low brain
levels of adrenaline and high levels of activity in the locus
coeruleus, a nucleus in the brain stem. The syndrome is termed
Attention Deficit Disorder with Hyperactivity (ADDH).
locus coeruleus, or LC exerts major control of both attention
and sleep with a high rate of LC neuron firing associated
with alertness. Very high levels of LC firing result in hypervigilance
or, perhaps, hyperactivity.
levels of brain adrenaline can calm the LC. In an interview
with B/M B, Mefford explained that the locus coeruleus receives
input fibers from adrenaline (or epinephrine) producing cells
in the medulla of the brain. The epinephrine from these cells
decreases the firing rate of locus coeruleus neurons.
of the compounds used in the treatment of hyperactivity are
known to cause increased systemic adrenaline and could cause
increased brain adrenaline levels, or behave like adrenaline
evidence for their hypothesis comes from studies of hyperactive
children taking stimulants. According to Mefford, reporting
work by Judith Rapoport and others, "We observed only
urinary excretion of ephinephrine or... its major metabolite,
metanephrine, were increased in these children."
showed that drugs used to treat hyperactivity elevate adrenaline
levels in these children. "Since we know that amphetamine
and ritalin cross the blood-brain barrier into the brain,
the drugs could have a similar effect on the neurons innervating
the LC. This could lead to higher adrenal levels in the LC,
causing the activity of the LC to decrease."
rat studies to test their hypothesis, they inhibited an enzyme
called phenylethanolamine-N-methyl-transferase or PNMT, to
cause higher adrenaline levels. In animals that had not learned
fear reactions, their activity increased. In older animals,
the treatment caused decreased activity and anxiety. This
seems analogous to the paradoxical effects of amphetamines
causing calming in hyperactives.
the authors say in their report in Medical Hypotheses 29:33-42,
"the hypothesis synthesizes behavioral, neuroanatomical,
biochemical and pharmacological information from both animal
and human studies to relate this disorder to a primary biochemical
defect. It is proposed that childhood hyperactivity is the
juvenile expression of excessive vigilance, a normal mammalian
such as rabbits, do not have adrenaline producing cells controlling
their locus coeruleus. This seems related to their constitutional
hyperactivity. Chronic low adrenaline levels in hyperactive
children may lead to a similar state causing "inability
to maintain focused attention, difficulty in falling asleep,
or light levels of sleep, inattention to consumptive behaviors...
inappropriate response to reward ... Cognitive deficits may
Ivan N. Mefford, Clinical Pharmacology, National Institutes
of Mental Health, 9000 Rockville Pike, Bethesda, MD 20892
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