New drug may treat cognitive disorders

Recent discoveries in a joint study by the Yale School of Medicine and the University of Crete School of Medicine may lead to a breakthrough in the treatment of cognitive disorders like bipolar disorder, schizophrenia and ADHD.

According to a report in Cell on April 20, a neurobiology research team has found the first evidence of a molecular mechanism that affects higher brain network connections. The discovery may lead to drug therapies that could treat normal cognitive deficits resulting from aging, as well as more severe disorders.

“Our study provides the first evidence of a molecular mechanism that dynamically alters the strength of higher brain network connections,” said associate research assistant Min Wang, one of the co-authors of the report. “This discovery has immediate implications for the design of effective clinical therapies [to treat these cognitive disorders].”

The research deals with the mechanism that either connects or disconnects the networks in the brain’s prefrontal cortex, or PFC, which controls some of the more sophisticated brain functions, lead author and neurobiology professor Dr. Amy Arnsten said. One of the effects of normal aging is the decrease in the ability of the PFC to maintain these functions, and this ability is further weakened in people with ADHD and more severe disorders like schizophrenia and bipolar disorder.

“The prefrontal cortex is the most highly-developed part of our brains and it subserves what are called the executive functions — the ability to abstract, plan and organize for the future and to inhibit inappropriate thoughts and actions,” Arnsten said. “It regulates our emotions as well. My lab has shown some time ago that during stress this part of the brain goes ‘offline.’ We now understand why this loss of prefrontal function occurs through this very powerful mechanism that disconnects these networks temporarily.”

The research team found that brain cells in the PFC contain hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that can open when they are exposed to cyclic adenosine monophosphate (cAMP). When the HCN channels open, they disconnect the neuron-to-neuron network and prevent the brain from carrying out the normal functions of the PFC. If the production of cAMP is inhibited, the channels close and the network reconnects.

ADHD, a disorder which is often characterized by a weaker regulation of attention and behavior, is often treated by enhancing stimulation of the norepinephrine receptors, a natural brain chemical which inhibits the production of cAMP. Similarly, schizophrenia and bipolar disorder often involve the mutation of the molecule DISC1, which regulates cAMP.

The discovery has already led to the development of a drug called guanfacine, which is currently being used to treat ADHD in humans, Arnsten said. Guanfacine stimulates alpha-2A adrenergic receptors that are located near the HCN channels and can inhibit the production of cAMP, allowing information to pass continuously through the cells. According to the April 20 report, Arnsten and Yale have made a license agreement with Shire Pharmaceuticals to develop the drug.

Guanfacine is also being tested as a treatment for cases of traumatic brain injury, post-traumatic stress disorder and schizophrenia. Arnsten said that she recently spoke with Dr. Ralph Hoffman, a professor in the department of psychiatry, about the possibility of treating schizophrenia with the drug.

According to Dr. Constantinos Paspalas, a researcher at the University of Crete, future research will seek answers to certain important questions about this mechanism, including whether other receptors affect the state of the HCN channels and whether guanfacine could be used to reverse certain detrimental effects of aging in the PFC.

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