Arvid Carlsson was born in Uppsala, in Sweden in 1923. He is famous for his work in neurophysiology not least the discovery of the neurotransmitter, dopamine and its links with movement. This work led him to discover that Parkinson’s Disease is caused by a lack of dopamine, and later followed his work on schizophrenia. Carlsson won the Nobel Prize for Physiology or Medicine in 2000.
Network interactions in schizophrenia – therapeutic implications
Arvid Carlsson aimed to provide an up-to-date review of the current status of the dopamine hypothesis, as an explanation of schizophrenia. He wished to raise awareness of the potential role of other neurotransmitters, such as glutamate, serotonin and GABA and present suggestions for future drug treatments for people with schizophrenia, many of whom are “treatment resistant” or who live with the extreme side-effects of typical anti-psychotics (see p000).
The role of dopamine
Carlsson says that excess dopamine may be the by-product of dysfunction of another neurotransmitter and explains that excess in one region can be the brain’s way of a way of compensating for a deficiency in another. He believes that hyperdopaminergia is only part of the puzzle and cites the fact that some people with schizophrenia show dopamine levels within the normal range and says that dopaminergic dysfunction may only account for symptoms in a sub-group of patients. In fact, some people with ‘catatonic’ symptoms have hypodopaminergic activity.
Carlsson explains that dopamine levels may be controlled by serotonin levels, so if serotonin levels are too high, this could be linked to increased dopamine levels. He also indicates that low levels of glutamate may allow both serotonin and dopamine levels to become too high. For example, glutamatergic failure in the cerebral cortex may lead to negative symptoms while the problems in the basal ganglia could be responsible for the positive symptoms.
Carlsson explains that glutamate controls dopamine and acts as both “an accelerator and a brake” in different brain regions. In the meso-cortical pathway glutamate acts as an accelerator leading to increased dopamine activity. If this goes wrong and glutamate levels fall too low, dopamine levels drop leading to negative symptoms. In the meso-limbic pathways, glutamate acts as a brake, signaling to GABA neurons to inhibit dopamine production. If the brake does not work (i.e. glutamate levels are too low) this leads to low levels of GABA and high levels of dopamine. This, in turn, leads to positive symptoms.
Future drug treatments
Carlsson suggests a variety of options regarding future drug treatment include ng the use of serotonin antagonists and glutamate agonists, which would decrease serotonin and increase glutamate respectively. He believes that differing symptoms result from differing neurochemical aetiologies making it necessary to tailor treatments to the symptoms for best results.
Stretch and challenge
Brain cell transplants as a potential future treatment
Carlsson et al (2000) raised awareness of the need to explore creative and innovative treatment options for people with schizophrenia based on state of the art research. His focus on the role of GABA interneurons has led to some extraordinary advances not least the work of Stephanie Perez and Daniel Lodge who have investigated the potential for literally replacing deficient interneurons in the hippocampus. Having created schizophrenic like symptoms in rats, they then transplanted GABAergic precursor cells directly into the hippocampus, with the effect of reversing abnormal dopamine activity. Perez and Lodge (2014) suggest that this treatment could lead to ‘a more permanent therapeutic approach for the treatment of schizophrenia’.
How might the researches have created ‘schizophrenic-like’ symptoms in the rats?
Research on glutamate antagonists
Support for the idea that low levels of glutamate are linked to elevated dopamine comes from experiments with PCP (angel dust) and ketamine.
These studies demonstrate that PCP and ketamine, which are antagonists on the NMDA, glutamate receptor can induce schizophrenic-like symptoms.
This is important because it shows that PCP has a very similar effect to drugs such as amphetamine which increase dopamine levels, suggesting that schizophrenia may be linked to hypoglutamatergic activity.
Competing argument: This said, research suggests that PCP sometimes enhances rather than reduces glutamate and more recent research by Scott Schoebel and colleagues (2013) suggests that schizophrenic-symptoms may result from excess glutamate and atrophy in the hippocampus.
Support from animal research
A further strength of hypoglutamatergia as an explanation for schizophrenia is the evidence provided by Carlsson and his daughter Maria, (1989).
Mice were given a drug to reduce motor activity and then given MK80, which reduces glutamate and increases serotonin and dopamine in the nucleus accumbens. This restarted motor activity but continued use of MK801resulted in highly abnormal behaviour, psychotic-like behaviour.
This suggests that schizophrenia may be caused by glutamate irregularity and also implies that glutamate agonists may be effective treatments.
Ignoring the role of culture
One weakness of Carlsson’s work neurotransmitters as a cause of schizophrenia, is that much of research has been based on animals models.
This means that it is impossible to study the role of culture; research by Tanya Luhrmann (2015) clearly demonstrates cultural differences in the experience of auditory hallucinations. For example, US participants were more likely to hear violent and frightening voices whereas Ghanaian and Indian people more positive experiences.
This shows that the use of animal models may be reductionist as for humans it is the holistic experience, including other people’s reactions to the symptoms, which determine the lived experience of the disorder.
Applications: Advances in drug treatments
A strength of Carlsson’s focus on serotonin and glutamate is that it has led to the development of new drug treatments.
For example, both serotonin antagonists and glutamate agonists are effective in reducing positive and negative symptoms of schizophrenia.
These advances are particularly important as the drugs have worked for patients who had been previously treatment resistant. Furthermore, drug compliance has been enhanced, by the reduction in side effects, such as tardive dyskinesia.
EXTRA: Issues and debates
One pertinent issue in this discussion is that of gender as on average age of onset is later and prognosis generally more positive in females.
Research by Andrea Gogos et al. (2015) point to the neuroprotective role of estrogen, the primary female sex hormone, which appears to help to regulate glutamate, serotonin and dopamine.
This shows that estrogen-based medications may provide yet another pathway for treating schizophrenia.
- With reference to Carlsson et al. (2000), explain how two neurotransmitters, other than dopamine, maybe linked to schizophrenia (4)
- Explain one strength and one weakness of Carlsson et al. (2000). (4)
- Standard: Evaluate Carlsson et al.’s (2000), review of the role of neurotransmitters in schizophrenia (8, 12, 16, 20)
- I & D: With reference to Carlsson et al. (2000), assess the extent to which understanding of schizophrenia has developed over time (20)