Exposure to heroin sharply reduces levels of the protein necessary for developing and maintaining the brain’s synapses, a preclinical study[1] by University at Buffalo researchers has found. The development of addiction relapse is directly related to the impact that reductions in this protein, called drebrin, have on specific cells involved in the brain’s pleasure-seeking/reward pathways.

“Very few research studies have examined the molecular mechanisms of heroin relapse and there is almost nothing published about the specific cell types that these changes occur in. These findings lead us to a better understanding of the neurobiology of relapse to opiates. In combination with other findings, the research will hopefully provide avenues toward treatments that can prevent relapse behaviors,"

said David Dietz, PhD, senior author on the paper.

Opiate Addiction Relapse

Most currently available treatments are replacement therapies, none of which address the fundamental changes that occur in addiction and lead to relapse, which remains an intractable issue. Dietz and his colleagues have focused much of their research on relapse after opiate addiction and withdrawal and the structural plasticity in the brain that they cause.

[caption id=“attachment_100110” align=“aligncenter” width=“700”]Drebrin restores opiate-induced deficits in synaptic plasticity Drebrin restores opiate-induced deficits in synaptic plasticity.
Credit: Jennifer A. Martin, et al. CC-BY[/caption]

Drebrin was of interest because loss of the protein has been previously implicated in brain diseases, such as Alzheimer’s disease and Down syndrome.

“Since drebrin is responsible for developing and maintaining synapses, we wondered if it was also involved in addiction to drugs of abuse, ultimately leading to relapse,"

said Dietz.

In experiments with rodents, the UB team determined that exposure to heroin and morphine reduced drebrin levels in the nucleus accumbens, a key part of the brain’s reward pathway.

Synaptic Rewiring

The researchers found that opiate exposure causes synaptic rewiring in this part of the brain, as well as a decrease in dendritic spines, the protrusions on neurons that play key roles in neuronal transmission, learning and memory.

“Opiates fundamentally change how the brain communicates with itself,"

Dietz said.

The researchers found that the reduction in drebrin levels is regulated by changes in how an enzyme called HDAC2 facilitates access to the DNA. In addition, the study demonstrates that these changes occur exclusively in a specific type of cell within the nucleus accumbens, known as D1, which contains medium spiny neurons, the type of cells that make up this part of the reward center.

“Restoring drebrin back to normal levels in these specific brain cells was sufficient to reduce relapse behaviors,"

said Dietz.

The research provides a critical and understudied insight into the mechanisms behind addiction and relapse behaviors, which in combination with future studies may lead to a novel and effective treatment to prevent relapse.

[1] Jennifer A. Martin, Craig T. Werner, Swarup Mitra, Ping Zhong, Zi-Jun Wang, Pedro H. Gobira, Andrew. F. Stewart, Jay Zhang, Kyra Erias, Justin N. Siemian, Devin Hagarty, Lauren E. Mueller, Rachael L. Neve, Jun-Xu Li, Ramesh Chandra, Karen C. Dietz, Mary Kay Lobo, Amy M. Gancarz, Zhen Yan, David M. Dietz. A novel role for the actin-binding protein drebrin in regulating opiate addiction. Nature Communications volume 10, Article number: 4140 (2019)

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