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October 01, 1996
John A. Bowersox

Although cocaine users typically report that the drug enhances their feelings of well-being and reduces anxiety, cocaine also is known to bring on panic attacks in some individuals. What's more, studies have shown that long-term cocaine use leads to increased anxiety. Severe anxiety, along with restlessness and agitation, is also among the major symptoms of cocaine withdrawal.

Recent NIDA-funded research now suggests that there could be a different aspect to the relationship between cocaine use and anxiety: anxiety and stress may be among the factors that lead to cocaine abuse.

In separate studies that may prove useful for understanding the behavioral and biological mechanisms involved in the initiation of cocaine use and dependence, Dr. Nick E. Goeders of Louisiana State University in Shreveport and Dr. Klaus Miczek of Tufts University in Boston have reported that rats under stress learn to give themselves cocaine more quickly than do nonstressed rats.

The stressed rats in the experiment learned to self-administer cocaine twice as fast as did animals that were not exposed to the stressor.

Both studies involved exposing rats to stressful situations and then assessing how quickly the animals learn to self-administer cocaine by pressing a bar in the testing chamber. Cocaine doses were at first very low but were increased gradually to determine the minimum dose at which the rat would learn the cocaine self-administering task.

In Dr. Goeders' experiment, the level of stress the rats were under was determined by measuring levels of the stress hormone corticosterone in their blood. "It looks like cortico-sterone may make them more sensitive to cocaine," says Dr. Goeders, who found that rats with the highest levels of corticosterone learned the cocaine self-administration task at doses far lower than did rats with low levels of the stress hormone.

Initially, three groups of rats learned that if they pressed a bar in the testing chamber they would be rewarded with food pellets. Environmental stress was then introduced by periodically delivering very brief (one thousandth of a second) electric shocks to the animals' feet.

One group received random footshocks that were delivered noncontingently - that is, whether or not the animals pressed the food bar. Another group also received random shocks but only after the food bar was pressed. The third group served as the control and received no footshocks. As measured by levels of corticosterone in their blood, the group that received random, noncontingent footshocks experienced a significantly higher level of stress than did either of the other two groups.

Each group of animals was then given the opportunity to self-administer a cocaine solution by pressing a second bar in the testing chamber. Rats in the noncontingent shock group required only half as much cocaine as animals in the other two groups did to learn to press the bar for the drug.

Instead of footshocks, Dr. Miczek's experiment employed a "social stress" design in which a rat is exposed to, but shielded from, a more aggressive rat. "Although the first animal is protected from the aggressive rat by a screen and cannot be injured, it still is threatened," explains Dr. Miczek.

A variety of physiological indicators of stress, including increased blood pressure, heart rate, and plasma corticosterone levels, confirmed that animals presented with this situation experienced stress. Dr. Miczek reports that the stressed rats in his experiment learned to self-administer cocaine twice as fast as did animals that were not exposed to the stressor.

Research also is important for understanding how external factors may make some individuals more vulnerable to cocaine abuse

As strong as his and Dr. Goeders' findings appear to be, however, he cautions that further studies are needed before broad conclusions about the association between stress and vulnerability to cocaine abuse can be made.

"Support for the notion that stressors sensitize animals to self-administration of drugs remains controversial," says Dr. Miczek. He adds that certain important stressors, such as being threatened, have been shown to activate the same dopaminergic brain region that cocaine self-administration is known to activate. Although the recent studies report strong correlations between stress and how quickly rats learn to self-administer cocaine, they do not provide direct evidence of a biological mechanism through which this occurs, he notes.

Dr. Goeders says that his laboratory is trying to provide such evidence by blocking corticosterone receptors in the rat brain and then performing the same studies of stress and cocaine self-administration described above. If the stress hormone is responsible for increasing the rate at which stressed rats learn to self-administer cocaine, he explains, blocking the hormone's brain receptors should block the effect of the hormone.

"We're trying to determine if a specific type of corticosterone receptor mediates the effect of stress on cocaine self-administration." These studies could help scientists gain a better understanding of the biology of initiation of cocaine use and abuse, he says.

Dr. Roger Brown, who heads NIDA's Behavioral Neurobiology Research Branch, adds that this kind of research also is important for understanding how external factors may make some individuals more vulnerable to cocaine abuse. These studies shed light on "the situations or conditions that contribute to drug abuse," he says. "In humans, we know that there are factors beyond drug/brain receptor interactions that affect drug-taking behavior." In these studies, he adds, scientists have begun to address how one of these possible factors, stress, interacts with the biochemical pathways known to be involved in cocaine abuse.

Sources

  • Goeders, N.E., and Guerin, G.F. Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats. Psychopharmacology 114:63-70, 1994.
  • Goeders, N.E. Potential involvement of anxiety in the neurobiology of cocaine. Annals of the New York Academy of Sciences 654:357-67, 1992.
  • Miczek, K.A.; Hubbard, N.; and Cantuti-Castelvetri, I. Increased cocaine self-administration after social stress. Neuroscience Abstracts 21:1954 (Abstract Number 766.9), 1995.
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