Schizophrenia Research Forum - A Catalyst for Creative Thinking

Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison KE. Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning. Proc Natl Acad Sci U S A. 2007 Oct 9 ; 104(41):16311-6. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Patricia Estani
Submitted 16 November 2007
Posted 16 November 2007
  I recommend the Primary Papers

Primary Papers: Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning.

Comment by:  Phil Corlett
Submitted 29 November 2007
Posted 29 November 2007
  I recommend this paper

The earliest formulations of schizophrenia hypothesized that the formation of inappropriate associations between stimuli, thoughts, and percepts was a core disease process (Bleuler, 1911/1950; Schneider, 1930). Having developed an understanding of association formation both psychologically and physiologically in experimental animals, Pavlov attempted to apply what he had learned to psychiatric patients at the Balinskiy Psychiatric Hospital (Pavlov, 1928). This attempt is being realized through translational behavioral neuroscience studies of the role of dopaminergic neurotransmission in the midbrain, striatum, and prefrontal cortex in associative learning, implicating aberrant learning processes and their brain basis in the mesocorticolimbic dopamine system in the genesis of positive psychotic symptoms (Kapur , 2003) and in particular delusional beliefs (Corlett et al., 2006; Corlett et al., 2007; Corlett et al., 2007).

The work reported by Michael Frank and colleagues (Frank et al., 2007) contributes to this enterprise, shedding new light on the roles of dopamine in reinforcement learning through a combined computational and genetic analysis of healthy individuals’ behavior on a prediction error-driven reinforcement learning task. Given the link between reinforcement learning, dopamine, and psychosis, these data will likely aid our understanding of the pathophysiological processes underpinning the genesis of psychotic symptoms, especially since the genes of interest in the present analysis (DRD2, DARPP-32, and COMT) have all been associated with risk for schizophrenia (Talkowski et al., 2007).

However, there may be some inconsistencies between Frank and colleagues' results and prior data on the links between the functionality of the genes of interest, cognitive performance, brain structure and function, and risk for schizophrenia. In brief, variation in the gene that codes for DARPP-32 has also been associated with enhanced working memory task performance, as well as with striatal activity and frontostriatal structural and functional connectivity during a working memory task (Meyer-Lindenberg et al., 2007). Additionally, that same locus of variability was linked with increased risk for schizophrenia in a family association study. These data highlight the various biological and psychological processes that dopaminergic genes can impact upon and the importance of appreciating how interactions between brain structures can influence psychological processes. Put simply, the notion that genes act at the level of single neurotransmitters, single brain regions, and single psychological processes is likely overly simplistic.

Furthermore, the process of interaction between genes in subtending particular phenotypes (epistasis) may be particularly important in the case of the genes under examination in Frank and colleagues’ paper, since, ultimately, all of the genes impact in some way upon dopamine function across distinct but interacting brain regions. In particular, the possibility that COMT function in prefrontal cortex may impact upon dopamine levels and responsivity subcortically could well influence the neurobiological locus of the effects that Frank and colleagues report. That is, although COMT function has a direct impact upon dopamine levels in PFC, it may also have effects on subcortical responsivity through feedback projections to striatum (Bilder et al., 2004; Meyer-Lindenberg et al., 2002), a possibility not captured by Frank and colleagues’ interpretation of their results.

In addition, DARPP-32 has multiple functions—critically, it also modulates D2 function (Greengard, 2001), which might lead one to expect an impact upon both Go and NoGo learning, rather than the specific effect on Go learning that Frank and colleagues hypothesize. Indeed, Figure 2A seems to suggest that there was a trend towards an impact on NoGo learning, also. Additionally, DARPP-32 interacts with serotonin and acetylcholine signaling, amongst many other neurotransmitters and neuromodulators (Greengard, 2001). These relationships need to be taken into account, especially since both serotonin (Daw and Doya, 2006) and acetylcholine (Pauli and O'Reilly, 2007) have been implicated in reinforcement learning.

Ultimately, Frank and colleagues proffer an exciting new method of understanding the relationship between dopamine function and reinforcement learning. Combining this approach with functional neuroimaging, pharmacological manipulations, and studies of schizophrenic patients, whilst considering the role of genetic interactions, will aid our understanding of the neurobiology of learning and its dysfunction in schizophrenia.


Bleuler E. Dementia Praecox or the Group of Schizophrenias. New York, International University Press, 1911/1950.

Schneider C. Die Psychologie der Schizophrenen. Leipzig, Germany Thieme, 1930.

Pavlov IP. Lectures on conditioned reflexes. London, Lawrence & Wishart, 1928.

Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003; 160(1):13-23. Abstract

Corlett PR, Honey GD, Aitken MR, Dickinson A, Shanks DR, Absalom AR, Lee M, Pomarol-Clotet E, Murray GK, McKenna PJ, Robbins TW, Bullmore ET, Fletcher PC. Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis. Arch Gen Psychiatry 2006; 63(6):611-21. Abstract

Corlett PR, Honey GD, Fletcher PC. From prediction error to psychosis: ketamine as a pharmacological model of delusions. J Psychopharmacol 2007; 21(3):238-52. Abstract

Corlett PR, Murray GK, Honey GD, Aitken MR, Shanks DR, Robbins TW, Bullmore ET, Dickinson A, Fletcher PC. Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions. Brain 2007; 130(Pt 9):2387-400. Abstract

Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison KE. Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning. Proc Natl Acad Sci U S A 2007; 104(41):16311-6. Abstract

Talkowski ME, Bamne M, Mansour H, Nimgaonkar VL. Dopamine genes and schizophrenia: case closed or evidence pending? Schizophr Bull 2007; 33(5):1071-81. Abstract

Meyer-Lindenberg A, Straub RE, Lipska BK, Verchinski BA, Goldberg T, Callicott JH, Egan MF, Huffaker SS, Mattay VS, Kolachana B, Kleinman JE, Weinberger DR. Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J Clin Invest 2007; 117(3):672-82. Abstract

Bilder RM, Volavka J, Lachman HM, Grace AA. The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 2004; 29(11):1943-61. Abstract

Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002; 5(3):267-71. Abstract

Greengard P. The neurobiology of slow synaptic transmission. Science 2001; 294(5544):1024-30. Abstract

Daw ND, Doya K. The computational neurobiology of learning and reward. Curr Opin Neurobiol 2006; 16(2):199-204. Abstract

Pauli WM, O'Reilly RC. Attentional control of associative learning-A possible role of the central cholinergic system. Brain Res 2007. Abstract

View all comments by Phil Corlett