Schizophrenia Research Forum - A Catalyst for Creative Thinking

Biology of Reinforcement—Dopamine Linked to Three Separate Reward Paths

16 October 2007. Pavlov may not have known it, but his bell got more than saliva flowing. His experiments undoubtedly spurred dopamine release in his dogs’ brains, and probably in his own as well. We now know that the neurotransmitter mediates positive reinforcement associated with reward. More controversial is whether dopamine plays any role in negative reinforcement, as in learning to avoid displeasurable, or non-rewarding stimuli. A paper in the October 8 PNAS suggests that it does.

Researchers led by Michael Frank at the University of Arizona, Tucson, have correlated genetic polymorphisms with reward learning in young, healthy adults. Their findings indicate that dopamine plays a role in three independent reward pathways—short-term adaptability, and positive and negative long-term reinforcement. The findings are of interest to schizophrenia researchers given that compromised decision-making is one of the most debilitating facets of the disease.

Frank and colleagues studied the DARPP-32, DRD2, and COMT genes, all three linked to dopamine function: DRD2 is the gene for the D2 dopamine receptor; DARPP-32 codes for dopamine and cAMP regulated phosphoprotein of 32 kDa, which mediates the effects of dopamine D1 activation on synaptic plasticity; and COMT codes for catechol-O-methyl transferase, an enzyme that degrades dopamine. All three are candidate risk genes for schizophrenia (see SRF related news story and SRF news story).

The authors focused on an A/G DARPP-32 polymorphism that modulates striatal function (see SRF related news story). They predicted that this polymorphism might affect reward-based learning, since the DARPP-32 is highly abundant in the striatum, where D1 activation has been linked to decision-making based on positive outcomes. They focused on a C957T polymorphism in the DRD2 gene that affects post-synaptic D2 density, predicting that it might influence decisions associated with negative outcomes. And they looked at the Val158Met polymorphism in the COMT gene, which is associated with changes in dopamine level in the prefrontal cortex (see SRF related news story). The authors write that “this genetic marker of prefrontal DA function would predict the extent to which participants maintain negative outcomes in working memory to quickly adjust their behavior on a trial-to-trial basis.” The prefrontal cortex is an area of particular interest to schizophrenia researchers.

The authors correlated the three polymorphisms with reinforcement learning. Frank had healthy, young undergraduate students take part in a computerized test that simultaneously measures how well positive and negative feedback is learned. Briefly, the volunteers learn that on a probabilistic basis one possibility, “A,” is best chosen, while another, “B,” is best avoided.

The results supported the predictions. Averaging over a number of trials, DARPP-32 AA homozygotes were better than G carriers in the “choose-A” positive reinforcement scenario. In contrast, compared to those carrying the C allele, DRD2 TT homozygotes were much better in the “avoid-B” scenario, suggesting that they learn better from negative feedback. The Val/Met COMT polymorphism had no effect on positive reinforcement learning or avoidance learning over the long term. However, it did affect behavior on a trial-to-trial basis. Volunteers homozygous for the Val allele (and also the lowest prefrontal cortex dopamine) were less likely to alter their response based on a prior negative outcome.

“One of the surprising findings was that we saw such a large effect with individual genes,” said Frank in an interview with SRF. He noted that the results do not suggest 100 percent predictability; in other words, you cannot look at any one person’s genotype and know exactly how he or she is learning, “but nevertheless, across the samples the effect sizes we found were relatively large,” said Frank.

The other surprise was the D2 dopamine receptor role in negative reward learning, which has been a highly debated topic. Frank explained that work in primates has shown there is a pause in dopaminergic firing when the animals fail to get an expected reward. This has led to the suggestion that a dip in dopamine release may be involved in negative feedback learning. “The reason that is controversial is because the pause in these dopamine cells that happens during negative feedback is relatively small and because the baseline firing rate is already pretty low, so when they pause the change in firing rate is not nearly as big as during reward,” he explained. “In our specific model we can account for that because this negative-feedback learning depends on the D2 receptor, which is really sensitive to dopamine levels: essentially it is more sensitive to these small changes than the D1 receptor, which requires greater activation,” he said. He also stressed that this latest finding does not rule out the involvement of other neurotransmitters in avoidance learning.

Do these findings have any significance for schizophrenia research? The disease is certainly linked to dopamine dysfunction (see SRF Current Hypothesis) and also to deficits in the prefrontal cortex. Frank has already done a study in schizophrenic patients, in collaboration with Jim Gold’s lab at the University of Maryland, Baltimore. They found that people with schizophrenia were indeed impaired in that same measure of rapid learning from negative feedback, but they were just fine on long-term integration of negative feedback over many trials (see Waltz et al., 2007). But though the dopamine hypothesis for schizophrenia is a long-standing one, “there are many other factors that need to be considered in schizophrenia,” said Frank. “However, I do think that studying schizophrenia from a motivational standpoint, looking at reward processing, can be very fruitful. If there is a fundamental dysfunction in reward learning circuitry, that can lead to compounding effects on all sorts of behaviors," he said.—Tom Fagan.

Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison K. Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning. PNAS. 2007 Oct 8;104:16311-16316. 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

Comments on Related News

Related News: New Genetic Variations Link Schizophrenia and Bipolar Disorder

Comment by:  Mary Reid
Submitted 28 September 2006
Posted 29 September 2006

It's of interest that Vazza and colleagues suggest that 15q26 is a new susceptibility locus for schizophrenia and bipolar disorder. I have suggested that reduced function of the anti-inflammatory SEPS1 (selenoprotein S) at 15q26.3 may reproduce the neuropathology seen in schizophrenia.

View all comments by Mary Reid

Related News: New Genetic Variations Link Schizophrenia and Bipolar Disorder

Comment by:  Patricia Estani
Submitted 5 October 2006
Posted 6 October 2006
  I recommend the Primary Papers

Related News: The New "Inverted U”—Cellular Basis for Dopamine Response Pinpointed

Comment by:  Andreas Meyer-Lindenberg
Submitted 8 February 2007
Posted 8 February 2007

This fascinating paper contributes to our mechanistic understanding of a fundamental nonlinearity governing the response of prefrontal neurons during working memory to dopaminergic stimulation: the “inverted U” response curve (Goldman-Rakic et al., 2000), which proposes that an optimum range of dopaminergic stimulation exists, and that either too little or too much dopamine impairs tuning, or the relationship between task-relevant (“signal”) and task-irrelevant (“noise”) firing of these neurons. On the level of behavior, this is predicted to result in impaired working memory performance outside the optimum middle range, and this has been confirmed in a variety of species. This is a topic of high relevance for schizophrenia where prefrontal dysfunction and related cognitive deficits, and dopaminergic dysregulation, have long been in the center of research interest (Weinberger et al., 2001), and may be linked (Meyer-Lindenberg et al., 2002). In particular, evidence for abnormally decreased dopamine levels in prefrontal cortex would predict that patients with schizophrenia are positioned to the left of the optimum. This line of thought has recently received impetus from genetic studies on COMT, the major enzyme catabolizing dopamine in prefrontal cortex (Tunbridge et al., 2004). Neuroimaging studies have shown that genetic variants with high COMT activity are positioned to the left, those with lower activity nearer the optimum of the inverted U curve, and that this position predicts nonlinear response to amphetamine stimulation (Mattay et al., 2003), as well as interactions between dopamine synthesis and prefrontal response (Meyer-Lindenberg et al., 2005). Variants with sub- (Egan et al., 2001; Nicodemus et al., 2007) or superoptimal (Gothelf et al., 2005) stimulation were associated with schizophrenia risk. Task-related and task-unrelated prefrontal function reacted in opposite ways to genetic variation in dopamine synthesis, suggesting a tuning mechanism (Meyer-Lindenberg et al., 2005). Recently, interacting genetic variants in COMT have also been found to affect prefrontal cortex function in an inverted U fashion (Meyer-Lindenberg et al., 2006).

A seminal contribution to the cellular mechanisms of the inverted U curve is the paper by Williams (one of the authors of the current study) and Goldman-Rakic in Nature 1995 (Williams and Goldman-Rakic, 1995). In this work, dopamine D1 receptor antagonists were used and shown to increase prefrontal cell activity in low levels, whereas high levels inhibited firing. This implicated a mechanism related to D1 receptors and suggested that the neurons studied were to the right of the optimum on the inverted U curve, that is, their dopamine stimulation was excessive. The present study, from Amy Arnsten’s lab at Yale, further defines the cellular mechanisms underlying the inverted U curve in recordings from PFC neurons of awake behaving monkeys exposed to various levels of stimulation by a dopamine 1 receptor agonist. A spatial working memory paradigm was used, enabling the determination of the degree to which the neurons were tuned by comparing the firing rate to stimuli in the preferred spatial stimulus direction (“signal”) to the firing rate to nonpreferred stimuli (“noise”). The authors recorded both from neurons that were highly tuned (supposedly receiving optimum stimulation) and neurons that were less tuned. As would be predicted from the model, highly tuned neurons did not improve, or worsened, during stimulation, while weakly tuned neurons became more focused in their activity profile. It is not quite clear to me why the previous paper (Williams and Goldman-Rakic, 1995) found neurons that were predominantly to the right of the optimum, while this work identified neurons using a similar paradigm that were either to the left or near the optimum. Perhaps it is because Williams and Goldman-Rakic (Williams and Goldman-Rakic, 1995) screened neurons for a response to the D1 antagonist first. In both studies, extracellular dopamine was not actually measured, meaning that the state of basal stimulation can only be inferred indirectly from the response to the iontophoresed agonist or antagonist. Importantly, the effect of D1 stimulation was always suppressive; effects on tuning were due to the fact that the reduction in response to the signal and the noise were different in extent, such that for weakly tuned neurons and low levels of D1 stimulation, the noise firing was more suppressed than that of the signal, resulting in increased signal to noise. In a second set of pharmacological experiments, which included validation in a rat working memory model, the authors show that these effects are cAMP, but not PKC-dependent, suggesting a preferential cellular mechanism through Gs-proteins, which might be useful for exploration of more specific drug targets.

