July 8, 2014. On April 6, a SIRS 2014 session titled "New vistas in dopamine receptor research: implications for novel therapies in schizophrenia" put the dopamine D1 receptor in the spotlight. Speakers discussed both preclinical and clinical evidence suggesting that enhancing D1 receptor activity would improve cognition in schizophrenia, as well as ways to effectively target the receptor and preliminary data demonstrating the efficacy of an agonist in patients with schizotypy.
It is generally accepted that dopaminergic hyperfunction through striatal D2 receptors is implicated in the positive symptoms of schizophrenia, said speaker John Waddington, Royal College of Surgeons in Ireland, Dublin. However, much more tenuous is the hypothesis that dopaminergic hypofunction through cortical D1 receptors plays a role in the negative symptoms and cognitive deficits of the illness, he added. To examine this hypothesis, Waddington characterized the phenotype of three mouse models with an early, progressive loss of D1 receptor-containing cells in the striatum only, cortex only, or forebrain (striatum and cortex).
When given a choice between exploring a social chamber or an empty one, none of the mouse strains showed signs of impaired sociability. However, early loss of either cortical or forebrain D1 receptor-containing cells disrupted social novelty preference (in which the mouse must choose between a new animal and one it has met before), suggesting that social cognition involves cortical D1 receptors. In contrast, spatial working memory was disrupted only by the loss of forebrain D1-containing cells, but not a deletion in either the cortex or striatum alone, indicating that D1 receptors in both locations are necessary for intact working memory. Taken together, the results are yet another piece of evidence pointing to the strong need for a selective D1 agonist to test in schizophrenia, Waddington said.
Patricio O'Donnell, Pfizer, Cambridge, Massachusetts, discussed the influence of dopamine on glutamatergic and GABAergic systems in the prefrontal cortex. The interactions between excitatory and inhibitory activity are very tightly modulated by dopamine, using both D1 and D2 receptors, he said. Whereas activation of the two receptor subtypes has opposite effects on interneuron excitability during early life, this modulation matures during adolescence so that activation of both D1 and D2 receptors increases excitability in adulthood.
Early-life manipulations that model some aspects of schizophrenia can affect this dopamine modulation. For example, in both mice expressing a dominant-negative form of DISC1 and rats with a neonatal ventral hippocampal lesion, prefrontal cortical interneurons are not properly activated by D2 receptors. These data suggest that that enhancing D1 receptor activity could be a useful strategy for restoring excitatory-inhibitory balance in schizophrenia, concluded O'Donnell.
Looking to D1
Despite substantial preclinical evidence suggesting that enhanced D1 activity would be beneficial, attempts to produce a D1 agonist for this purpose have so far failed, leading to the popular view that the D1 receptor is "undruggable," said Richard Mailman, Penn State University, Hershey. He then presented data suggesting that the development of useful compounds that enhance D1 is indeed possible thanks to modern methodologies.
A variety of problems have plagued D1 agonist development, he explained, including the potential for seizures and hypotension, rapid tolerance, and the need for a selective agonist to avoid undesirable D2-mediated effects. Mailman described recent advances in medicinal and computational chemistry that can circumvent many of these issues. For example, high-resolution crystal structures of G protein-coupled receptors have produced a deeper understanding of the mechanisms involved in ligand binding and activation. This may lead to the modification of non-catechols, which have D1 agonist properties, to yield novel therapeutic compounds. In addition, he described how new approaches to drug discovery, such as the identification of functionally selective ligands (that activate only specific D1-mediated pathways) and allosteric modulation of receptors, may also lead to better drugs.
Larry Siever, Mt. Sinai School of Medicine, New York City, reviewed data suggesting that a single nucleotide polymorphism (SNP) in the D1 receptor gene (DRD1) promoter is associated with cognitive function in a combined postmortem cohort of subjects with schizophrenia or Alzheimer's disease. The same SNP is also associated with strategic planning, an executive function that depends on working memory, in healthy controls.
Siever also presented a study of the highly selective full D1 receptor agonist DAR-100A in schizotypal patients, who exhibit cognitive deficits that are small in magnitude but qualitatively similar to those found in schizophrenia. Without any D2 receptor activity, the side effects of DAR-100A were quite minor, Siever said. Cognitive testing following three days of infusion revealed that the drug significantly improved working memory performance on the paced auditory serial addition task (PASAT) and produced a trend toward improvement on the N-back task. Based on these "promising" preliminary data, a larger study with a more complete cognitive battery is now underway, he said.
Looking beyond D1
Moving away from schizophrenia and the D1 receptor, Katherine Burdick, Zucker Hillside Hospital-North Shore Long Island Jewish Health System, Glen Oaks, New York, discussed the use of D2/D3 agonist pramipexole (currently approved to treat Parkinson's disease) as a cognitive enhancer in bipolar disorder. The cognitive deficits in schizophrenia and bipolar disorder are qualitatively similar, although generally less severe in bipolar disorder, and neurocognition is a strong predictor of function in both illnesses, she said.
Burdick and colleagues have previously reported that pramipexole can improve working memory and processing speed in euthymic bipolar disorder patients (Burdick et al., 2012). However, based on evidence from Parkinson's disease that the drug can induce pathological gambling and other impulse control difficulties, the researchers examined the effect of pramipexole on reward processing using the Iowa Gambling Task.
Consistent with the Parkinson's disease data, Burdick found that euthymic patients taking pramipexole were not able to learn to select from the conservative card decks that lead to an overall monetary gain, instead consistently choosing the high-risk/high-reward cards that produce a net loss (Burdick et al., 2014). The inability to learn seemed to stem from patients' stronger attention to gains rather than losses, and preliminary evidence suggests that a polymorphism in the dopamine transporter gene is a possible underlying mechanism.—Allison A. Curley.