Exposure to heroin sharply reduces levels of the protein necessary for developing and maintaining the brain’s synapses


Exposure to heroin sharply reduces levels of the protein necessary for developing and maintaining the brain’s synapses, a preclinical study 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.

The UB research paper, one of the first to trace the pathophysiology of addiction relapse, was published online on Sept. 12 in Nature Communications.

The neurobiology of relapse

“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,” said David Dietz, PhD, senior author on the paper, chair of the Department of Pharmacology and Toxicology in the Jacobs School of Medicine and Biomedical Sciences at UB and a faculty member in UB’s neuroscience program.

“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.”

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.

He was recently awarded more than $2 million from the National Institutes of Health (NIH) to continue research on drebrin and other potential targets for treating drug addiction.

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 drenditic 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.

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.

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.

“Our lab is focused on improving our understanding of the neurobiology of addiction and relapse so that we can figure out the best way to target these pathways for future therapeutic use,” Dietz said.

In addition to Dietz, UB co-authors are Jennifer A. Martin; Craig T. Werner; Swarup Mitra; Zi-Jun Wang; Pedro H. Gobira; Andrew F. Stewart; Jay Zhang; Kyra Erias; Justin N. Siemian; Lauren. E. Mueller; Jun-Xu Li; and Karen C. Dietz of the Department of Pharmacology and Toxicology and Ping Zhong and Zhen Yan of the Department of Physiology and Biophysics.

Devin Hagerty and Amy M. Gancarz of California State University, Bakersfield; Rachel L. Neve of Massachusetts General Hospital; Mary Kay Lobo and Ramesh Chandra of the University of Maryland School of Medicine are also co-authors.

Funding: The work was funded by the National Institute on Drug Abuse of the NIH.

Drug addiction can be defined as a chronically relapsing disorder, characterised by compulsion to seek and take the drug, loss of control in limiting intake, and emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) when access to the drug is prevented.

From a diagnostic perspective, the term addiction is now encompassed by the term substance use disorders.

In 2013, DSM-51 combined what was previously conceptualised as two separate and hierarchical disorders (substance abuse and substance dependence) into one construct, defining substance use disorders on a range from mild to moderate to severe, with the severity of an addiction depending on how many of the established criteria apply.

Although much of the early research with animal models focused on the acute rewarding effects of drugs of abuse, focus is shifting to the study of chronic drug administration-induced brain changes that decrease the threshold for relapse, which corresponds more closely to human imaging studies of individuals who have substance use disorders.

One of the main goals of neurobiological research is to understand changes at the molecular, cellular, and neurocircuitry levels that mediate the transition from occasional, controlled substance use to loss of control in drug intake and chronic addiction.2 

Because only some substance users make this transition, neurobiological factors that influence the diverse individual differences in drug responses have also attracted increasing interest.

Cogent arguments have been made that addictions are similar to other chronic relapsing disorders—with individual differences in responses to the same exogenous challenges and limited effi cacy of treatment—such as diabetes, asthma, and hypertension.3

The purpose of this Review is twofold. First, we aim to elaborate a heuristic framework based on the neuropsychopharmacological and brain imaging phenotype of addiction in the context of three functional domains (incentive salience, negative emotional states, and executive function) mediated by three major neuro-biological circuits (basal ganglia, extended amygdala, and prefrontal cortex).

Second, we aim to identify neurochemically defined mini circuits that can independently or interactively mediate functional neuroplasticity within the three major circuits to produce incentive salience and compulsive-like habits, negative emotional states of low reward and excessive stress, and compromised executive function.

Building on previous identification of the three overall domains, this Review provides a framework for integration of the ever-expanding neuroplastic complexity of motivational systems that are involved in addiction and for identification of new targets for diagnosis, treatment, and prevention of addiction.

Addiction can be conceptualised as a three-stage, recurring cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving)—that worsens over time and involves neuroplastic changes in the brain reward, stress, and executive function systems.46 

Derived from a confluence of information from social psychology of human self-regulation failure, psychiatry, and brain imaging, these three stages provide a heuristic framework for the study of the neurobiology of addiction.4,5 

A definition of impulsivity is “a predisposition toward rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to themselves or others”.7 A definition of compulsivity is the manifestation of “perseverative, repetitive actions that are excessive and inappropriate”.8 

Impulsive behaviours are often accompanied by feelings of pleasure or gratification, but compulsions in disorders such as obsessive-compulsive disorder are often performed to reduce tension or anxiety from obsessive thoughts.8

 In this context, individuals move from impulsivity to compulsivity, and the drive for drug-taking behaviour is paralleled by shifts from positive to negative reinforcement (figure ​(figure1).1). However, impulsivity and compulsivity can coexist, and frequently do so in the different stages of the addiction cycle.8

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Object name is nihms-985499-f0001.jpg
Figure 1:
Model of interacting circuits in which disruptions contribute to compulsive-like behaviours underlying drug addictionThe overall neurocircuitry domains correspond to three functional domains: binge/intoxication (reward and incentive salience: basal ganglia [blue]), withdrawal/negative affect (negative emotional states and stress: extended amygdala and habenula [red]), and preoccupation/anticipation (craving, impulsivity, and executive function: PFC, insula, and allocortex [green]). Arrows depict major circuit connections between domains, and numbers refer to neurochemical and neurocircuit-specific pathways known to support brain changes that contribute to the allostatic state of addiction. PFC=prefrontal cortex. ACC=anterior cingulate cortex. OFC=orbitofrontal cortex. NAc-VTA=nucleus accumbens-ventral tegmental area. Modified from Koob and Volkow (2010)9 with permission from Nature Publishing Group.

Understanding of the neurobiology of addiction has progressed through the study of animal models10 and, more recently, through brain imaging studies in individuals with addiction. Although no animal model of addiction fully emulates the human condition, they permit investigations of specific signs or symptoms that are associated with the psychopathological condition. If the model adequately mimics the phenomenology observed in humans as they transition from experimentation to addiction, then it is more likely to have construct or predictive validity.11 The phenomena under study can be models of different systems (genetic, epigenetic, transcription, cellular, and network), psychological constructs (positive and negative reinforcement), symptoms outlined by psychiatric nosology (craving, hypohedonia, and dysphoria), and stages of the addiction cycle.4 Recently developed animal models take advantage of individual and strain diversity in responses to drugs, incorporate complex environments with access to and choices of alternative reinforcers, and test effects of stressful stimuli, allowing the investigation of neuro biological processes that underlie the risk for addiction and environmental factors that provide resilience against vulnerability. Animal models have also started to explore the influence of developmental stage and sex in drug response to better understand the greater vulnerability to substance use disorders when drug use is initiated in adolescence, and the distinct drug use trajectories that are observed in men and women. The neurobiological mechanisms involved in the stages of the addiction cycle can be conceptualised as domains, with a focus on specific brain circuits, the molecular and neurochemical changes in those circuits during the transition from drug taking to addiction, and the way in which those changes persist in the vulnerability to relapse.12 Equally convincing, animal models of the specific stages of the addiction cycle can be paralleled by human laboratory models13 and studied with neuroimaging.14

University at Buffalo
Media Contacts:
Ellen Goldbaum – University at Buffalo
Image Source:
The image is in the public domain.

Original Research: Open access
“A novel role for the actin-binding protein drebrin in regulating opiate addiction”. 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 .
Nature Communications doi:10.1038/s41467-019-12122-8



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