This work has interesting implications for our understanding of prefrontal function in schizophrenia. Since dopamine stimulation was found to be almost exclusively suppressive, cortical dopamine depletion in schizophrenia would be predicted to lead to relatively increased, but inefficient (untuned) cortical cognitive response, as has indeed been observed (Callicott et al., 2000). However, it is an open question precisely how cortical physiology assessed by imaging relates to these cellular events. The data by Arnsten suggest that each patch of prefrontal cortex will contain a population of neurons at various states of tuning that will respond differently to drug-induced or cognitively related changes in extracellular dopamine, with some improving, some decreasing their tuning. Depending on whether imaging signals and tasks are more sensitive to overall firing rate, or to specific signal-to-noise properties, the resulting blood flow change might be quite different. Perhaps this contributes to some of the puzzling discrepancies between hypo- and hyperactivation both being observed in comparable tasks and regions of prefrontal cortex in schizophrenia.


1. 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

2. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry. 2001 Dec 1;50(11):825-44. Review. Abstract

3. 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 Mar;5(3):267-71. Abstract

4. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004 Jun 9;24(23):5331-5. Abstract

5. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. Epub 2003 Apr 25. Abstract

6. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005 May;8(5):594-6. Epub 2005 Apr 10. Abstract

7. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22. Epub 2001 May 29. Abstract

8. Nicodemus KK, Kolachana BS, Vakkalanka R, Straub RE, Giegling I, Egan MF, Rujescu D, Weinberger DR. Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Hum Genet. 2007 Feb;120(6):889-906. Epub 2006 Sep 28. Abstract

9. Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov;8(11):1500-2. Epub 2005 Oct 23. Abstract

10. Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR. Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry. 2006 Sep;11(9):867-77, 797. Epub 2006 Jun 20. Abstract

11. Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature. 1995 Aug 17;376(6541):572-5. Abstract

12. Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R, Goldberg TE, Weinberger DR. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex. 2000 Nov;10(11):1078-92. Abstract

View all comments by Andreas Meyer-Lindenberg

Related News: DARPP-32 Haplotype Affects Frontostriatal Cognition and Schizophrenia Risk

Comment by:  Jonathan Burns
Submitted 14 February 2007
Posted 14 February 2007

This study provides hard empirical evidence for the hypothesis that psychosis (and schizophrenia in particular) represents a costly "byproduct" of complex human (social) brain evolution. Interestingly, the activation paradigms in the fMRI study (N-back and emotional face-matching tasks) are both testing social cognition. And the demonstrated changes in frontostriatal connectivity support the hypothesis that schizophrenia is a disorder of evolved intrahemispheric circuits comprising the Social Brain in our species.

I would suggest that further candidates (conferring vulnerability to psychosis) should be sought from amongst those genes known to have played a significant role in human brain evolution.


Burns J. (2007) The Descent of Madness: Evolutionary Origins of Psychosis and the Social Brain. Routledge Press: Hove, Sussex.

Burns J. The social brain hypothesis of schizophrenia. World Psychiatry. 2006 Jun;5(2):77-81. Abstract

Burns JK. Psychosis: a costly by-product of social brain evolution in Homo sapiens. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Jul;30(5):797-814. Epub 2006 Mar 3. Review. Abstract

Burns JK. An evolutionary theory of schizophrenia: cortical connectivity, metarepresentation, and the social brain. Behav Brain Sci. 2004 Dec;27(6):831-55; discussion 855-85. Review. Abstract

View all comments by Jonathan Burns

Related News: The New "Inverted U”—Cellular Basis for Dopamine Response Pinpointed

Comment by:  Terry Goldberg
Submitted 6 April 2007
Posted 6 April 2007

In this landmark study, Arnsten and colleagues used a full dopamine agonist in awake behaving monkeys to make key points about the inverted U response at the cellular level and how this maps to the behavioral level. There were a number of surprises. The first was that stimulation of the D1 receptor had consistently suppressive effects on neuronal firing during delays in a working memory task. The second was that when responses were optimized, suppressive effects differentially affected non-preferred directional neurons, rather than preferred direction neurons. Thus, it appeared that noise was reduced rather than signal amplified. Too much D1 stimulation resulted in suppression of both classes of neurons.

