Decoding the Brain’s Addiction Circuitry

By Keith Gillogly

Their imbalance can contribute to anxiety, depression and onset of neurodegenerative diseases. They also play a major role in addictive behaviors. Yet most pharmacotherapies for addiction and drug-use disorder are ineffective, underscoring the need for better treatments.

“These neurotransmitters are important for controlling and modulating emotional processes, including reward, stress, and happiness,” says Jinwoo Park, PhD, associate professor of biotechnical and clinical laboratory sciences in the Jacobs School of Medicine and Biomedical Sciences. “But most scientists are interested in dopamine circuits.”

Park, however, studies both dopamine and norepinephrine, specifically how their interactions and “crosstalk” affect feelings and behavior. He’s also investigating how sex differences and the female reproductive cycle influence neurotransmitter levels, suggesting the need for more targeted, sex-specific treatments for addiction and other conditions.

To advance this work, Park received a $3.7 million, five-year grant from the National Institute on Drug Abuse, part of the National Institutes of Health, in July for his project, “Interplay Between Limbic Norepinephrine and Dopamine Circuits in Sex Differences in Reward and Aversion.” 

Dopamine has long been a popular target for research and is present across many brain regions. But Park’s research hones in on dopamine and norepinephrine together and how they interact within specific brain circuits.

For this research, he and his colleagues are targeting dopamine neurons in the brain's ventral tegmental area and norepinephrine neurons in the locus coeruleus and nucleus of the solitary tract, as well as limbic structures of the brain implicated in drug use disorders, stress and motivation.

The researchers believe that norepinephrine signals from these specific areas may be modulating the dopamine neurons, shaping how the brain’s ventral striatum processes reward and aversion.

Through collaboration with Brian N. Kim, PhD, at the University of Texas at Dallas, Park and the research team will use multi-array probes containing more than 100 sensors to map brain areas and dopamine and norepinephrine levels in rats.

With the help of Caroline E. Bass, PhD, associate professor of pharmacology and toxicology at the Jacobs School, the team will use engineered viruses to deliver genes to specific dopamine and norepinephrine neurons. Using these genetic instructions, the neurons will produce either light-sensitive proteins or chemically sensitive receptors.

The researchers can then selectively turn these neurons on or off using optogenetics and chemogenetics, tools that can manipulate neurons using light or lab-designed drugs, and track the resulting changes in neurotransmitter levels and behaviors observed. 

“We can selectively target local dopamine or norepinephrine circuits in a specific brain area, and then we monitor behavioral outputs,” Park says.

Park and his colleagues will also look closer at how the female estrous cycle affects neurotransmitter levels, which could be a significant, if underexplored, factor. “Previous studies haven’t really studied the different phases of the cycle; they’ve just compared male and female,” Park says.

“In the estrus phase for females, the dopamine level is higher and the norepinephrine level is lower. In the non-estrus phases, it’s the opposite. Norepinephrine level is higher than dopamine,” Park notes. “Yet we treat the same way for males and females even though they show these differences.”

Further understanding these sex differences and their effects on neurotransmitter levels could lead to new strategies to treat males and females; more precisely targeting brain circuitry involved in addiction and stress could ultimately improve therapies.