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See comments below by:
Shoji Tanaka—15 December 2006
Daniel Weinberger—27 December 2012
Philip Seeman—27 December 2012

Comment by Shoji Tanaka—15 December 2006

Note: This comment was submitted to the 2006 edition of this hypothesis paper.

I appreciate the excellent review by Dr. Abi-Dargham on the current status of the dopamine (DA) hypothesis of schizophrenia. Although it covers many important issues, I here would like to add a new perspective on the dopaminergic modulation of the activity of the prefrontal cortex (PFC) and its relevance to schizophrenia. It is a circuit dynamics perspective.

As Dr. Abi-Dargham reviewed, the relationship between cortical dopaminergic transmission and symptoms of schizophrenia is not yet definitive, even though many studies have suggested hypodopaminergic transmission in the PFC in association with cognitive and negative symptoms. The so-called inverted U-shaped profile of the dependence of working memory performance on the D1 receptor activation level illustrates how the cognitive function declines with the deviation of the DA level in the PFC from the optimum point (Goldman-Rakic et al., 2000). A recent computational study, however, suggests that the PFC circuit is not always stable along the inverted U- shaped curve (Tanaka, 2006).

The stability of the PFC circuit depends on the DA tone in the PFC, and may have more direct links to schizophrenia than the dopaminergic transmission itself. The closed-loop circuitry of the prefronto-mesoprefrontal system (Frankle et al., 2006; Sesack and Carr, 2002) can work as a "regulator" of the PFC activity for working memory if the system is stable (Tanaka, 2006). A conventional stability analysis shows that the closed-loop circuit is indeed stable when the DA level is around the optimum point or higher (Tanaka, 2006). Under hypodopaminergic conditions, in contrast, the system becomes unstable and no longer works as a regulator of the PFC activity. This is because the closed-loop gain of the system varies with the DA level in the PFC, and the switchover from a negative feedback system to a positive feedback system occurs as the cortical DA level decreases. The dysregulation of the PFC activity would be responsible for cognitive deficits in schizophrenia.

Because of the instability of the PFC circuit, an increase in DA releasability in the PFC would cause a "catastrophic jump" in the PFC activity from a very low level to a high level (Tanaka, 2006). And, provided that a hypodopaminergic state of the PFC is relevant to schizophrenia, as reviewed by Dr. Abi-Dargham, this can lead to overactivation of the PFC of patients with schizophrenia during working memory performance. This may be one of the reasons why functional MRI studies of patients with schizophrenia show seemingly inconsistent activation of the PFC (Callicott et al., 2003; Manoach, 2003). Due to the circuit instability, the PFC activity would be intrinsically fluctuating in schizophrenia, which may have implications for understanding the nature of schizophrenia. Although further studies are obviously necessary, the research into the mechanisms of schizophrenia would require a dynamic, rather than a static, point of view.

References:

Callicott JH, Mattay VS, Verchinski BA, Marenco S, Egan MF, Weinberger DR. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry. 2003 Dec;160(12):2209-15. Abstract

Frankle WG, Laruelle M, Haber SN. Prefrontal cortical projections to the midbrain in primates: evidence for a sparse connection. Neuropsychopharmacology. 2006 Aug;31(8):1627-36. Abstract

Goldman-Rakic PS, Muly EC 3rd, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000 Mar;31(2-3):295-301. Review. No abstract available. Abstract

Manoach DS. Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res. 2003 Apr 1;60(2-3):285-98. Review. Abstract

Sesack SR, Carr DB. Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav. 2002 Dec;77(4-5):513-7. Review. Abstract

Tanaka S. Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective. Neuroscience. 2006 Apr 28;139(1):153-71. Epub 2005 Dec 1. Review. Abstract

Comment by Daniel Weinberger—27 December 2012

I applaud Dr. Abi-Dargham for her thoughtful and objective review of evidence supporting the role of DA in psychosis and schizophrenia. She has illustrated with clarity and depth that the dopamine hypothesis has been of singular heuristic value and enormously influential in guiding research about the pathophysiology of psychosis.

She also has highlighted that early hypotheses based on too much or too little dopamine in the brain are not tenable as explanations for complex perceptual and cognitive abnormalities, but the jury is still out on what is the cart and what is the horse. What are the basic mechanisms of dopaminergic dysregulation associated with psychosis, whether it be at the striatal or cortical level? It is interesting to note that most functional imaging studies of psychotic experiences highlight physiologic alterations at the cortical, not striatal, level, and legendary intracortical stimulation studies of Wilder Penfield and more recent studies by Jerome Engel and colleagues at UCLA suggest that psychotic experiences are most reliably induced by electrophysiological activation of mesial temporal cortices. Is the dopamine factor a passenger phenomenon, enlisted by the experience of chronic cortical dysfunction and disorganized processing of complex environmental stimuli leading to a state of chronic cognitive and emotional stress? Chronic stress depletes prefrontal DA terminals, which lack transporters to recycle synaptic dopamine, and leads both directly and indirectly via loss of prefrontal inhibition of midbrain DA neurons to recruitment of DA cell firing and activation of nigrostriatal terminal activity.

The only objective clues to the etiological components of schizophrenia that are not potentially secondary to something else are the genetic clues. The most recent GWAS from the PGC analysis reported at the Psychiatric Genetics Congress in Hamburg in 2011 revealed that the DRD2 gene is now in the catalogue of GWAS-significant genes. Whether this means it is suddenly a legitimate risk factor for schizophrenia, while before the PGC imprimatur it was not, is up for debate. Regardless, Einstein is quoted as saying that "nature is subtle but not malicious." It is likely that the role of DA in the pathophysiology of schizophrenia is much more subtle than originally conceived, but it would seem malicious to think that it is not relevant.

Comment by Philip Seeman—27 December 2012

In addition to the points raised in the excellent review by Anissa Abi-Dargham, it should be noted that the postsynaptic dopamine supersensitivity found in schizophrenia patients by Thompson et al. (Thompson et al., 2012) may be readily explained by the consistent increase in dopamine D2(high) receptors in all animal models of psychotic-like dopamine-supersensitive behavior (Seeman, 2010).

By the way, the discovery of the antipsychotic/dopamine D2 receptor was reported in Seeman et al. (Seeman et al., 1975) and not in Seeman and Lee (Seeman and Lee, 1975), as mentioned in this review.

References:

Seeman P, Chau-Wong M, Tedesco J, Wong K. (1975) Brain receptors for antipsychotic drugs and dopamine: Direct binding assays. Proc Nat Acad Sci USA 72:4376-80. Abstract

Seeman P, Lee T. (1975) Antipsychotic drugs: Direct correlation between clinical potency and presynaptic action on dopamine neurones. Science 188:1217-9. Abstract

Seeman P. (2010) All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors. CNS Neuroscience and therapeutics 17(2):118-32. Abstract

Thompson JL, Urban N, Slifstein M, Xu X, Kegeles LS, Girgis RR, Beckerman Y, Harkavy-Friedman JM, Gil R, Abi-Dargham A. (2012) Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol Psychiatry Aug 7. Abstract