A new take on mental illness(Was Re: discovery of dopamine...)
Alan J. Robinson
robin073 at maroon.tc.umn.edu
Mon Nov 20 18:35:51 EST 1995
On 16 Nov 1995 19:23:55 GMT,
john cox <j.e.cox at cranfield.ac.uk> wrote:
>It's always puzzled me why some mental disorders should occur at
>all. If a disorder is caused by a deficiency in one or more
>neurotransmitters, why doesn't normal cellular metabolizm lead
>to a similar repression in neurotransmitter resceptor sites?
>Why doesn't the brain addapt to the new level of neurotransmitter?
>The basic processes of life are geared toward homeostatic regulation;
>genes are constantly switching on and off in response to changes in
>the external environment. Can the level of neurotransmitters and
>their resceptor sites really be arbitrary and unconnected?
>Shouldn't they eventually reach a balance? What is it that
>sets the 'normal' levels anyway if it isn't a process of feed-
>back regulation? Poisoning of the brain with chemicals such
>as alcohol and MDMA do lead to a re-adjustment of resceptor
>levels along with a loss in neurotransmitter activity.
>What is it about a 'diseased' brain that prevents it from
>adjusting its sensitivity to itself? Surely the interesting
>thing about neurotransmitter deficiencies is not the loss
>of the transmitter but the fact that the sensitivity to the
>transmitter is unaffected by its absence. This seems to go
>against everything that is known about the biochemistry of
>cells which have amazing powers of self regulation.
>Could it be that these diseases have causes oposite to the
>usual explaination. Perhaps the resceptors for certain
>neurotransmitters are over expressed. Maybe its this that
>causes a drop in neurotransmitter levels as the brain
>attempts to keep itself regulated. Maybe low transmitter
>levels are not the cause of disfunction but a _result_
>of a more fundamental disfunction at the genetic
The great majority of psychiatric disorders probably include
dysfunction at a system level in addition to dysfuction at a cellular
lefvel. This overlaps with the unresolved question of how and where
plastic changes are made in the brain. In a disease like manic
depression we see long term oscillations (> 1 year), which can become
progressively worse. Obviously this state change has to be reflected
in the brain, but where?
Once the human genome is sequenced it will be a routine, but massive
job, to correlate genetic polymorphisms with age related gene
expression in different brain pathways, and with psychiatric
disorders. It will also be useful to correlate these polymorphisms
with personality and intelligence, because these aspects of brain
function appear to be more stable throughout an individual's
lifetime. Moreover, these traits can be measured on a continuum.
The number of genes which appear to be expressed in the brain is a
substantial fraction of the genome, and many of these genes are
probably ONLY expressed in the brain. Thus it could well be
possible that the number of genes involved in the genetic
susceptibility to various psychiatric disorders could run into
the thousands, though many of them would only make a very small
Part of the genetic susceptibility is believed to be reflected in
abnormally high or low base neural firing rates of the monoaminergic
modulatory pathways (Cloninger). This could lead to saturation of
certain neural pathways during large homeostatic swings, resulting in
lockup in pathological states. A complicating factor is that the
sensitivity of these pathways changes with age. Note that these
pathways are strongly interconnected and themselves involve heavy
negative feedback for homeostatic control.
It's very likely that many different aspects of brain cellular and
system functioning will be found to be associated with the psychiatric
disorders. The one gene - one disease (OGOD) model is entirely
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