2 -  Trophic control of development
Investigations of neurotransmitter systems over the
last three decades underscore the complexity of
biochemical development in the brain.  Research at
the level of synaptic transmission and mechanisms
involved in axon growth and proliferation holds out
hope for refinement of understanding and design of
pharmacological treatments that go beyond trial and
error.  These are the functions that require energy
supplied by aerobic metabolism.  Neurotransmission in
the brainstem nuclei of high metabolic rate is
constantly active.  Lapses in autonomic control of
breathing and heart rate are fatal.  Sensory input,
especially acoustic stimuli, appear to be of equal
importance in maintaining homeostasis within the
central nervous system.  Brainstem systems are
elaborated first in the developing fetus and appear to
produce trophic substances that guide migration of
newly formed neurons and formation of cortical
structures that will be their final targets for biochemical
signal transmission.

VonHungen et al. (1974, 1975) set out to determine
the response of the post-synaptic enzyme adenylate
cyclase to the monoamine transmitters serotonin,
dopamine, and norepinephrine in laboratory rats [1-
3].  Adenylate cyclase produces cyclic adenosine
monophosphate (cAMP), which is thought to be a post-
synaptic “second-messenger.”  The response is not
only different in different parts of the brain, but also
declines with maturation.  VonHungen et al. concluded
that adenylate cyclase receptors may be important in
establishment of developing synapses.  They also
found the highest response to serotonin was in the
inferior and superior colliculi, which led to further
research using tissue pooled from all four colliculi.  
Gal and Patterson (1973) developed a method for
measuring activity of the enzyme that catalyzes the
first step in the synthesis of serotonin and also found
a significantly higher rate in the colliculi than in any
other brain region [4].

In addition to confirming a decline in adenylate
cyclase response to serotonin with age, VonHungen
et al. (1975) studied the effects of several substances
including D-lysergic acid diethylamide (LSD),
chlorpromazine, haloperidol, propranlol, morphine,
and gamma amino butyric acid (GABA).  The goal in
testing enzyme response with psychoactive
substances was to obtain an estimate of the numbers
and kinds of enzyme receptors.  For example, LSD
stimulated the enzyme but inhibited the stimulation by
serotonin.  The chemical structure of LSD is similar to
that of serotonin [5].  The results of the experiments
by vonHungen et al. indicated that both LSD and
serotonin attach to the same receptor.  With the
substances employed vonHungen et al. demonstrated
that there are multiple receptors that can control the
activity of adenylate cyclase production of the cAMP
post-synaptic messenger.

Serotonin and gamma-amino butyric acid (GABA) both
appear to function as inhibitory neurotransmitters.  
However, GABA did not stimulate cAMP production,
nor did it inhibit the stimulation by serotonin.  Von
Hungen et al. therefore concluded that GABA inhibits
neural activity through a receptor system that is
different from that for serotonin.  How
neurotransmitters work is not as simple therefore as
suggested in some reports of supposed serotonin
disturbances detected by blood and urine tests in
autistic children.  Useful pharmacologic treatments (if
any) await far more research on brain development
and function in experimental animals.

1. VonHungen K, Roberts S
   (1974) Neurotransmitter-
   sensitive adenylate systems
   in the brain.
   
2. VonHungen K et al. (1974)
   Developmental and regional
   variations in neurotransmitter-
   sensitive adenylate cyclase
   systems in cell-free
   preparations from rat brain.
   
3. VonHungen K et al. (1975)
   Serotonin-sensitive adenylate
   cyclase activity in immature
   rat brain.
   
4. Gal EM, Patterson K (1973)
   Rapid nonisotopic assay of
   tryptophan-5 hydroxylase
   activity in tissues.
   
5. Snyder S (1986) Drugs and
   the Brain.
   

References

Full References

1. VonHungen K, Roberts S (1974) Neurotransmitter-sensitive adenylate systems in the brain.  
   In Ehrenpreis S, Kopin II, eds, Reviews of Neuroscience, vol I, Raven Press, New York, pp
   231-281.
   
2. VonHungen K, Roberts S, Hill DF (1974) Developmental and regional variations in
   neurotransmitter-sensitive adenylate cyclase systems in cell-free preparations from rat brain.
   Journal of Neurochemistry 22:811-819.
   
3. VonHungen K, Roberts S, Hill DF (1975) Serotonin-sensitive adenylate cyclase activity in
   immature rat brain. Brain Research 84:257-267.
   
4. Gal EM, Patterson K (1973) Rapid nonisotopic assay of tryptophan-5 hydroxylase activity in
   tissues.  Analytical Biochemistry 52:625-629.
   
5. Snyder S (1986) Drugs and the Brain.  New York: Scientific American Library.
   

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