New dopamine mechanism equals new drugs?

The neurotransmitter, dopamine, is normally associated with triggering feelings of pleasure, excess concentrations of dopamine underlie schizophrenia, attention deficit hyperactivity disorder and other psychiatric conditions.

Current drug treatments for dopamine-related conditions have suffered from a spate of safety concerns that have plagued existing antidepressant classes, particularly the selective serotonin reuptake inhibitors.

The SSRI class of drugs, which includes GSK's Paxil/Seroxat (paroxetine), Eli Lilly's Prozac (fluoxetine) and Pfizer's Zoloft (sertraline), already carries a "black box" warning highlighting an increased risk of suicidal behaviour amongst children and adolescents.

Moreover, the class has some serious drawbacks, including a two to six week lag before they start to work, a low rate of response and a low rate of remission. If triple reuptake inhibitors can demonstrate a more rapid onset, higher efficacy and fewer side effects, their commercial success will be assured.

This sustained action of dopamine may be particularly important for understanding psychiatric conditions, which are characterised by high levels of the brain messenger.

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

In the current study with mice, the team from Duke University Medical centre 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 behaviours, such as locomotion, associated with dopamine. In addition to the behavioural deficits, the animals also lack normal regulation of Akt.

"These results provide direct physiologically relevant evidence for the emerging concept that beta-arrestin 2 not only controls desensitisation but also participates in slow synaptic transmission here by acting as a scaffold for signalling molecules in response to dopamine receptor activation,"​ said senior author Marc Caron, of Duke University.​

"The observations also provide an alternative pathway by which dopamine receptor activation leads to the expression of dopamine-associated behaviours,"​ he added.

Dopamine's prolonged effects might also apply to understanding the impact of sustained drug use on the brain. 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.

"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,"​ commented Jean-Martin Beaulieu of Duke University.

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.

Further work is required to identify which dopamine-dependent behaviours 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.

The researchers report their findings in the July 29, 2005, issue of Cell.​