Physical Activity Reduces Return to Cocaine Seeking in Animal Tests

Exercise also decreases neural change linked with drug seeking during abstinence.
April 2012
By Lori Whitten, NIDA Notes Staff Writer

Aerobic exercise might help cocaine abusers establish and maintain abstinence, recent NIDA-funded animal research suggests. In two independent studies, running on an exercise wheel reduced rats’ cocaine seeking during forced abstinence and their eagerness to resume cocaine seeking following the abstinence. One study indicated that exercise may produce these effects in part by lowering brain levels of a protein that has been linked to drug craving.

The research teams, one led by Dr. Marilyn Carroll at the University of Minnesota and the other by Dr. Wendy Lynch at the University of Virginia, examined the impact of exercise on drug seeking with a protocol that researchers often use to test potential addiction medications. Their work highlights the potential usefulness of such protocols for assessing behavioral approaches to addiction treatment as well.


The research teams varied details of the test protocol, but both preserved its basic three-phase structure, which parallels a person’s acquisition of chronic drug abuse, establishment of abstinence, and exposure to a relapse trigger:

  • Self-administration: The animal self-administers cocaine infusions by pressing a lever, ultimately leveling off at a dosage that it apparently finds optimal.
  • Extinction (of the lever-pressing behavior): The researchers deactivate the lever and observe how rapidly the rat tapers off its lever pressing in the absence of the drug reward.
  • Reinstatement: The researchers expose the rat to some strong reminder of the rewarding sensations produced by the drug—e.g., a priming dose or drug-associated cues—and observe how avidly the animal resumes lever pressing.

In studies with this protocol, researchers administer a potential treatment after the self-administration phase and judge it to be effective if it results in reduced lever pressing during extinction and/or reinstatement. Hence, the Virginia and Minnesota teams moved their animals to cages with exercise wheels after the self-administration stage (see chart).Both found that animals that ran on the wheels tapered off lever pressing faster during extinction and took it up less avidly during reinstatement, compared with control animals placed in cages with locked running wheels.

Photo shows a white rat in a glass cage with access to a running wheel that is attached to a monitoring computer The Experimental Protocols Using slightly different procedures, each team combined standard drug self-administration and reinstatement procedures—an animal model of relapse—with access to a running wheel to investigate whether exercise reduces cocaine seeking.

Team Carroll Lynch
Sex of Rats Female Male
Training In Running Wheel 6 hours daily for 8 days None
Self-Administration in Absence of Wheel
(lever delivers cocaine)
6 hours daily for 10 days 24-hour access for 10 days
Forced Abstinence
(no lever, no cocaine)
None 2 hours daily for 14 days
Wheel or Locked Wheel
(lever no longer delivers cocaine)
6 hours daily for 14 days
Wheel or Locked Wheel
6 to 8 sessions, 1 hour each
Reinstatement After Trigger
(lever no longer delivers cocaine)
Single 6-hour test

Trigger = Priming injection
Wheel or Locked Wheel
Single 1-hour test immediately after extinction session
Trigger = Drug-associated cues

In the Minnesota study, female rats that exercised pressed the lever about half as often, on average, during the first 9 days of the 14-day extinction phase. Dr. Carroll and colleagues also found that exercise reduced lever pressing during reinstatement when animals ran on the same day that they received a priming dose of cocaine, but not when there was a delay between receiving the priming dose and being introduced to the wheel.

In the Virginia study, male rats that exercised for up to 2 hours a day during a 2-week period of forced abstinence between self-administration and extinction pressed the lever about 35 percent less often during the extinction phase and about 45 percent less often during reinstatement.

Decreased Neuroadaptation

Both studies indicate that exercise does more than simply provide an alternative activity that reduces the time available for drug seeking, the researchers say. The researchers note that both exercise and addictive drugs raise levels of dopamine in the brain’s reward system, and as a result, exercise may compete with cocaine as a source of pleasurable sensations. In addition, the Virginia researchers found evidence suggesting that exercise may alter levels of the neurotransmitter glutamate in their rats’ prefrontal cortex (PFC). Such an effect might weaken the progressive intensification (incubation) of craving that takes place during early abstinence from cocaine and appears to depend largely on glutamate.

