Updated December 2012
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The venerable dopamine hypothesis of schizophrenia proposes that aberrations in the brain's dopamine system cause some symptoms of the disorder. Countless studies have explored this long-standing idea, and in 2006, Anissa Abi-Dargham comprehensively summarized the work in a Current Hypothesis paper on the SRF website. Now in 2012, she has updated her review, which includes many more brain imaging studies. To highlight the new developments, Abi-Dargham spoke to us by phone from her office in New York City, where she works as a professor of clinical psychiatry and radiology at Columbia University.
SRF: It's been six years since you posted the latest findings relevant to the dopamine hypothesis of schizophrenia on the SRF website. What's new?
Abi-Dargham: There are three main developments. One of the biggest findings is that the precommissural dorsal caudate, or head of the caudate, shows a larger dysregulation in dopaminergic transmission than the ventral striatum does. Presynaptic dopamine, or D2 receptor occupancy by dopamine, measured with the α-MPT paradigm (Editor's note: α-methylparatyrosine acutely depletes dopamine) or the F-DOPA method used by Oliver Howes and colleagues, both show the same pattern. The head of the caudate is interesting because that's the area that receives projections from dorsal lateral prefrontal cortex (DLPFC). It's also interesting because it also receives a projection from limbic cortices, like the orbital frontal cortex (OFC). So you have integration across functional domains.
SRF: What's interesting about the DLPFC and OFC projections?
Abi-Dargham: Brain imaging studies have pinpointed inefficient activation in DLPFC when patients with schizophrenia are processing working memory tasks. There is also so much information about abnormalities there with respect to neurotransmitters, the neuronal circuitry, the findings about GABAergic deficits in chandelier cells, and other indices of GABA transmission. So imaging and neuropathology studies point to the DLPFC as an area of pathology in schizophrenia.
The OFC and the cingulate cortex send projections to the precommissural dorsal caudate, in addition to the DLPFC, which is interesting given the aberrant salience hypothesis that Shitij Kapur put forth (Kapur, 2003). Aberrant salience means that neutral stimuli may take on an emotional, non-neutral, significance. The convergence in the precommissural dorsal caudate area of projections from limbic, emotional information processing areas, along with cognitive associative information processing areas, in the presence of enhanced dopamine transmission, may give an anatomical substrate for this aberrant salience.
The second biggest development is the finding that dopamine dysregulation occurs in prodromal patients, as found by Oliver Howes (Howes et al., 2011; SRF related news story). So it can be a biomarker of who may convert to schizophrenia over time. So this indicates that it's a very early abnormality in the brain in schizophrenia. We don't know how much earlier than the prodrome this happens, but we know it's as early as the prodromal stage at least.
The third biggest development is an animal model that is very relevant to schizophrenia neurobiology—the D2 receptor-overexpressing mice developed in the lab of Eric Kandel (see SRF related news story). These show that a small increase in D2R expression in the dorsal striatum during development can lead to profound alterations in cognition in those mice, and that this cognitive deficit is irreversible. Which means that the striatal pathology that may be occurring very early on could have pathogenic effects on the rest of the circuitry and lead to cognitive deficits.
SRF: These last two items suggest that dopamine dysfunction happens early on in the development of schizophrenia. Does this move dopamine dysfunction closer to a proximal cause of schizophrenia?
Abi-Dargham: It doesn't necessarily show that it's primary, but it doesn't rule it out either. As long as we don't know how early it starts, and why, we cannot really answer this question. You have to go back in development, even in utero, to know more about how dopamine dysfunction starts. These data do not answer this question directly, but they do highlight the fact that dopamine dysregulation is happening very early on, and if it were to happen during development it could possibly lead to a lot of the abnormalities that we see.
SRF: In your mind, where does the dopamine hypothesis of schizophrenia stand now?
Abi-Dargham: These three new developments have refined it, and confirmed that dopamine plays a central part in schizophrenia. But we need to go beyond just knowing that dopamine is abnormal. We need to understand how, when, where, and what are the consequences. We need to understand in cellular terms the dopamine dysfunction and how it emerges. Is it only presynaptic, or also postsynaptic? Which one leads to the other? When does it happen during development? How early? What are the consequences? We almost have more questions than when we started.
SRF: How do you think about integrating dopamine dysfunction with the other neurotransmitter abnormalities reported in schizophrenia?