The implications of this work are important because it suggests that there is a neurobiological algorithm at work that can reliably produce this unexpected physiological pattern (perhaps as the authors suggest on the basis of baseline activity). It remains to be elucidated whether the D1 receptor effects are mediated by glutamatergic neurons or GABA interneurons, or both. There is another layer of complexity to the story. As Arnsten and colleagues note, possible excitatory influences of D1 stimulation may not have been observed because endogenous dopamine had already triggered this process. It is unclear if D2 receptors in the cortex have a role in shaping or terminating this activity.

Last, it is tempting to speculate about the implications of these findings for other types of tasks that engage prefrontal cortex in humans. What does tuning mean in the context of tasks like the N Back which demands updating, the ID/ED test from the CANTAB, which involves suppression of salient distractors at early set shifting stages, or a task which demands heavy doses of cognitive control like the flanker task, all of which have been shown to be sensitive to manipulations of the dopamine system (Goldberg et al., 2003; Jazbec et al., 2007; Diaz-Asper et al., in press; Blasi et al., 2005)?

View all comments by Terry Goldberg

Related News: DARPP-32 Haplotype Affects Frontostriatal Cognition and Schizophrenia Risk

Comment by:  Daniel Durstewitz
Submitted 8 June 2007
Posted 8 June 2007
  I recommend the Primary Papers

The phosphoprotein DARPP-32 occupies a central position in the dopamine-regulated intracellular cascades of cortical and striatal neurons (Greengard et al., 1999). It is a point of convergence for multiple signaling pathways, is differentially affected by D1- vs. D2-class receptor activation, and mainly through inhibition of protein-phosphotase-1 mediates or contributes to a number of the dopaminergic effects on voltage- and ligand-gated ion channels. These, in turn, by regulating intracellular Ca2+ levels, themselves influence phosphorylation of DARPP-32 and thereby interact with dopamine-induced processes.

Given its central, vital role in dopamine-regulated signaling pathways, it is quite surprising that (to my knowledge) only a few studies exist on the implications of DARPP-32 variations for cognitive functions and brain activity. Therefore, this comprehensive series of studies by Meyer-Lindenberg et al. combining human genetics, structural and functional MRI, and behavioral testing represents an important milestone. Meyer-Lindenberg et al. identified different functionally relevant DARPP haplotypes, associated with differential DARPP mRNA activity in postmortem studies, and found that these were linked to significant differences on a number of cognitive tests probing “executive functions,” as well as to differences in putamen volume and activity, and structural and functional covariation between striatal and prefrontal cortical areas. Thereby, they paved the way for detailed investigations of the role of DARPP-32 in human cognition.

Since DARPP-32 is so intricately interwoven into so many intracellular and physiological feedback loops, as with dopamine itself (Durstewitz and Seamans, 2002), mechanistic accounts for the functional involvement of DARPP-32 variations in neural network dynamics may be hard to obtain. “Linear” causal thinking usually breaks down in such complex functional networks constituted of so many interacting positive and negative feedback loops on different time scales. Thus it may still be a while until we gain a deeper, biophysically based understanding of the neural processes that mediate the influence of DARPP variations on cognition, and integrative computational approaches may be required to help resolving these issues. Given the complexity of DARPP-regulated networks, I also would expect that fine-grained behavioral testing and analysis of error types of human subjects on different cognitive tasks may ultimately reveal quite subtle and differential effects of DARPP polymorphisms. Moreover, the effects on neural network dynamics may be such (e.g., changing the temporal organization of spiking patterns) that they may not always be detectable by current neuroimaging methods, meaning that while the most dramatic effects were found on activation and volume of striatum, where DARPP-32 is most abundantly expressed, a significant contribution of other brain areas in DARPP-associated cognitive differences may not be ruled out. Regardless of these difficulties in unraveling the underlying neural mechanisms, the work by Meyer-Lindenberg et al. allows us to tackle the question of how the balance in dopamine-regulated intracellular networks relates to cognition in humans, and points toward the neural structures and interactions most interesting to look at.

View all comments by Daniel Durstewitz

Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?

