Combining alcohol with cocaine rewires the brain’s relapse pathways differently than cocaine alone

A recent study published in the journal Neuropsychopharmacology provides evidence that using cocaine and alcohol together alters the brain pathways responsible for drug relapse. The research suggests that the specific brain circuits driving a return to cocaine use in single-drug scenarios are no longer the primary drivers when alcohol is involved. These findings indicate that treating polysubstance use might require completely different medical approaches than treating isolated cocaine use.

Scientists conducted this research to better understand how the brain changes when multiple addictive substances are consumed. Most laboratory models of addiction focus entirely on a single substance, such as cocaine. However, the vast majority of people who struggle with cocaine addiction also consume alcohol, often drinking sequentially after a period of using cocaine.

To explain the motivation behind the study, researcher Lori Knackstedt provided some background. Knackstedt is a professor of psychology at the University of Florida, a researcher at the Center for Addiction Research and Education, and holds titles as a UF Term Professor (2017-2020) and a UF Research Foundation Professor (2023-2026).

“Despite years of research, there are still no FDA-approved medications for cocaine use disorder,” Knackstedt said. “While many compounds reduce cocaine-seeking in rodent models of cocaine use disorder, these compounds fail to reduce cocaine use in humans.”

“One reason for this discrepancy may be that 50-90% of humans with cocaine use disorder consume alcohol on the same day that they consume cocaine,” Knackstedt explained. “Alcohol and cocaine produce both similar and opposing effects on neurobiology.”

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“Thus, our research program is aimed at determining whether rodents taking both cocaine and alcohol have distinct neuroadaptations from those that consume only cocaine,” she added. “If this is true, then different treatments may need to be used in people who use both drugs compared to only cocaine.”

Previous studies on single substances have established that a specific neural pathway plays a significant role in triggering a relapse. This pathway connects the prelimbic cortex, an area of the brain responsible for decision making, to the nucleus accumbens core, a region heavily involved in processing rewards. When scientists block the signals between these two brain regions, animals usually stop seeking cocaine.

The researchers designed their experiment to test if this exact same brain circuit still controls the urge to seek drugs after a history of using both cocaine and alcohol. To answer this question, the scientists studied 84 rats over a series of controlled experiments.

First, the animals underwent surgery so researchers could insert specialized biological tools into their brains. These tools, known as chemogenetics, allow scientists to selectively turn specific brain pathways on or off using a specially designed chemical injection.

Following recovery, the rats were placed in specialized chambers and trained to press a lever to receive small, intravenous doses of cocaine. The animals participated in these daily sessions for two hours at a time until they consistently self-administered the drug. The drug delivery was paired with specific lights and sounds to create strong environmental cues.

Afterward, the rats were divided into two main groups and returned to their home cages. One group received standard drinking water, while the other group received a choice between water and a liquid containing twenty percent alcohol for six hours. This setup models the human behavior of using alcohol sequentially after cocaine.

Next, the animals went through a process called extinction training. During this phase, pressing the lever no longer provided any cocaine or triggered any lights or sounds. Over a period of at least ten days, the animals gradually learned to stop pressing the lever, mimicking a period of drug abstinence.

Finally, the researchers conducted a test to measure the reinstatement of drug seeking behavior, which is the laboratory equivalent of a relapse. They exposed the animals to the lights and sounds that were previously paired with cocaine to trigger an urge for the drug. Right before this test, the scientists gave the rats the specialized chemical to either block or stimulate the neural pathway connecting the decision making center to the reward center.

The researchers found that blocking this brain pathway had different effects depending on what the animals had been drinking in their home cages. In the rats that only consumed water, turning off the neural pathway successfully prevented them from pressing the lever to seek cocaine. This outcome matches previous studies involving only one substance.

In the rats that consumed both alcohol and cocaine, blocking the exact same brain circuit failed to stop their drug seeking behavior. These animals continued to press the lever at high rates when exposed to the cocaine-related cues. This suggests that the combination of alcohol and cocaine shifted the control of relapse behaviors to a completely different, currently unidentified brain network.

To verify that their biological tools were working properly, the researchers examined the animals’ brain tissue under a microscope. They looked for the presence of a specific protein that naturally builds up inside brain cells when those cells are highly active. By measuring the levels of this protein, the scientists confirmed that their chemical injection successfully quieted the targeted brain cells in both groups of animals.

During this tissue analysis, the researchers also looked at the basolateral amygdala, an almond shaped structure deep in the brain linked to processing emotions and environmental cues. They found that animals with a history of alcohol use showed heightened cellular activity in this emotional center during the relapse test. This provides evidence that chronic alcohol consumption tends to make certain brain areas more sensitive to triggers associated with other addictive substances.

In a separate experiment, the scientists tried artificially stimulating the pathway connecting the decision center to the reward center rather than blocking it. They wanted to see if boosting the communication between these brain regions would increase the intensity of drug seeking behaviors. To do this, they used a different version of the chemogenetic tools designed to excite the neurons rather than silence them.

The researchers found that stimulating this brain circuit did not increase lever pressing or overall physical movement in either the single-drug or the multiple-drug group. The animals pursued the drug cues at the same rate regardless of whether the brain pathway was artificially stimulated.

“We were surprised that while we could suppress relapse to cocaine seeking by inhibiting the brain pathway from the prefrontal cortex to the nucleus accumbens, stimulating the same pathway did not increase relapse further,” Knackstedt told PsyPost. “This implies that there is a ceiling for the ability of this pathway to control relapse.”

While the study provides helpful new insights, there are a few potential limitations and misinterpretations to consider. The specific timing of the substance use in this model only represents one way humans consume these drugs.

“This study assessed only one pattern of cocaine-alcohol polysubstance use, one where cocaine is taken first and alcohol second,” Knackstedt explained. “Humans also engage in simultaneous cocaine-alcohol use, which may produce different effects on the brain.”

Additionally, the exact mechanisms behind the increased activity in other brain regions remain unexplored. Future studies will need to identify exactly which new brain pathways take over the relapse process when alcohol and cocaine are combined.

Moving forward, Knackstedt and her team plan to “continue to assess neurobiological changes in response to cocaine-alcohol polysubstance use in efforts to find medications to reduce cocaine use in this condition.” Ultimately, the main takeaway for the average person is “that polysubstance use, the use of more than one addictive drug within a period of time, can change the brain in unique ways,” Knackstedt noted.

The study, “The role of the prelimbic cortex to nucleus accumbens core projection in the reinstatement of cocaine-seeking after cocaine-alcohol polysubstance use,” was authored by Javier R. Mesa, Sydney Y. Dick, Kassandra Greenan, Lizhen Wu, and Lori A. Knackstedt.