Identifying dopamine-regulating ion channels a ‘major step’ towards new mental illness drugs

Ion channel research from the University of Washington Medical School has shed new light on the workings behind dopamine release. The findings could lead to better drugs for depression and other conditions - including schizophrenia, addiction, and autism spectrum disorder.

Scientists have taken a ‘major step’ towards better developing mental illness treatments by successfully manipulating two ion channels that control dopamine release.

The University of Washington Medical School researchers found that switching off the Kv4.3 channel regulating slower – or ‘tonic’ – dopamine release made mice more motivated.

Meanwhile, switching off the BKCa1.1 channel responsible for more rapid, ‘phasic’, activity made them quicker to complete experimental tasks.

The findings shed new light onto the mechanisms behind dopamine release - and may be a first step towards developing drugs that target ion channels in order to treat conditions like depression, addiction, schizophrenia and autism spectrum disorder.

“This is what we've been working toward for some time: to understand how dopamine signals are regulated so that we can come up with better therapeutics,” said study co-author Larry S. Zweifel.

“They may not target these specific channels, but now that we're beginning to get a handle on the mechanism, we might be able to find other players in the process that make for better targets.”

The Washington team showed that disrupting Kv4.3 and BKCa1.1 through genetically altering laboratory mice changes the way they behave by “differentially affect(ing) action potential firing patterns and neurotransmitter release” in the ventral tegmental area (VTA) of the midbrain.

“(Those) two ion channels… regulate the pattern of dopamine neuron firing and dopamine release on different time scales to influence separate phases of reinforced behavior in mice,” they said, adding: “These data demonstrate that disruption of intrinsic regulators of neuronal activity differentially affects dopamine dynamics during reinforcement and extinction learning.”

Through experiments where the mice were rewarded with food by pressing a lever correctly, the researchers found that removing the channel that controls tonic activity resulted in the mice entering a hypertonic flow. This, in turn, created an increased motivational state that encouraged the animals to reattempt their tasks.

When the researchers removed the ion channel controlling phasic dopamine release, it increased transient high levels of dopamine in response to specific events – causing the mice to learn tasks faster.

Given that humans also possess hundreds of ion channels that regulate the chemical and hormonal processes behind behaviour and mood, Zweifel said the results may hold the key to “improving cognitive function, for example, in patients who have learning disabilities”.

They could also help with “increasing motivation in individuals who have depression, where you have a reduced motivational state”, and pave the way for numerous new drug candidates to be tested in clinical trials.

“We're hoping that's ultimately what we can do," Zweifel said.

The findings of the research – involving 17 scientists from Zwiefel’s laboratory supervised by lead author Barbara Juarez – are published in the journal Science Advances.

Juarez is now a professor at the University of Maryland School of Medicine in Baltimore.