Recent research published in journals neuropsychopharmacology There is evidence that using cocaine and alcohol together alters brain pathways that contribute to drug relapse. This study suggests that the specific brain circuits that promote return to cocaine use in single-drug scenarios are no longer the primary driving force when alcohol is involved. These findings indicate that treating polysubstance use may require a completely different medical approach than treating cocaine use alone.
Scientists conducted this study to better understand how the brain changes when ingesting multiple addictive substances. Most laboratory models of addiction focus entirely on a single substance, such as cocaine. However, the majority of people who suffer from cocaine addiction also consume alcohol, and often use cocaine for a period of time followed by drinking.
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 the titles of University Term Professor (2017-2020) and University Research Foundation Professor (2023-2026).
“Despite years of research, there is still no FDA-approved treatment for cocaine use disorder,” Knackstedt said. “While many compounds reduce cocaine seeking in rodent models of cocaine use disorder, these compounds are unable to reduce cocaine use in humans.”
“One reason for this discrepancy may be that 50 to 90 percent of people with cocaine use disorder consume alcohol on the same day they take cocaine,” Knackstaedt explained. “Alcohol and cocaine have both similar and opposing effects on neurobiology.”
“Our research program therefore aims to determine whether rodents that consume both cocaine and alcohol have different neuroadaptations than those that consume only cocaine,” she added. “If this is true, different treatments may need to be applied to people who use both drugs and those who only use cocaine.”
Previous studies on single substances have demonstrated that specific neural pathways play an important role in inducing relapse. This pathway connects the prelimbic cortex, an area of the brain responsible for decision-making, and the nucleus accumbens core, an area deeply involved in reward processing. When scientists block the signals between these two brain regions, animals usually stop seeking cocaine.
The researchers designed an experiment to test whether this very same brain circuit controls the urge to seek drugs after using both cocaine and alcohol. To answer this question, scientists studied 84 rats in a series of controlled experiments.
First, the animals underwent surgery so researchers could insert special biological tools into their brains. These tools, known as chemical genetics, allow scientists to selectively turn on or off specific brain pathways using specially designed chemical injections.
After recovery, the rats were placed in a special room and trained to press a lever to administer small doses of cocaine intravenously. Animals participated in these daily sessions for 2 h at a time until they consistently self-administered the drug. Drug delivery was combined with specific lights and sounds to create powerful environmental cues.
The rats were then divided into two main groups and returned to their home cages. One group was given standard drinking water, and the other group was given a choice of either water or a liquid containing 20% alcohol for 6 hours. This setup models the behavior of humans who use cocaine followed by alcohol sequentially.
The animals then went through a process called extinction training. At this stage, pressing the lever no longer delivered cocaine and no longer triggered lights or sounds. Over at least 10 days, the animals gradually learned to stop pressing the lever, mimicking a period of drug withdrawal.
Finally, the researchers conducted a test to measure recovery of drug-seeking behavior. This is equivalent to a recurrence in the laboratory. They exposed the animals to light and sound that had been previously combined with cocaine to induce the urge for the drug. Just before the experiment, the scientists gave the rats a special chemical that blocked or stimulated the neural pathways that connect decision-making and reward centers.
The researchers found that blocking this brain pathway had different effects depending on what the animals were drinking in their home cages. In rats that consumed only water, the researchers were able to prevent them from pressing the lever in search of cocaine by turning off neural pathways. This result is consistent with previous studies that focused on only one substance.
In rats given both alcohol and cocaine, blocking the exact same brain circuits failed to stop drug-seeking behavior. These animals continued to press the lever at high speeds when exposed to cocaine-related cues. This suggests that the combination of alcohol and cocaine shifts the control of relapse behavior to a completely different and currently unidentified brain network.
To make sure the biological tool was working properly, the researchers examined the animals’ brain tissue under a microscope. They looked for the presence of specific proteins that naturally accumulate within brain cells when they are actively working. By measuring levels of this protein, the scientists confirmed that the injection of the chemical was successful in calming the target brain cells in both groups of animals.
During this tissue analysis, the researchers also observed the basolateral amygdala, an almond-shaped structure deep in the brain associated with processing emotions and environmental signals. They found that animals with a history of alcohol use showed increased cellular activity in this emotional center during relapse testing. This provides evidence that chronic alcohol consumption tends to make certain areas of the brain more sensitive to triggers associated with other addictive substances.
In another experiment, scientists tried to artificially stimulate, rather than block, the pathway connecting decision-making and reward centers. They wanted to see if strengthening communication between these brain regions would increase the intensity of drug-seeking behavior. To do this, they used different versions of chemical genetic tools designed to excite neurons rather than silence them.
The researchers found that stimulating this brain circuit did not increase lever presses or overall body movements in either the single- or multiple-drug groups. Animals tracked drug cues at the same rate regardless of whether the brain pathway was stimulated artificially.
“While we were able to reduce cocaine-seeking relapse by inhibiting a brain pathway from the prefrontal cortex to the nucleus accumbens, we were surprised that stimulating the same pathway did not further increase relapse,” Nackstedt told PsyPost. “This means that the ability of this pathway to suppress relapse is limited.”
Although this study provides useful new insights, there are some potential limitations and misconceptions that should be considered. The specific timing of substance use in this model represents only one way in which humans ingest these drugs.
“In this study, only one pattern of polysubstance use, cocaine and alcohol, was evaluated: cocaine consumed first and alcohol consumed second,” Knackstedt explained. “Humans can also use cocaine and alcohol at the same time, which can have different effects on the brain.”
Moreover, the exact mechanisms behind the increased activity in other brain regions are still unknown. Future research will need to pinpoint exactly which new brain pathways take over the relapse process when alcohol and cocaine are combined.
Going forward, Knackstaedt and her team plan to “continue to evaluate the neurobiological changes in response to cocaine-alcohol compound use and continue our efforts to find drugs that reduce cocaine use in this condition.” Ultimately, the main takeaway for the average person is that “polysubstance use, the use of multiple addictive drugs within a period of time, can change the brain in unique ways,” Knackstedt noted.
The study, “The role of prelimbic cortex on nucleus accumbens core projections in 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.
