New form of brain signaling affects addiction-related behavior

University of Iowa researchers have discovered a new form of neurotransmission that influences the long-lasting memory created by addictive drugs, like cocaine and opioids, and the subsequent craving for these drugs of abuse. Loss of this type of neurotransmission creates changes in brains cells that resemble the changes caused by drug addiction.

The findings, published June 22 in the journal Nature Neuroscience, suggest that targeting this type of neurotransmission might lead to new therapies for treating drug addiction.

“Molecular therapies for drug addiction are pretty much non-existent,” says Collin Kreple, UI graduate student and co-first author of the study. “I think this finding at least provides the possibility of a new molecular target.”

The new form of neurotransmission involves proteins called acid-sensing ion channels (ASICs), which have previously been shown to promote learning and memory, and which are abundant in a part of the brain that is involved in drug addiction. The researchers, led by John Wemmie, professor of psychiatry in the UI Carver College of Medicine, reasoned that disrupting ASIC activity in this brain region (the nucleus accumbens) should reduce learned addiction-related behaviors. However, their experiments showed that loss of ASIC signaling actually increases learned drug-seeking in mice.

When mice learned to associate one side of a chamber with receiving cocaine, animals that lacked the ASIC protein developed an even stronger preference for the “cocaine side” than control mice, suggesting that loss of ASIC had increased addiction behavior. The same result was seen for morphine, another drug of abuse, which has a different mechanism of action than cocaine.

"Always before, the data suggested that when you get rid of ASICs, learning and memory are impaired," Wemmie says. "So we expected the same trend when we studied reward-related learning and behavior and we were surprised to find the opposite."

In a second experiment, rats learned to press a lever to self-administer cocaine. Blocking or removing ASIC in the rat brains caused the animals to self-administer more cocaine than control animals. Conversely, increasing the amount of ASIC by over-expressing the protein seemed to decrease the animals’ craving for cocaine.

"There are many forms of addiction," says Wemmie, who also holds appointments in the UI Departments of Molecular Physiology and Biophysics and Neurosurgery, and with the Iowa City VA Medical Center. "We'd like to see if these mechanisms also apply to other addictions besides cocaine and morphine. And, we want to move forward to see if this pathway can be used to target addiction."

Novel neurotransmission

As the name suggests, acid-sensing ion channels are activated by acid, in the form of protons. This research and a second UI study recently published in PNAS show that protons and ASICs form a previously unrecognized neurotransmitter pair that helps neurons communicate in a novel way; and appear to influence several forms of learning and memory, including fear, as well as addiction.