Model links Locus Coeruleus

and

Hyperactivity

by Michael T. Hyson, Ph.D. **

Published in the Brain-Mind Bulletin (1989)

**Formerly:
Associate Editor,
Brain-Mind Bulletin
Currently: Research Director,
Sirius Institute, Puna, Hawai’i

Stimulants 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.

Ivan 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).

The 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.

Higher 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.

Most 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 themselves.

Clinical 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."

This 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."

In 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.

As 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 protective mechanism."

Animals, 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 occur secondarily."

Information: Ivan N. Mefford, Clinical Pharmacology, National Institutes of Mental Health, 9000 Rockville Pike, Bethesda, MD 20892 Phone:(301) 496-2615.

Children, Drugs, "Ice" - & Ways Out

Supporting Documents

Model Links Locus Coeruleus & Hyperactivity

Is Ritalin Raising Kids To Be Drug Addicts?