Comment by:  Fuller TorreyRobert Yolken
Submitted 2 December 2008
Posted 2 December 2008

The research being carried out by Dr. Sapolsky and colleagues at Stanford is potentially very important for understanding schizophrenia. (In regard to full disclosure, it should be noted that the Stanley Medical Research Institute (SMRI) is funding Dr. Sapolsky’s research as well as other research on dopamine and Toxoplasma gondii.)

The origin of interest in dopamine and T. gondii appears to have been the 1985 paper by Henry H. Stibbs, then in the School of Public Health and Community Medicine at the University of Washington. Stibbs had been studying trypanosomes and sleeping sickness for 10 years and discovered that this organism increased dopamine levels by 34 percent in infected rats (Stibbs, 1984). He therefore turned his attention to T. gondii because of its known ability to alter learning, memory, and behavior in infected mice and rats. He infected 30 mice with the C56 strain of T. gondii. Ten mice were infected, became symptomatic, and were killed at 12 days (= acute group). Ten mice were infected, treated with sulfadiazine, did not develop symptoms, and were killed at five weeks (= chronic group). Ten control mice were also killed at five weeks. The brains were assessed neurochemically and compared to the controls. There were no changes in serotonin or 5-HIAA. Norepinephrine was 28 percent decreased in acute but not in chronic infection. Homovanillic acid (HVA) was 40 percent increased in acute but not chronic infection. Dopamine was normal in acute infection but 14 percent increased in the treated mice with chronic infection. Stibbs concluded that T. gondii causes abnormalities in catecholamine metabolism and that these “may be factors contributing to the psychological and motor changes” seen in experimentally infected rodents (Stibbs, 1985).

Joanne Webster and her colleagues at Oxford infected rats with T. gondii, then treated them with haloperidol, an antipsychotic known to block dopamine. The effect of the haloperidol was to reverse the behavioral effects of T. gondii. They speculated that possible explanatory mechanisms include the ability of haloperidol “to inhibit T. gondii replication and to reduce, directly and indirectly, dopamine levels” (Webster et al., 2006).

Jaroslav Flegr and his colleagues in Prague have studied the effects of T. gondii infection on the behavior of mice. They reported that giving the mice a dopamine reuptake inhibitor (GBR 12909) altered the behavior of the mice and concluded that “the proximal causes of alterations in mice behavior induced by Toxoplasma gondii are probably changes in the dopaminergic system” (Skallová et al., 2006). In other publications, Flegr and colleagues have speculated that dopamine is the “missing link between schizophrenia and toxoplasmosis,” specifically suggesting that dopamine is increased by activated cytokines (e.g., IL–2) as a consequence of infection (Flegr et al., 2003; Flegr, 2007).

The intriguing thing about this research is its possible relevance to schizophrenia. For more than 40 years, it has been clear that an excess of dopamine is somehow involved in the pathogenesis of schizophrenia. Despite hundreds of studies, however, relatively few abnormalities have been identified in the dopamine production of individuals with schizophrenia. If T. gondii is part of the disease’s etiology, the excess dopamine may be being introduced exogenously by the parasite. If true, this would introduce a whole new approach to treatment.

An important aspect of this body of work is that it provides an evolutionary basis for why an infectious agent might lead to altered behavior. In terms of Toxoplasma, this association is based on the organism’s life cycle. The primary host for Toxoplasma is the cat. Toxoplasma organisms can complete their replication cycle, including their sexual stage, within members of the feline species. If other animals become infected, the organisms can undergo some replication but cannot complete the sexual stage. The Toxoplasma organism must thus do something in order to get back into the cat if it is to complete its life cycle. Since the organism cannot get around on its own, it has to alter the behavior of its host if it is to accomplish this vital evolutionary goal. Dr. Sapolsky and others have documented the behavioral alterations associated with Toxoplasma infection. If the host is a rodent, the end result of these alterations is that the rodent gets eaten and the Toxoplasma is quite happy (even if the rodent is obviously not). This may also have been the case for prehistoric humans, who were also the frequent prey of large cats. While getting eaten by cats is not a problem for most modern humans, the Toxoplasma organism does not know this and still attempts to alter the behavior of its host. The vestigial effect of Toxoplasma infection may thus result in the altered behaviors that are the hallmark of schizophrenia, bipolar disorder, and other psychiatric disorders.

A summary of current research on T. gondii and schizophrenia can be found on the SMRI website (Laboratory of Developmental Neurovirology, Toxoplasmosis–Schizophrenia Research).


