July 28, 2005

Potential New Drug Development Strategy

Duke University reported today on a Discovery of new dopamine action may yield alternative psychiatric drugs (such as those used for Schizophrenia).

Durham, N.C. – Duke University Medical Center researchers have discovered a new mechanism by which chronically high levels of the neurotransmitter dopamine exert their effects on the brain. Normally associated with triggering feelings of pleasure, excess concentrations of dopamine underlie schizophrenia, attention deficit hyperactivity disorder and other psychiatric conditions. The findings therefore provide new research avenues to understand and potentially manage such dopamine-related human disorders, the researchers said.
"We've thought that neurotransmitters relay messages to the brain in two speeds: fast and slow," said lead author of the study Jean-Martin Beaulieu, Ph.D. of Duke. "However, our new findings reveal that brain receptors that respond to dopamine actually have two slow modes: one that takes place over a period of minutes and a second -- newly discovered -- that lasts for hours. In fact, it may be that this effect continues for as long as dopamine remains in the system."

This sustained action of dopamine may be particularly important for understanding psychiatric conditions, which are characterized by persistently high levels of the brain messenger, Beaulieu said. The researchers report their findings in the July 29, 2005, issue of Cell.

"This mechanism appears to be more important than those earlier described for prolonged stimulation by dopamine, as would be the case in those with psychiatric conditions," said senior author Marc Caron, Ph.D., of Duke. "The new pathway can now be evaluated for potential new inhibitors that might be better at controlling particular psychotic behaviors." Caron is a professor of cell biology at Duke and faculty member at the Duke Institute for Genome Sciences & Policy.

Dopamine's prolonged effects might also apply to understanding the impact of sustained drug use on the brain, Caron added. Virtually all addictive drugs, including cocaine and amphetamines, directly or indirectly raise dopamine levels. The neurotransmitter therefore plays a major role in drug-induced highs and in addiction, he explained.

Neurotransmitters such as dopamine are chemical messengers that one neuron launches at receptors on another to trigger a nerve impulse in the receiving neuron. Receptors are protein switches on the surfaces of neurons that recognize neurotransmitters and translate their signals into a cellular response. Dopamine exerts its functions in the brain by binding to two broad classes of receptors -- one class that transmits signals fast and another that acts through signaling pathways to relay messages more slowly.

Dopamine receptors exist in two forms, D1 and D2 class receptors, both belonging to a class of slow-acting receptors known as G protein-coupled receptors. One method by which dopamine relays messages to the brain over a period of minutes has been well worked out. The new study by Caron and his colleagues reveals a second mechanism whereby chronic dopamine affects the brain, perhaps indefinitely.

The Duke team's previous work suggested that the regulatory protein beta-arrestin 2, normally involved in desensitization of receptor signals, is required for normal dopamine-related behavior. They also found that prolonged stimulation of D2 receptors leads to inactivation of a regulatory protein called Akt.

Furthermore, they showed, Akt inactivation occurred more slowly and was maintained for longer than other similar biochemical events that had previously been observed. However, the mechanism behind that inactivation remained unclear.

In the current study in mice, the Duke team found that Akt inactivation by dopamine involves the formation of a previously unidentified complex containing beta-arrestin 2, Akt and a third protein phosphatase 2A that inactivates Akt. Mice lacking beta-arrestin become less responsive to certain drugs and exhibit abnormalities in behaviors, such as locomotion, associated with dopamine. In addition to the behavioral deficits, the animals also lack normal regulation of Akt, they report.

"These results provide direct physiologically relevant evidence for the emerging concept that beta-arrestin 2 not only controls desensitization but also participates in slow synaptic transmission here by acting as a scaffold for signaling molecules in response to dopamine receptor activation," Caron said.

"The observations also provide an alternative pathway by which dopamine receptor activation leads to the expression of dopamine-associated behaviors."

The findings reveal another mechanism that could be targeted for the treatment of schizophrenia and other psychiatric disorders, the researchers said.

Further work is required to identify which dopamine-dependent behaviors rely on each pathway. If the two mechanisms control separate functions, particular drugs might target some dopamine-related behaviors and not others, thereby limiting the side effects of psychiatric therapy.

Akt also plays important roles in many other processes in the body, including inflammation, cell death and the cell proliferation that can spur cancer, the researchers added. Therefore, similar mechanisms might also underlie other disease pathways.

Collaborators on the study include Tatyana Sotnikova, Sebastien Marion, Robert Lefkowitz and Raul Gainetdinov, all of Duke. The work was supported by the National Institutes of Health, the Human Frontier Research Program and the Canadian Institutes of Health Research.

Source: Duke University


Unless otherwise noted, the compounds mentioned below are in the early stages of human testing. Their developers or producers are listed in parentheses.

Stimulators of NMDA-type glutamate receptors aim to overcome the signaling deficits that apparently contribute to many schizophrenic symptoms. Examples: Glycine (Medifoods), D-serine (Glytech). As natural substances, both of them are sold, but they remain under evaluation specifically for their value in treating schizophrenia.

Stimulators of AMPA-type glutamate receptors--also called ampakines-- may improve some aspects of memory and cognition in people with schizophrenia. Example: CX516 (Cortex Pharmaceuticals)

Modulators of another class of glutamate receptors--metabotropic receptors--can regulate glutamate release and potentially restore the balance between the activity of NMDA and AMPA receptors. Example: LY354740 (Eli Lilly)

Inhibitors of glycine transport reduce glycine removal from synapses, which should increase signaling by NMDA receptors. Example: GlyT-1 (NPS Pharmaceuticals and Janssen Pharmaceutica)

Stimulators of alpha 7 nicotinic receptors, the same receptors activated by the nicotine in cigarettes, indirectly stimulate the brain's NMDA receptors. Schizophrenics often smoke heavily, probably because the nicotine, acting on alpha 7 receptors, helps them to focus. Example: DMXB-A (University of Colorado Health Sciences Center)

Stimulators of D1 dopamine receptors are being developed mainly for Parkinson's disease and have passed initial safety trials. They might also correct dopamine deficiencies in schizophrenia, but clinical trials for that purpose have not yet been performed. Example: ABT-431 (Abbott Laboratories)

There are more than 50 substances in clinical development regarding schizophrenia and I would recommend this pharma pipeline database to

Posted by: Kir Zila at May 31, 2006 04:29 AM

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