Challenging the Dopamine Dogma: Do We Need to Ditch the Mesolimbic Focus?
The dogma that hyperactivity in the mesolimbic dopaminergic pathways underlies the psychotic symptoms of schizophrenia continues to feature in psychiatric textbooks—despite the fact that it was largely based on rodent, rather than human, studies. Two recent positron emission tomography (PET) studies have taken advantage of improvements in scanner resolution and new understanding of primate meso-striato-cortical circuits to evaluate this mesolimbic dogma in patients. Last year, we used PET to show that patients with schizophrenia have elevated presynaptic dopamine synthesis capacity in the part of the striatum linked to associative cortical regions (the “associative striatum”) (Howes et al., 2009). Now, in this month’s Archives of General Psychiatry, Lawrence Kegeles and colleagues at Columbia University, New York, write that they used PET to study synaptic dopamine levels in schizophrenia. They report increased levels of synaptic dopamine in the same associative subdivision of the striatum where we found increased dopamine synthesis capacity.

The findings of these two studies fit together nicely, suggesting as they do that related aspects of dopamine neurotransmission—the synthesis and storage of dopamine for release, and synaptic dopamine levels following release—are all elevated in the same area in schizophrenia. Both studies found little evidence of changes in the parts of the striatum linked to limbic areas. We also found that dopamine activity was elevated in the same associative region in people with prodromal signs of schizophrenia, indicating that this associative localization predates the onset of frank psychosis (Howes et al., 2009).

On the basis of their findings and the strong connections between the associative striatum and prefrontal cortex demonstrated in primate studies (Haber, 2003), Kegeles et al. predict that increased dopamine activity in the associative striatum will impair dorsolateral prefrontal cortical function. We investigated the functional links of the associative striatum to cognition and prefrontal cortical function in people with prodromal signs of schizophrenia. Consistent with the prediction by Kegeles et al., we found that greater elevation in dopamine synthesis capacity in the associative striatum was linked to poorer performance on a task of executive function and to altered prefrontal activation during the same cognitive task (Fusar-Poli et al., 2009). This relationship has yet to be investigated in patients with established schizophrenia as well.

Interestingly, in both our study and that by Kegeles et al., in absolute terms the magnitude of dopamine activity in the sensorimotor striatum was also greater in patients. Whilst this difference was not significant in either study, this may be due to a lack of power. Traditionally, these dopaminergic pathways have been considered as unaffected in untreated schizophrenia. However, the sensorimotor striatum links to the motor and supplementary motor cortex to integrate the control of motor output, and studies of drug-naïve, first-episode patients have found that abnormal and involuntary movements are present at the beginning of the illness (Pappa and Dazzan, 2009). Dopaminergic dysfunction in the sensorimotor striatum might explain these motor abnormalities seen in schizophrenia prior to any treatment with antipsychotic drugs.

There are some methodological caveats to these findings in striatal subdivisions—partial volume effects, for example, may particularly influence small regions such as the limbic striatum (Shidahara et al., 2009)—and the results warrant replication in other samples. Nevertheless, taken together these findings suggest that the locus of dopaminergic dysfunction in schizophrenia should be reconsidered.

References:

Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009 January;66(1):13-20. Abstract

Haber SN. The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat. 2003 December;26(4):317-30. Abstract

Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC, Montgomery AJ, Grasby PM, McGuire P. Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis. Mol Psychiatry. 2009 December 1. Abstract

Pappa S, Dazzan P. Spontaneous movement disorders in antipsychotic-naive patients with first-episode psychoses: a systematic review. Psychol Med. 2009 July;39(7):1065-76. Abstract

Shidahara M, Tsoumpas C, Hammers A, Boussion N, Visvikis D, Suhara T, Kanno I, Turkheimer FE. Functional and structural synergy for resolution recovery and partial volume correction in brain PET. Neuroimage. 2009 January 15;44(2):340-8. Abstract

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