Stibbs HH, Neurochemical and activity changes in rats infected with Trypanosoma brucei gambiense, J Parasitology 1984;70:428–432. Abstract

Stibbs HH, Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice, Ann Trop Med Parasitol 1985;79:153–157. Abstract

Webster JP, Lamberton PH, Donnelly CA, Torrey EF. Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour. Proc Biol Sci. 2006 Apr 22;273(1589):1023-30. Abstract

Skallová A, Kodym P, Frynta D, Flegr J. The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an ethological and ethopharmacological study. Parasitology. 2006 Nov 1;133(Pt 5):525-35. Abstract

Flegr J, Preiss M, Klose J, Havlícek J, Vitáková M, Kodym P. Decreased level of psychobiological factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite Toxoplasma gondii Dopamine, a missing link between schizophrenia and toxoplasmosis? Biol Psychol. 2003 Jul 1;63(3):253-68. Abstract

Flegr J, Effects of Toxoplasma on human behavior, Schizophr Bull 2007;33:757-760. Abstract

View all comments by Fuller Torrey
View all comments by Robert Yolken

Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?

Comment by:  Tamas Treuer
Submitted 9 December 2008
Posted 9 December 2008

Congratulations to Profs. Sapolsky, Torrey, and Yolken for their important contribution to this field. The question for me is rather an evolutionary one: is there any trace in the neuron-immuno-endocrine system of patients with schizophrenia that can reflect the adaptation to this hijacking attempt of this protozoon? Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia (Torrey and Yolken, 2007). Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the product of a long evolutionary process. The neurochemical background of delusions of parasitosis is potentially similar to ancient evolutionary traces of altered neurotransmission and neuropeptide gene expression caused by parasites; these include fungal and viral infections. This is very unique in medicine if a class of drugs is effective in the treatment of an illness but also cures the delusion of the same disorder as well. Furthermore, metabolic disturbances such as hyperglycemia and insulin resistance were reported several decades before the antipsychotic era. Toxoplasmosis may also be linked to insulin resistance.

Although it would be important to established treatment trials, specifically by demonstrating that medications suppressing T. gondii infections improve the clinical symptoms of schizophrenia, it is not clear whether this would be a direct link. This experiment would be similar to the observations made in children affected by the PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) syndrome. The term is used to describe children who are believed to have developed obsessive-compulsive disorder (OCD) and/or tic disorders such as the Tourette syndrome following a group-Aβ-hemolytic streptococcal infection. However, studies with PANDAS children have shown that antibiotic treatment is not consistently effective in reducing the infection rate or the severity of obsessive-compulsive and/or tic symptoms in these children. Once the damage has occurred, corrective treatment against the infective agent is not always beneficial.

Schizophrenia research can benefit from understanding this evolutionary link. New chemical entities that are liable to alter neurochemical changes related to the brain's perception of the risk of predation secondary to parasites may result in new approaches for the treatment of psychosis. Neuroendocrine changes in the brain and body of people with schizophrenia are probably ancient traces of survival strategy on these individuals. These findings suggest that further research is needed to clarify this evolutionary link between parasite infection and delusions of parasitosis. I believe this model may well open up new avenues of research in the discovery of drugs to counteract schizophrenia and related disorders (Treuer and Karagianis, 2006; Treuer et al., 2007; Treuer et al., 2008).


Torrey Ef, Yolken RH. Schizophrenia and Toxoplasmosis. Schizophrenia Bulletin. 2007;33:727-728. Abstract

Treuer T, Martenyi F, Karagianis J: Parasitosis, Dopaminergic Modulation and Metabolic Disturbances in Schizophrenia: Evolution of a Hypothesis. NeuroEndocrinology Letters. 2007 Oct;28(5):535-40. Abstract

Treuer T, Karagianis J: Is Hunger a Driver of Cognitive Development? Neuropsychopharmacology. Oct 2006;(31)10:2326-2327. Abstract

Treuer T, Karagianis J, Hoffmann VP: Can Increased Food Intake Improve Psychosis? A Brief Review and Hypothesis. Current Molecular Pharmacology. 2008 November;1(3):270-272.

Treuer T: The Potential Role of Ghrelin in the Mechanism of Sleep Deprivation Therapy for Depression. Sleep Medicine Reviews. 2007 Dec;11(6):523-4.

View all comments by Tamas Treuer

Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?

Comment by:  Jaroslav Flegr
Submitted 9 December 2008
Posted 9 December 2008

The results of the research performed by Dr. Sapolsky and colleagues at Stanford, elaborating the results obtained by Drs. Berdoy and Webster at Oxford (Berdoy et al., 2000), are really fascinating. It should not be forgotten, however, that dopamine is not the only suspected molecule. There are several indirect and recently even direct indications for changed levels of testosterone in subjects with latent toxoplasmosis (Flegr et al., 2008). Moreover, the increased levels of dopamine in Toxoplasma infected mice and men seem to be byproducts of local brain inflammations, rather than a product of biologically important manipulation of the host behavior by the parasite. The results from human cytomegalovirus, i.e., the parasite transmitted by direct contact, not by predation, suggest that an infection of brain tissue by various parasites could increase the level of brain dopamine (Skallová et al., 2005). From the point of view of schizophrenia research or even clinical practice, the question of whether the increased level of dopamine is a product of manipulation or a byproduct of brain infection, is, of course, not so important.

