1. NETWORK INTERACTIONS IN SZ – THERAPEUTIC IMPLICATIONS
CARLSSON ET AL 99
NETWORK INTERACTIONS IN SZ – THERAPEUTIC IMPLICATIONS
Awarded the Nobel Peace prize for their work on neural transmission.
Arvid is best known for his work into the relationship between dopamine and Parkinson’s disease.

2. METHODOLOGY This is NOT a study
It is a PAPER REVIEW of research findings
Obtained evidence about the role of neurotransmitters in SZ;
Carlsson’s own work
Work of others
Animal research (rodents and primates)
PET scans
Parkinson’s and Huntington’s patients
Published in a journal
Does not gather direct data

3. DOPAMINE GLUTAMATE Controls the brains reward and pleasure centres
Feelings of pleasure, addiction, movement and motivation
People repeat behaviours that lead to dopamine production
Most common neurotransmitter accounting for 90% of synaptic connections
Involved in learning and memory
Regulates development and creation of nerve contacts
Glutamate bond to NMDA receptors

4. Watch videos
Professor Jeffrey Lieberman discusses the glutamate hypothesis of schizophrenia. The drug PCP acts on glutamate receptors, producing schizophrenia-like symptoms.
Schizophrenia.html
TRANSCRIPT 1: The second neurochemical hypothesis of schizophrenia is the glutamate hypothesis. Now glutamate is also a neurotransmitter. It's a chemical that is in the brain that is secreted into synapses and facilitates nerve impulse propagation. Glutamate stimulates a receptor, a group of receptors. Now there is a recreational drug that is frequently used called PCP, phencyclidine, angel dust. And it was observed that this drug, when people take it, makes them have symptoms, makes them act like they have schizophrenia. Turns out that PCP acts at one of the receptors that glutamate stimulates to block the affects of glutamate. As a result of that, we now believe that one of the reasons why schizophrenia occurs is because people with schizophrenia have a deficiency or a defect in this receptor and the receptor cannot be properly stimulated by glutamate.
TRANSCRIPT 2: So how does glutamate relate to schizophrenia? For probably forty years, most of the work on schizophrenia was focused on dopamine. But because the evidence has increasingly centered around areas of the brain like the frontal lobe and the hippocampus, which are the so-called cortical regions of the brain, there’s been a lot more interest in what are the neurotransmitters that are critical for how the cortex works. And in the cortex, the main neurotransmitters are amino acid neurotransmitters like glutamate and GABA. Glutamate is the principle neurotransmitter of cells that communicate across long distances in the brain. Such as across cortical regions and from the cortex down into the spinal cord or out into the rest of your body. And glutamate is a critical molecule for the function of the cortex. Based on those observations, there’s been a lot of research to look at glutamate. And there’s a pharmacological model of schizophrenia based on the blocking of certain glutamate receptors, a particular glutamate receptor called the NMDA receptor, which is the N-methyl-D-aspartate receptor. There’s a drug, a street drug, called PCP which blocks this receptor. Associated with the use of this drug is a psychotic-like state – not just a psychotic state but also change in cognitive function, change in the ability to pay attention, distraction which have certain features of schizophrenia. So there’s been a pharmacological model of schizophrenia based on glutamate. Turns out, so far, most of the genes that have been found that relate to schizophrenia, particularly neuregulin, dysbindin, COMT – some other genes like GRM3, AKT1, calcineurin, etc. – many of these genes seem to impact on the function of glutamate in the brain. So glutamate might be a final common pathway that many of the biological risk factors impact upon to translate into the kind of behavior and brain function we see in schizophrenia
Professor Daniel Weinberger discusses evidence from a number of research areas that highlight the importance of the neurotransmitter glutamate in schizophrenia

5. AIM HYPERDOPAMINERGIA – high levels of dopamine
To produce drugs that REDUCE levels of relapse and negative side effects
Low levels of glutamate is associated with high dopamine levels
HYPERDOPAMINERGIA – high levels of dopamine
HYPOGLUTAMTERGIA – low levels of glutamate
Dopamine hypothesis has been strengthened with improvement in technology showing more complex neural interactions with dopamine and other neurotransmitters (glutamate).
Most patients complain about the side effects and quality of life when on antipsychotics.
This has implications on the drugs given to SZ patients as a treatment need to be tested for effectiveness.
Drugs that affect glutamate functioning may help to control negative symptoms of SZ

6. RATIONALE There is no ‘one cause’ for SZ
It follows that if neurotransmitter functioning cause SZ symptoms then drug treatments can help
Antipsychotic drugs work to suppress hallucinations and delusions
After 60 years of research, there are now likely safer antipsychotic medications, but they have failed to become more effective overall
As more knowledge is uncovered about how neurotransmitters work together, the more we can improve and develop drug treatments
where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, glutamate antagonists mimic some positive and negative symptoms with less brain harm

7. AGREED FINDINGS PCP Glutamate failure
acts as an antagonist of a glutamate receptor
Glutamate deficiency more likely to be result in psychosis (Moghaddam & Adams 98)
Glutamate failure
in the cerebral cortex may lead to negative symptoms
In the basal ganglia may lead to positive symptoms
Clozapine is a highly effective drug for SZ
fewer reported side effects
Reduces levels of dopamine and serotonin
More effective in patients who have not previously responded to treatment

8. ANIMAL STUDIES
Research done on mice in early 2009 has shown that administering NMDA antagonists in late/post foetal stage increases neuronal death which is linked to adult schizophrenia like behaviour.
This led to symptoms (such as disturbed social function, inability to adapt to predictable future stressors) that overlap with schizophrenia.

9. CONCLUSIONS Further research is needed in developing drugs to treat SZ
to avoid negative side effects
Consider the role of other neurotransmitters
Different types of SZ could be due to abnormal levels of different neurotransmitters (not just DA)

10. Conclusions….
How useful are drugs relating to dopamine? Carlsson et al. Explain that drugs have been developed that can stabilise The dopaminergic system without lowering levels of dopamine too far.
Why is this a concern?
Extrapyramidal side effects
There may be sub populations of those with SZ and there may be different causes of SZ within these sub populations.
Implications in terms of treatment? Individual differences?

11. Explain how NMDA receptor antagonists relate to glutamate deficiency [2]
NMDA receptors regulate dopamine neurons
Glutamate bond to NMDA receptors
PCP is an NMDA antagonist reducing glutamate production
Dopamine production is increased
Give evidence to show that limited glutamate might link to psychotic like symptoms [4]
Evidence from animal studies and neuroimaging is strong (Carlsson et al 99)
PCP acts as an antagonist of a glutamate receptor. Glutamate deficiency more likely to be result in psychosis (Moghaddam & Adams 98)
Glutamate failure in the cerebral cortex may lead to negative symptoms whereas in the basal ganglia may lead to positive symptoms
Research done on mice in early 2009 has shown that administering NMDA antagonists in late/post foetal stage increases neuronal death which is linked to adult schizophrenia like behaviour.

12. EVALUTION
Read the text and find evaluation points that link directly as method to study schizophrenia
Research method
Strengths
Limitations
SECONDARY DATA
PET SCANS
ANIMAL RESEARCH

13. POINT
EXPLANTION/EXAMPLE
EXTENSION + comment