Dr. Lynch and colleagues assayed brain tissue from the PFC of their animals 1 day after the end of reinstatement. Exercise was associated with 32- and 42-percent reductions in the activity of two proteins, extracellular signal-regulated kinase (ERK) 1 and 2, whose levels are regulated by both dopamine and glutamate. Previous research has established associations between ERK, drug-seeking behavior, and the incubation of cocaine craving.

Activity Reduces Rats’ Return to Cocaine In a study at the University of Minnesota, female rats that had access to a functional running wheel during extinction pressed the cocaine-delivery lever less often during this period than rats that did not have such access (left-hand graph). In response to a priming injection of the drug, rats that had access to a running wheel during reinstatement pressed the cocaine-delivery lever less often at this stage than rats with a locked wheel or access to a running wheel only during extinction (right-hand graph).
Text Description of Activity Reduces Rats’ Return to Cocaine Graphic

Dr. Lynch and colleagues continue to investigate whether exercise counters changes in glutamate neurotransmission and other neuroadaptations that characterize the transition from drug abuse to addiction (see “Medications That Normalize Brain Glutamate Reduce Drug Seeking in Rats”). Dr. Carroll and colleagues are exploring the relationships among propensity for wheel running, neuronal activity in the brain’s reward pathway, and subsequent levels of cocaine self-administration (see box below).

Propensity for Wheel Running Linked to Response to Drugs

Prior research led by Dr. Marilyn Carroll at the University of Minnesota, a pioneer in the behavioral study of exercise as a treatment for drug abuse, found that among female—but not male—rats, the propensity for wheel running was related to substance abuse vulnerability. Animals that ran avidly before drug exposure went on to self-administer more cocaine than rats that ran less. They also sought cocaine more during reinstatement compared with those that had been less active prior to drug exposure. Researchers studying the impact of exercise on addiction processes, therefore, must ensure that propensity for wheel running does not influence their results. Dr. Carroll and others have also demonstrated relationships between some other behavioral characteristics—e.g., novelty seeking and high intake of saccharine—and increased drug self-administration.

Source: Pharmacology, Biochemistry and Behavior 82(3):590–600, 2005. Abstract Available

“These studies are valuable because they establish a causal link between exercise and a decrease in drug-seeking behavior and demonstrate two independent mechanisms by which this may be achieved,” says Dr. Mark Smith of Davidson College, a researcher on exercise and drug abuse who was not affiliated with either study. “Dr. Carroll’s team showed that exercise functions as an alternative, nondrug reinforcer that decreases reinstatement, and Dr. Lynch’s team demonstrated that exercise mitigates the neurobiological consequences of cocaine self-administration that contribute to relapse. Both studies’ findings support the expanded use of exercise-based interventions in substance abuse treatment programs,” he says.

Drs. Carroll and Lynch agree that including exercise as an adjunct to residential substance abuse treatment is a good idea. “Patients in substance abuse treatment would probably need incentives to encourage exercise as an alternative behavior, but our research suggests that access to activity might help,” says Dr. Carroll.

Although research has not directly demonstrated that adding exercise to addiction treatment helps prevent relapse, results from extant clinical studies—mostly on smoking cessation—are promising. “The health benefits of exercise warrant inclusion in treatment, in addition to the potential benefits in relapse prevention,” says Dr. Lynch.

“An important question for future research is what aspect of locomotor activity is protective against drug taking or drug seeking?” says Dr. Cora Lee Wetherington of NIDA’s Division of Basic Neuroscience and Behavioral Research. Researchers need to identify the timing, extent, and other characteristics of locomotor activity (e.g, calorie expenditure) that might facilitate reductions in drug-related behaviors, she adds.

The protocols used in the Minnesota and Virginia studies will help scientists address these issues. “These studies are a testament to the importance of animal models that combine behavioral and environmental factors related to drug abuse, which then allow researchers to investigate the underlying neurobiology,” says Dr. Wetherington.


Lynch, W. J., et al. Aerobic exercise attenuates reinstatement of cocaine-seeking behavior and associated neuroadaptations in the prefrontal cortex. Biological Psychiatry 68(8):774–777, 2010. Full Text Available (PDF,188KB)

Zlebnik, N.E., et al. Reduction of extinction and reinstatement of cocaine seeking by wheel running in female rats. Psychopharmacology 209(1):113–125, 2010. Abstract Available

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