Recently, results of several large independent studies suggest that RHD positive subjects, especially heterozygotes, are protected against latent toxoplasmosis-induced impairment of reaction times (Novotná et al., 2008; Flegr et al., 2008). The RhD protein, which is the RHD gene product and a major component of the Rh blood group system, carries the strongest blood group immunogen, the D-antigen. The structure homology data suggest that the RhD protein acts as an ion pump of uncertain specificity and unknown physiological role. The protein is present mainly on the surface of erythrocytes; however, expression library data suggest that the RHD gene is expressed also in brain tissue. It seems to me that possible association between RhD phenotype and schizophrenia should be studied in the future.


Berdoy M, Webster JP, Macdonald DW. Fatal attraction in rats infected with Toxoplasma gondii. Proc Biol Sci. 2000 Aug 7;267(1452):1591-4. Abstract

Flegr J, Lindová J, Kodym P. Sex-dependent toxoplasmosis-associated differences in testosterone concentration in humans. Parasitology. 2008 Apr 1;135(4):427-31. Abstract

Skallová A, Novotná M, Kolbeková P, Gasová Z, Veselý V, Sechovská M, Flegr J. Decreased level of novelty seeking in blood donors infected with Toxoplasma. Neuro Endocrinol Lett. 2005 Oct 1;26(5):480-6. Abstract

Novotná M, Havlícek J, Smith AP, Kolbeková P, Skallová A, Klose J, Gasová Z, Písacka M, Sechovská M, Flegr J. Toxoplasma and reaction time: role of toxoplasmosis in the origin, preservation and geographical distribution of Rh blood group polymorphism. Parasitology. 2008 Sep 1;135(11):1253-61. Abstract

Flegr J, Novotná M, Lindová J, Havlícek J. Neurophysiological effect of the Rh factor. Protective role of the RhD molecule against Toxoplasma-induced impairment of reaction times in women. Neuro Endocrinol Lett. 2008 Aug 1;29(4):475-81. Abstract

View all comments by Jaroslav Flegr

Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?

Comment by:  Huan Ngo
Submitted 16 December 2008
Posted 16 December 2008

Drs. Sapolsky's and Vyas's recent body of data have provided significant mechanistic insights into the parasite manipulation hypothesis, the dopamine hypothesis of schizophrenia and the gene-environment etiological paradigm.

Since most of the human epidemiological data currently emphasizes Toxoplasma exposure from the prenatal period, do we know whether maternal infection results in dopamine alteration in the prenatal, neonatal or postnatal amydala? Is the effect caused directly by transplacental migration of the parasite to the prenatal amydala, or indirectly by maternal cytokine effects, such as IL6 or IL8, on the embryonic brain?

View all comments by Huan Ngo

Related News: Does Toxoplasma Gondii Hijack the Dopamine Reward System of Rats?

Comment by:  Artyom Tikhomirov
Submitted 18 December 2008
Posted 22 December 2008

It seems like both bacteria and protozoa have been shown to either increase or decrease certain defensin levels in humans (Sperandio et al., 2008; Wiesenfeld et al., 2002). Then there's a single report from Sabine Bahn's group of increased α-defensins in schizophrenia (Craddock et al., 2008). It is interesting to speculate whether Toxoplasma gondii might contribute to the change in defensin levels.


Sperandio B, Regnault B, Guo J, Zhang Z, Stanley SL, Sansonetti PJ, Pédron T. Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression. J Exp Med. 2008 May 12;205(5):1121-32. Abstract

Craddock RM, Huang JT, Jackson E, Harris N, Torrey EF, Herberth M, Bahn S. Increased alpha-defensins as a blood marker for schizophrenia susceptibility. Mol Cell Proteomics. 2008 Jul 1;7(7):1204-13. Abstract

Wiesenfeld HC, Heine RP, Krohn MA, Hillier SL, Amortegui AA, Nicolazzo M, Sweet RL. Association between elevated neutrophil defensin levels and endometritis. J Infect Dis. 2002 Sep 15;186(6):792-7. Abstract

View all comments by Artyom Tikhomirov

Related News: Cognition and Dopamine—D1 Receptors a Damper on Working Memory?

Comment by:  Michael J. Frank
Submitted 19 February 2009
Posted 19 February 2009

McNab and colleagues provide groundbreaking evidence showing that cognitive training with working memory tasks over a five-week period impacts D1 dopamine receptor availability in prefrontal cortex. Links between prefrontal D1 receptor function and working memory are often thought to be one-directional, i.e., that better D1 function supports better working memory, but here the authors show that working memory practice reciprocally affects D1 receptors.

