The Dopamine Hypothesis of Schizophrenia

1
The Dopamine Hypothesis of Schizophrenia Jeff
Hollerman FSPsy201
Antipsychotic drugs (APDs)
Dopamine agonists
It was over 40 year ago when researchers
assembled data from a variety of sources that
suggested that an abnormally high level of
neurotransmission using the chemical dopamine was
linked to psychosis in schizophrenia. This lead
to the idea of a dopamine hypothesis for
schizophrenia (although a specific statement of
such an hypothesis in its entirety was never
agreed on).
ABSTRACT/OVERVIEW
methamphetamine
D-amphetamine
Second generation APDs are generally considered
to have begun with the development of the drug
clozapine. Clozapine, while also having D2
antagonist effects, proved to be much more
effective therapeutically than would be predicted
just on its D2 actions. It has been reported to
have efficacy against both positive and negative
symptoms, and to have a much lower incidence of
motor side effects. Unfortunately, its side
effects include potentially lethal effects on the
liver which require very close monitoring. Other
atypical APDs are being developed based on the
clozapine model of combined action at dopamine,
norepinephrine, and/or serotonin receptors. The
initial promise of this new generation of drugs
has not yet been equalled in practice.
First generation APDs began with the development
of chlorpromazine and the discovery that in
addition to a general sedative effect, it
appeared to have a specific effect in reducing
psychotic symptoms, particularly those currently
labelled positive symptoms. Development of
other drugs from the same class (phenothiazines)
as well a drugs such as haloperidol (a
butyrophenone) followed. A common characteristic
underlying the efficacy of these drugs in
reducing psychotic symptoms was believed to be
their ability to act as antagonists at central
dopamine receptors, particularly those of the D2
type. However, in addition to their therapeutic
efficacty, typical APDs also produced motor side
effects, including both parkinsonism and tardive
dyskinesia, at very high rates.
Dopamine agonists include d-amphetamine and
cocaine, both of which have a prominent effect on
the dopamine transporter. In both cases, the
drugs prevent the reuptake of dopamine that has
been released into the synapse, prolonging its
duration of action. D-amphatamine, in addition,
appears to be able to make the transporter run in
reverse, extruding cytoplasmic dopamine into the
synapse. In both cases, dopamine transmission is
greatly facilitated. While small to moderate
doses of these drugs generally produce an
increase in physical and mental energy, as well
as a generally pleasant, even euphoric, effect,
high doses or prolonged use can result in a
condition called amphetamine psychosis, a
largely delusional state that can be nearly
indistinguishable symptomatically from paranoid
schizophrenia. Although both drugs also influence
norepinephrine and serotonin transmission, those
effects are not as strong, leaving excess
dopamine as the most likely explanation for the
schizophrenic-like behavior.
Schizophrenia is diagnosed in approximately 1
of the population and has tremendous effects not
only on the individual sufferers but also on
their friends and family and on society as a
whole. Increasing our understanding of this
disorder (or disorders), is essential to
alleviating these problems. Diagnosis of
schizophrenia is currently based on criteria
provided by diagnostic manuals (DSM-IV and
ICD-10, for example).To be diagnosed with
schizophrenia, a person must consistently display
two or more of the following symptoms (or just
delusions if they are marked enough), -delusions
-hallucinations -disorganized speech (e.g.,
frequent derailment or incoherence speaking in
abstracts). -grossly disorganized behavior (e.g.
dressing inappropriately, crying frequently) or
catatonic behavior -negative symptoms, i.e.,
affective flattening (lack or decline in
emotional response), alogia (lack or decline in
speech), or avolition (lack or decline in
motivation). There must also be evidence for a
social and/or occupational dysfunction, i.e.,
there must be a notable decrease in function in
an area or areas such as work, interpersonal
relations, or self-care. In addition, the
duration of the problems must be at least six
months, including at least one month of active
symptoms. Finally, exclusionary criteria include
diagnosis of mood disorder or pervasive
developmental disorder, or origin of symptoms due
to a drug or toxin or an identified medical
condition.
Schizophrenia

Dopamine pathways
CONCLUSION

• The dopamine systems that appear to be most
  relevant to schizophrenia are
• The mesocortical dopamine system, consisting of
  neurons with cell bodies in the ventral tegmental
  area and axon terminals in the cortex,
  particularly the prefrontal cortex in humans, a
  structure associated with higher cognitive
  functions.
• The mesolimbic dopamine system, consisting of
  neurons with cell bodies in the ventral tegmental
  area and axon terminals in the amygdala and
  nucleus accumbens, structures associated with
  motivation and emotion.
• The nigrostriatal dopamine system, consisting of
  neurons with cell bodies in the substantia nigra
  and axon terminals in the caudate nucleus and
  putamen, structure associated with voluntary
  movement.

Dopamine
tyrosine hydroxlase
dopa decarboxylase
Dopamine is a biogenic amine synthesized in
certain neurons from the amino acid tyrosine.
There are several distinct groups of dopamine
neurons identifiable by the location of their
cell bodies. Different groups of dopamine neurons
also target different brain regions for their
release of dopamine and appear to subserve
different functions in these different brain
regions. All of these different groups (or
systems, or pathways) will be affected by
systemically administered drugs because the basic
processes of synthesis, release, and reuptake are
similar if not identical.
REFERENCES