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Depression linked to previously unknown dopamine regulator


Finding advances hope for potential new target for antidepressants

Researchers from Harvard Medical School have found a molecule that is unexpectedly involved in dopamine signaling, and in a manner that supports the potential of dopamine as an alternative target for treating depression. The results provide evidence that there is a molecular link between impaired dopamine signaling and depression, which affects 16 percent of the adult population in the United States. The research appears in the July 29 issue of Cell.

Li-Huei Tsai, Harvard Medical School (HMS) professor of pathology, HMS research fellow Sang Ki Park, and colleagues worked with mice and found a novel function for the molecule Par-4 (prostate apoptosis response 4)--as a binding partner for dopamine receptor D2. When mice deficient in Par-4 were subjected to stress, they showed depression-like behaviors, proposing Par-4–as a molecular link between dopamine signaling and depression. Par-4 was previously implicated as a proapoptotic factor in neurodegenerative diseases such as Alzheimer’s disease. These new findings reveal an unexpected role for Par-4 in the dopamine system and present a rare glimpse of molecular mechanisms behind clinical depression.

"Current antidepression therapies are mostly based on the deficiency or imbalance of the serotonin and noradrenaline systems. Our study highlights the importance of the dopamine system, a less appreciated target in the current antidepression therapies," said Tsai, also a Howard Hughes Medical Institute investigator.

Although the cause of depression is multifaceted, a hypothesis based on deficiency or imbalance of serotonin and/or noradrenaline as the root of depression has been a central topic of research. Drugs that currently treat depression (SSRIs and MAOIs, which acutely modify levels of serotonin or noradrenaline at the synapse) have significant delays before becoming effective, and a large percentage of people are resistant to the current therapies, leaving room for improvement of therapeutic strategies.

The brain’s mood, reward, and motivation circuits are mainly governed by dopamine and have been regarded as potential alternative targets for treating depression. Many of these functions are integrated by the medium spiny neurons of the striatum, which lie below the cortex of the brain and respond to dopamine. Dopamine exerts its function in target cells through five known subtypes of dopamine receptors to regulate motor control, stereotypic behaviors, arousal, mood, motivation, and endocrine function. Impairment in the function of dopamine D2 receptor is implicated in various neuropsychiatric disorders including schizophrenia and drug addiction.

Understanding the details of the modulatory events in D2 dopamine receptor–mediated intracellular signaling may provide novel therapeutic targets for treating various associated disorders.

Leah Gourley | EurekAlert!
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