An influential body of empirical and theoretical research suggests that an optimal level of prefrontal D1 receptor stimulation is required for working memory function (e.g., Seemans and Yang, 2004). Because acute pharmacological targeting of prefrontal D1 receptors reliably alters working memory, causal directionality from D1 to working memory remains evident. Nevertheless, these findings cast several other studies in a new light. Namely, when a population exhibits impaired (or enhanced) working memory and PET studies indicate differences in dopaminergic function, it is no longer clear which variable is the main driving factor. For example, those who engage in cognitively demanding tasks on a day-to-day basis may show better working memory and dopaminergic correlates may be reactive rather than causal. Finally, the possibility cannot be completely discounted that the observed changes in D1 receptor binding may reflect a learned increase in prefrontal dopamine release; this would explain the general tendency for D1 receptor availability to decrease with cognitive training, due to competition with endogenous dopamine.

The McNab study also finds that only cortical D1 receptors, and not subcortical D2 receptors, were altered by cognitive training. The significance of this null effect of D2 receptors is not yet clear. First, all tasks used in the training study involved recalling the ordering of a sequence of stimuli and repeating them back when probed. While clearly taxing working memory, these tasks did not require subjects to attend to some stimuli while ignoring other distracting stimuli, and did not require working memory manipulation. Both manipulation and updating are characteristics of many working memory tasks, particularly those that depend on and/or activate the basal ganglia. Indeed, previous work by the same group (McNab and Klingberg, 2008) showed that basal ganglia activity is predictive of the ability to filter out irrelevant information from working memory. Similarly, Dahlin et al. (2008) reported that training on tasks involving working memory updating leads to generalized enhanced performance in other working memory tasks, and that this transfer of learned knowledge is predicted by striatal activity. These results are consistent with computational models suggesting that the basal ganglia act as a gate to determine when and when not to update prefrontal working memory representations and are highly plastic as a function of reinforcement. Thus, future research is needed to test whether training on filtering, updating, or manipulation tasks leads to changes in striatal D2 receptor function.


McNab, F. and Klingberg, T. (2008). Prefrontal cortex and basal ganglia control access to working memory. Nature Neuroscience, 11, 103-107. Abstract

Dahlin, E., Neely, A.S., Larsson, A., Bäckman, L. & Nyberg, L. (2008). Transfer of learning after updating training mediated by the striatum. Science, 320, 1510-1512. Abstract

Seamans, J.K. and Yang, C.R. (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology, 74, 1-57. Abstract

View all comments by Michael J. Frank

Related News: Cognition and Dopamine—D1 Receptors a Damper on Working Memory?

Comment by:  Terry Goldberg
Submitted 3 March 2009
Posted 3 March 2009

This is an important article that describes profound changes in the dopamine D1 receptor binding potential after working memory training in healthy male controls. The study rests on prior work that has demonstrated changes in brain volume with practice (e.g., Draganski and May, 2008), and dopamine can be released at the synapse in measurable amounts even during, dare I say, fairly trivial activities (e.g., playing a video game (Koepp et al., 1998). The present study demonstrated that binding potential of D1 receptors decreased in cortical regions (right ventrolateral frontal, right dorsolateral PFC, and posterior cortices) with training, and the magnitude of this decrease correlated with the improvement during training. Binding potential of D2 receptors in the striatum did not change. Unfortunately, D2 receptors in the cortex could not be measured with raclopride.

Two points come to mind. One is theoretical—how long would such a change remain, i.e., is it transient or is it fixed? This has implications for understanding practice-related phenomena and their transfer or consolidation. The second is technical. A number of studies have shown that practice can change not only the magnitude of a physiologic response, but also its location (see Kelly and Garavan for a review, 2005). Thus, the circuitry involved in learning a task may be different than the circuitry involved in implementing a task after it is well learned. By constraining areas to those activated in fMRI during initial working memory engagement, it is possible that other critical areas were not monitored for binding potential changes.


Draganski B, May A. Training-induced structural changes in the adult human brain. Behav Brain Res . 2008 Sep 1 ; 192(1):137-42. Abstract

Kelly AM, Garavan H. Human functional neuroimaging of brain changes associated with practice. Cereb Cortex . 2005 Aug 1 ; 15(8):1089-102. Abstract

Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, Brooks DJ, Bench CJ, Grasby PM. Evidence for striatal dopamine release during a video game. Nature . 1998 May 21 ; 393(6682):266-8. Abstract

View all comments by Terry Goldberg