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SIRS 2016—A New Day for Dopamine?

4 Apr 2016

April 5, 2016. The study of dopamine dysfunction, once the dominant theme in schizophrenia research, has faded a bit in recent years. But a Sunday afternoon, April 3, symposium at the Schizophrenia International Research Society meeting in Florence promised "Exciting New Findings About Dopamine." This report summarizes that session, along with two other relevant talks.

Dopamine-containing cells lie in the midbrain, sending connections far and wide throughout the brain. Too much dopamine marks the striatum in schizophrenia, and this surfeit engages the D2 subtype of dopamine receptors, driving psychosis. In contrast, in the cortex, a deficit of dopamine has been suspected, but detecting this has been stymied by the lack of a good tracer molecule that could give a signal among the fewer D2 receptors found there. Anissa Abi-Dargham of Columbia University in New York City has rectified the situation with a new radioactive tracer, FLB457, which binds D2/D3 receptors. Using positron emission tomography (PET) to image FLB457 binding before and after dopamine release induced by amphetamine, she reported, blunted dopamine release in schizophrenia subjects relative to healthy controls in the dorsal lateral prefrontal cortex (DLPFC) (Slifstein et al., 2015). This also correlated with DLPFC activity during a working memory task, suggesting that dopamine helps to mobilize this region when needed.

Though excessive dopamine swamps the striatum, particularly the associative striatum, in schizophrenia, exactly why this might be has been unclear. For example, postmortem studies examining tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, have been mixed. Tertia Purves-Tyson of Neuroscience Research Australia took a comprehensive look at the ecosystem of molecules involved in regulating dopamine levels in 50 postmortem brain samples from people with schizophrenia and 50 from controls. Zeroing in on the substantia nigra, she confirmed the lack of a difference in TH in mRNA and protein levels; however, she did find a 35 percent increase in mRNA of aromatic acid decarboxylase (AADC), the enzyme that converts L-DOPA to dopamine, in schizophrenia patients relative to controls. If this difference pans out in AADC protein, it could help explain the dopamine excess, as could other changes she detected among D2 receptors and transporters.

Cecillia Flores of McGill University in Montreal, Canada, explored the development of dopamine projections in mice. These projections, it turns out, take their time in getting established: Though they reach the striatum early in life, they do not fully innervate the cortex until adulthood. How this process unfolds in adolescence, she finds, has repercussions for adult brain organization. Flores has focused on netrin, an axon guidance molecule, and its receptor DCC. DCC signaling within dopamine-containing neurons influences cortical innervation (Manitt et al., 2011), and newer data with techniques to selectively disrupt DCC in dopamine-containing neurons in adolescence confirmed this, resulting in a significant increase in dopamine axons in the prefrontal cortex, though these were reduced in length and the number of synapses. This suggests that the dopamine network is particularly vulnerable during adolescence.

Dopamine signals can be brief or sustained, yet the mechanics of how these different signaling regimes come about has been unclear. Bita Moghaddam of the University of Pittsburgh in Pennsylvania addressed this by looking at the consequences of dopamine neuron stimulation in rats. Stimulating ventral tegmental area (VTA) neurons, which include dopamine neurons, led to long-lasting dopamine release measured by microdialysis in multiple brain regions, lasting for more than 40 minutes. The sustained release was actively maintained by neural activity and promoted by internalization of transporters that usually clear it from extracellular space. Small animal fMRI showed that VTA stimulation resulted in robust activation of dorsal striatum—a surprise, given there is no direct connection between the two, though consistent with fMRI signals found there in schizophrenia. Moghaddam proposed that VTA stimulation activates two separate pathways that converge on dorsal striatum.

In his comments about the talks, Anthony Grace of the University of Pittsburgh noted that Abi-Dargham's work supported the notion that problems with salience and cognition are linked to dopamine dysregulation in the striatum, and problems with working memory to dopamine in the cortex. He also noted that Moghaddam's data exhibited the multiple levels of regulation of the dopamine system, which is controlled through its own activity.

Clinical insights

On Monday afternoon, April 4, an imaging symposium featured two talks relevant to dopamine, both of which proposed clinical uses of imaging. Imaging can help interpret failed drug trials, noted Anissa Abi-Dargham while referring to newly published work on a D1 receptor agonist, called DAR-0100A. Based on work finding that trace levels of D1 receptor agonists could improve cognition in monkeys with haloperidol-induced impairments (Aleman et al., 2000), Abi-Dargham and colleagues embarked on a proof-of-concept trial of DAR-0100A in people with schizophrenia (Girgis et al., 2016). Low doses of DAR-0100A did not improve working memory, and brain imaging revealed that it did not even activate working memory circuitry. This suggests that the drug didn't work because it didn't engage the relevant circuitry, thus keeping alive the idea of D1 receptor activation as a pro-cognitive therapy.

Anil Malhotra of Zucker Hillside Hospital in Glen Oaks, New York, presented recently published work in which brain imaging can help predict treatment response. Based on resting-state fMRI, which detects a default pattern of brain activity when a person is not engaged in a task, he found that the pattern of connections between the striatum and 91 different regions in the brain can predict whether someone will respond to antipsychotic medicines (Sarpal et al., 2016). He also noted that variations in the gene encoding the D2 receptor (DRD2), the target of antipsychotic drugs, can matter. A new analysis of the DRD2 variant pinpointed by the PGC's genomewide association study (GWAS) of schizophrenia showed that the risk allele was associated with a slightly better response to antipsychotic drugs, consistent with Malhotra's earlier work of a different DRD2 variant (Zhang et al., 2010).

The discussant of the session, Shitij Kapur of King's College London, lamented that imaging had not yet reworked clinical practice in ways that his younger self had imagined 20 years ago. He outlined what he saw as the current obstacles: the need for longitudinal studies to really identify the operative changes; an uncertainty about what appropriate outcomes should be; a requirement for an assay to be simple enough to be included in a busy clinical practice; and cost.—Michele Solis.