Abi-Dargham: One of the most interesting stories that informs this type of question is the data from the MAM (Editor's note: methylazoxymethanol acetate) model of Tony Grace (see SRF related news story), which has a lot of face validity with schizophrenia. In this model, he finds that midbrain dopamine cell firing patterns are overactive, and these stem from changes in the hippocampus. The ventral hippocampus sends glutamatergic projections to the ventral striatum, which inhibits the ventral pallidum, which then sends an inhibitory projection down to midbrain dopamine cells. The MAM model presents a deficit in GABAergic interneurons in the hippocampus, which would lead to an overdrive of the glutamatergic projection from the ventral hippocampus into the ventral striatum, which over-inhibits the ventral pallidum projection that goes to midbrain dopamine cells. This disinhibits the midbrain dopamine cells and leads to their increased firing. And that could explain why there is increased dopamine in schizophrenia.
This model incorporates many well-known facts about schizophrenia, like the hippocampal pathology, the hippocampus being overactive, excess glutamate transmission. It connects the three together—the GABA story, the glutamate story, the dopamine story. It doesn't mean that's all that's happening. But models are good at explaining at least part of the circuitry, or parts of the interactions.
SRF: Is there a way for imaging studies to make some inroads into these kinds of interactions?
Abi-Dargham: Yes. For example, we have shown with imaging that under conditions of NMDA receptor blockade, dopamine release is increased in the striatum (Kegeles et al., 2002). To test Grace's model more directly, in prodromal studies, we could look at the co-occurrence of alterations in hippocampal activity and F-DOPA or midbrain dopamine cell activity. So we have to look at the different sites together. Phil McGuire's group has been doing some of these studies, and has found relationships between glutamate in hippocampus and F-DOPA. Though we don't know exactly how the MRS (magnetic resonance spectroscopy) signal relates to synaptic glutamate—it's complicated.
SRF: From your update, it seems like evidence for dopamine dysfunction in prefrontal cortex is still unclear.
Abi-Dargham: So for the cortex, the D1 receptor is the predominant dopaminergic receptor, and imaging data for it have been inconsistent. A Japanese group has found decreases, we have found increases, first in a mixed group of patients who are drug-free and drug-naive, and second in drug-naive patients only. There is evidence about D1R being downregulated by antipsychotics from monkey studies by Pat Goldman-Rakic, and from the data in our second cohort. So it seems like D1 receptors may change in response to antipsychotic exposure. It has been complicated also because the radiotracers themselves are not that selective for D1 receptors. A better approach might be to look at dopamine release itself, and we are doing it as we speak.
SRF: What needs to happen next?
Abi-Dargham: We need to understand the cellular mechanisms of dopamine dysfunction and its consequences. We need to understand the timing during development and its effects. We need to understand dopamine in the cortex better. That is not clear at this point. We need to understand the relationship between cortical and striatal dopamine, the relationship to other well-known sites of pathology like the hippocampus and to other transmitters, and we need to understand the functional correlates of dopamine dysregulation in the cortex that exists.
SRF: It sounds like a lot of basic science.
Abi-Dargham: It's translational science. It's a back and forth between basic science and brain imaging. Scientists are looking at mouse models, feeding information to the imagers, then going back again. And we need patients' participation and families' help to be able to figure out this problem.
SRF: Anything else you'd like to add?
Another direction comes from a new study in Molecular Psychiatry (Thompson et al., 2012). It will be confusing because it shows that a group of patients with schizophrenia who are also substance abusers have low presynaptic dopamine release—opposite of what I was just telling you. But when you give them amphetamines, they have still the same relationship between D2 receptor stimulation or increase in dopamine release and psychosis. Which means that the D2 receptor is somehow supersensitive to dopamine. So it's not just presynaptic abnormalities, because their presynaptic dopamine is down. It's the function, and not so much the expression of, the D2 receptor, that may be abnormal. There doesn't seem to be an increase in D2 receptor affinity, but one thing that hasn't been looked at is the possibility of altered internalization of the D2 receptor.
SRF: So this points to alterations in D2 receptor function in schizophrenia as well—it's not just a simple matter of counting D2 receptors.
Abi-Dargham: Yes, this points to alterations in D2 signaling, and you know that is not something you can test with imaging. So there is the presynaptic dysfunction, which is excess dopamine release, excess dopamine synthesis. And then there is the postsynaptic D2 receptor function, which could be abnormal. Not so much the expression, or the receptor numbers, but more the D2 signaling itself. So there are postsynaptic effects and presynaptic effects. And one big question that remains at this point: Which is primary [i.e.], which leads to the other, do they both occur, which is more predominant, are they compensatory phenomena? All of this is not clear.
SRF: It sounds like there is plenty of work ahead. Thanks for sharing your thoughts with us.
Abi-Dargham: Thank you.
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