A new take on mental illness(Was Re: discovery of dopamine...)

[Alan J. Robinson]

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
>transcription level.
>

John:

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 
contribution.

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 
inappropriate here.

AJR