Regaining Control of a Brain Region May Prevent Opioid Use

Changes in the activity of brain cells known as pyramidal neurons, which lead to drug-seeking in a preclinical model of opioid use disorder, have been detected by a team of neuroscientists at the Medical University of South Carolina (MUSC). When heroin was no longer available, these neurons became more excitable. By inhibiting the enzyme protein kinase A (PKA), the activity of these neurons was restored to normal. Inhibiting this enzyme lowered opioid-seeking behavior as well. Professor of neuroscience Jacqueline McGinty, Ph.D., and postdoctoral fellow Saurabh Kokane, Ph.D., recently published their team’s findings in the Journal of Neuroscience.

Returning to drug seeking and use, or relapse, after a period of not using the substance, or abstinence, can raise the chance of opioid overdose.

“Prevention of return to use is the key in successful development of effective treatments for substance use disorders,” said Kokane.

“After decades of research on opioid use disorder, three FDA-approved drugs exist, but they only reduce the severity of detoxification symptoms and don’t stop return to use. So, there is a definite need for more treatment options,” he said. “Currently, we lack a comprehensive understanding of the effects of opioids, like heroin, on the neurons that drive return to use. Better understanding these changes may lead to additional treatment options.”

The McGinty Lab at MUSC discovered that certain types of pyramidal neurons lead to relapse. They discovered that during abstinence from heroin, a commonly used opioid, these neurons in a specific brain region, the prelimbic prefrontal cortex, experience molecular and functional alterations that compromise their function. The prelimbic cortex is a brain region involved in decision-making and behavioral regulation. Opioids can interfere with normal brain activity in this area, which can lead to obsessive drug seeking in people with opioid use disorder.

Importantly, the researchers show in this preclinical study that restoring normal activity to these neurons by blocking a critical enzyme during heroin abstinence can prevent drug craving in a rodent model.

Recognizing Relapse

Substance use disorders are chronic, curable diseases that can be overcome. These disorders are distinguished in part by the continuous use of substances despite unfavorable consequences, as well as periods of abstinence followed by relapse.

Cue-induced relapse occurs when a person with a substance use disorder encounters a “cue” or “trigger” that causes that person to crave the use of a drug. Someone with an alcohol use problem, for example, may need a drink when he or she hears the pop of a champagne cork, but someone with an opioid use disorder may crave heroin if he or she witnesses drug usage on television.

“These overwhelming cravings may lead those with opioid use disorders to return to use, even if they do not want to,” said Kokane.

“The challenges with compulsive drug use are the loss of the ability to decide between different behavioral options and the lack of resistance to environmental stimuli that remind you of taking an opioid like heroin,” McGinty said.

Loss of control

Changes in several brain regions are responsible for cue-induced relapse and make it difficult for a person with substance use disorder to control drug cravings. In this study, Kokane and the McGinty Lab focused on two of these regions: the nucleus accumbens and the prelimbic cortex.

“The nucleus accumbens is a brain area that receives input from the prelimbic cortex and from dopamine-releasing pathways that cause the desire to take the substance again that is associated with all addictive drugs, including opioids,” explained Kokane. During abstinence, aberrant functioning of these pathways is a major contributor to cue-induced relapse.

Generally, the prelimbic cortex and other cortical regions are responsible for deciding whether to act on a feeling or desire. Through its connections with the nucleus accumbens, the prelimbic cortex either motivates us to stop from acting or pushes us to act, said Kokane.

Opioid-induced alterations in the function of these brain regions make quitting opioids much more difficult.

“The changes in the brain of someone recovering from substance use disorder drive a return to use when environmental drug cues become overwhelming, but the exact types of changes that occur have not been fully studied,” said McGinty.

The MUSC researchers discovered that neurons connecting the prelimbic cortex to the nucleus accumbens enhance their activity during periods of heroin abstinence using a rat model. Rather than slowing down, the increased activity of these neurons may aid the nucleus accumbens in driving relapse.

Drug use may then spiral out of control, despite negative social and psychological repercussions.

Regaining control
More study is needed, but Kokane and McGinty believe that restoring normal activity in the neurons of the prelimbic cortex may prevent cue-induced relapse.

“We need to understand the changes that occur in neurons during abstinence from heroin in more detail and determine how they lead to relapse,” Kokane said.

The MUSC study also discovered that an enzyme called PKA becomes more active during heroin withdrawal. Researchers discovered that reducing PKA locally restored neuronal activity to normal levels in the prelimbic cortex, where abstinence enhanced neuronal activity.

This discovery sparked a new thought for the MUSC researchers: perhaps inhibiting PKA could restore control.

“When we infused the PKA inhibitor into the prelimbic cortex during heroin abstinence, we saw a decrease in cue-induced relapse,” said Kokane.

The researchers uncovered one technique to restore control to the prelimbic cortex after opioid withdrawal in a mouse model by suppressing PKA. Importantly, regaining control of the brain resulted in better behavioral control since heroin cravings were reduced.

Our findings provide a novel molecular target for the development of future pharmacotherapies,” Kokane said. “We are at a very early stage in this research, but it has potential. Our findings suggest that research should be geared toward developing pharmacotherapies that specifically target functional changes that develop during heroin abstinence in particular types of neurons, like those we identified in the prelimbic cortex.”

Until then, the team is excited to continue its preclinical research to shed light on prelimbic control over opioid seeking and relapse and to uncover additional targets.

“It is important to realize that the brain is constantly adapting to the environment, and that the changes we have documented in the prefrontal cortex during heroin abstinence, while persistent, are not necessarily permanent and are subject to reversal,” said McGinty.

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