Download Carlsson et al (2000)

Network interactions in schizophrenia —
therapeutic implications
Arvid Carlsson (2000)
 reviews current
understanding of the
interactions between
different neurotransmitters
 “dramatic synergism
between a variety of
monoaminergic agonists
and MK-801 or other NMDA
receptor antagonists” may
provide a more advanced
neurochemical explanation
of schizophrenia”
PET Scanning evidence
 until recently the dopamine
hypothesis was only ever
supported by “indirect”
evidence, e.g. metabolite levels
in CSF
 PET imaging has now revealed
abnormal dopaminergic
activity in certain brain
regions in people with
schizophrenia
dopamine antagonists) bring the
person down to atypically low levels in
between psychotic episodes
 we urgently need to develop drugs that
prevent relapse without these side
effects
Treating schizophrenia
Research into dopamine…
 PET and SPECT scans using
radio-labelled dopa to measure
how the brain uses dopamine
in areas such as the basal
ganglia
 drug-naïve people with SZ are
compared with age matched
controls
 when the Pps were given
amphetamines, this enhanced
release of dopamine
significantly more in the SZ
group and was more likely to
induce SZ symptoms
Problems with the dopamine
research
 some people with
schizophrenia show
dopamine levels that are
within the normal range
 some research suggests that
people with ‘catatonic’
symptoms have
hypodopaminergic activity
 the stress of the brain
imaging procedures may
interfere with dopamine
levels
Problems cont’d
 Pps are usually in acute episodes, may not the same for
chronic symptoms
 amphetamine-induced release of dopamine in
schizophrenic patients in remission is within the
normal range
 just because radiolabelled dopamine is synthesised
more rapidly in Pps with SZ this does mean that
endogenous dopamine synthesis is equally abnormal.
Carlsson hypothesises that…
 excess dopamine may be a by-product of
dysfunction of some other neurotransmitter
 an excess in one area may be compensating
for a deficiency in some other area
 to understand schizophrenia we must…
 examine other neurotransmitters to see
whether there are abnormalities in people
with schizophrenia
Studying neurotransmitters
 the trouble is not all
neurotransmitters are so easy to study
in a living brain as dopamine.
 the easiest is SEROTONIN
 use a radiolabelled precursor (5hydroxytryptophan) in order to see
how quickly serotonin is synthesised
 similar research has been done with
people with depression and the
expected abnormalities revealed.
The glutamate hypothesis…
 PCP or ‘angel dust’ is a street
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drug and like amphetamines it
also induces schizophrenic-like
symptoms
PCP is a powerful antagonist on
the NMDA, glutamate receptor
PCP has the effect of reducing
glutamate levels
could hypoglutamatergic activity
be a causal factor in
schizophrenia?
If so is this because glutamate
regulates levels of dopamine
and/or serotonin?
Evidence
 SPECT imaging studies have found
that the NMDA antagonist ketamine
(effect: reduces glutamate levels)
enhances amphetamine-induced
dopamine release in human
 experiments with rats have also
looked at the role of NMDA
antagonists
 slight impact on dopamine release,
replicated in other labs.
 some NMDA antagonists, however,
seem to inhibit dopamine release;
suggesting that decreased glutamate
may bring about schizophrenic
symptoms via some route other than
increased dopamine release
 NMDA receptor antagonists appear to
stimulate 5-HT (serotonin) turnover and
release more consistently than dopaminergic
activity
 high levels of serotonin may also be linked to
reduced levels of glutamate.
 post mortem studies suggest
hyperserotonergic function in people with
paranoid schizophrenia
 PCP research seems contradictory, sometimes
PCP seems to enhance rather than reduce the
release of glutamate
Carlsson and Carlsson (1989)
 mice given drugs to reduce motor activity
 motor activity was induced again by blocking
glutamate receptors in the nucleus accumbens, using a
drug called MK-801; this may be seen as a good thing
BUT…
 systemic treatment with MK-801 caused a highly
abnormal motor activity
 low glutamate levels could also lead to negative
symptoms, e.g. hypofrontality
 glutamatergic failure in the …
 cerebral cortex may lead to negative symptoms
 basal ganglia could be responsible for the positive
symptoms.
Glutamate and dopamine
 SZ can be explained by an interplay between dopamine
and glutamate pathways
 Pathways leading to the striatum from the lower
brainstem (mesolimbic) and cortex (mesocortical)
 Glutamate can control dopamine in two ways, ‘brake’
and ‘accelerator’
The Accelerator; the cortex
 When everything is working well…
 glutamate pathways can acts as an accelerator (speed
up) the meso-cortical dopamine pathway controlling
higher brain centres in the cortex
 When things go wrong…
 e.g. NMDA receptors in the midbrain are dysfunctional,
dopamine misfiring may contribute to cognitive
impairments and symptoms of schizophrenia
The brake; limbic system
 When everything is working well…
 glutamate neurons that connect to dopamine neurons in
the limbic system have a GABA interneuron in-between
 GABA inhibits the release of dopamine, acting as a brake
on dopamine pathways
 When things go wrong…
 less glutamatergic activity, means GABA doesn’t put the
brakes on! Too much dopamine is released and leads to
positive symptoms of psychosis
Treatment options
 Experiments have compared Haloperidol (blocks D2
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dopamine receptors ) and M100907 (blocks 5HT serotonin
receptors) to see which is best able to overcome
amphetamine-induced hyperactivity
Haloperidol was more effective
They then brought about hyperactivity by lowering
glutamate levels with MK-801 (NMDA blocker)
This time the serotonin blocker was more effective than the
dopamine blocker in reversing the problems!
So can M100907 (serotonin antagonist) be used as an
antipsychotic
may be that it works for some patients more than others
possibly due to different causes of their symptoms
Advances in drug treatment
 using both types of drug together
may be more effective than either
on its own
 For example clozapine and other
‘atypical’ antipsychotics are both
anti-dopaminergic and antiserotonergic
 clozapine is often effective for
treatment resistant schizophrenics
for whom decreasing dopamine
levels has not worked
More on drug treatments
 this may be because their symptoms
are being caused by low glutamate
levels which are in turn affecting
serotonin levels.
 drugs that affect glutamate levels
could provide relief for people with
schizophrenia who have not
experienced relief from other
medications, e.g. glutamate agonists
 AJW says, for more information see:
Seeman and Guan, (2009)
In conclusion, Carlsson suggests …
 subpopulations with different
pathogenesis may exist among
patients with schizophrenia
 a mechanism involving a
glutamatergic deficiency
appears to deserve special
attention.
 this deficiency may well be
secondary to, for example, a
failure of connectivity arising at
an early developmental stage
A glutamatergic deficiency linked
to..
 the meso-cortical pathways
could be responsible for a
variety of cognitive and
negative symptoms
 in subcortical, meso-limbic
pathways could lead to
elevated dopamine levels,
potentially triggering a
compensatory reduction of
presynaptic dopaminergic
activity
Final thoughts
 elevated serotonergic activity, pre-
and post-synaptically probably
contributes to positive and negative
symptomatology
 we need further research into the
development of the disease over
time, e.g. why psychotic episodes
appear to lead to further
deterioration
 other neurotransmitters, such as
acetylcholine, gaba and
neuropeptides, should also be
explored