In recent studies, Dr. Marilyn Carroll and her colleagues at the University of Minnesota looked at the impact of two interventions on self-administration of heroin and cocaine by rats and found that, in each case, the intervention produced a greater effect on the female rats studied than on the male rats. These findings and the results of other studies looking at sex differences suggest that the most effective drug abuse treatments for men and women may be quite different.

In one study, Dr. Carroll found that administering baclofen, a muscle relaxer, suppressed the establishment of cocaine use significantly more in female rats than in males. The other study looked at the effect of offering wheel-running as an alternative to drug-seeking behavior; again, the result was that only female rats significantly decreased their levels of drug self-administration--in this case, cocaine.

"These studies highlight the importance of paying attention to sex differences in the development of pharmacotherapies and in other drug abuse research," says Dr. Cora Lee Wetherington, NIDA's women and gender research coordinator. "For example, some smoking cessation medications seem to work better for men; others work better for women. As new medications are developed for other forms of drug abuse, the story may be similar. Treatment effects may not be the same in males and females."

Baclofen Slows Establishment of Cocaine Use in Females More Than Males Pretreatment with baclofen has been shown to slow the establishment of cocaine use in rats. Among rats pretreated with baclofen, only 15.4 percent of females self-administered an average of 100 cocaine infusions for 5 consecutive days during a 30-day trial, compared to 77.7 percent of males. Under saline pretreatment, all of the animals tested reached this injection frequency and consistency within 30 days.

"We are increasingly finding that sex and hormonal status are important determinants of drug abuse at all phases of addiction--acquisition, maintenance, escalation/dysregulation, and reinstatement," says Dr. Carroll, whose previous animal research has consistently found that females tend to use more drugs, more quickly. Recent epidemiological data indicate that in humans, females also tend to progress to dependence at a faster rate than males.

In the first study, Dr. Carroll and her colleagues examined the effects of baclofen on 44 rats that had never been exposed to cocaine. Previous animal studies have demonstrated the promise of baclofen, which modulates several neurotransmitter systems, as a potential treatment medication. Each rat participated in 30 daily sessions. During the first six hours of each session, the rats were given repeated, random infusions of baclofen at a relatively low dose of 0.2 mg/kg. For each infusion, a lever extended into the cage where it stayed for 15 seconds, after which the cocaine was administered and the lever retracted. If the animal touched the lever during the 15-second latency period, cocaine was administered immediately. In this manner, the rats learned within a few days to associate the lever with drug infusions and to push the lever to self-administer cocaine. A second 6-hour component each day allowed the rats to freely self-administer cocaine; the lever remained extended into the cage and a dose of cocaine was delivered each time the lever was pressed.

To test the effects of baclofen on the rate of acquisition of a habit of regular drug-taking, investigators divided the rats into four groups. One male and one female group were injected with baclofen prior to each session; another male and another female group were pretreated with saline. Researchers measured the number of infusions each rat received during the self-administration session until it reached the acquisition criterion or level at which it was considered to have developed a habit of cocaine use, defined as an average of 100 infusions per day for 5 days.

All of the female rats pretreated with saline reached the acquisition criterion by day 14. All males pretreated with saline met the criterion by day 19. In the group of female rats pretreated with baclofen, only 15.4 percent met the acquisition criterion within the 30-day limit. In contrast, 77.7 percent of males pretreated with baclofen met the criterion within the 30-day limit. When baclofen treatment was discontinued, all of the females who initially did not meet the acquisition criterion did so within 11 days.

"Pretreatment with baclofen slowed the rate at which the rats reached the specified level of cocaine self-administration and reduced the percentage of rats reaching that level to a greater extent in females than in males," says Dr. Carroll. "The propensity of the female rats to use cocaine at the specified levels was no different than that of the males, because they all acquired a habit of cocaine use without baclofen. It was just that the baclofen had a different effect on the females."

The next study looked at sex differences identified as a result of a behavioral intervention to reducing drug use. "Enriching the environment is a promising approach to reducing the initiation, maintenance, and reinstatement of drug abuse," says Dr. Carroll. (See also, "Social Environment Appears Linked to Biological Changes in Dopamine System, May Influence Vulnerabilility to Cocaine Addiction," NIDA NOTES Vol. 17, No. 5.) In this study, rats were offered access to a running wheel as an alternative to self-administering cocaine. Wheel-running is an activity rats enjoy, and research has shown that when given a choice between food and running wheels, rats often chose running over eating.

Seventeen rats were initially given access to a running wheel alone until their average daily number of wheel rotations stabilized. Next, rats were trained to self-administer cocaine (0.2 mg/kg) until they reached an average of 100 infusions a day for 5 consecutive days. The rats were then given concurrent access to cocaine and the running wheel. Researchers calculated the mean number of wheel rotations and mean number of cocaine infusions during the last five sessions of each phase.

Under cocaine-only conditions, both males and females averaged 30 infusions per hour. Females saw a reduction of 70.6 percent in infusions to fewer than 10 per hour when there was concurrent access to the running wheel. In males, while infusions decreased slightly (21.9 percent) to an average of 25 infusions per hour, the reduction was not statistically significant.

"Taken together, these studies suggest that females rats are more responsive than males to treatments for drug abuse," says Dr. Carroll. Although few data exist on sex differences regarding treatment of drug abuse in humans, research is beginning to point to hormones as one cause of sex differences in drug abuse. "A growing body of research indicates that ovarian hormones, such as estrogen, may account for many of the sex differences in drug abuse, increasing the subjective effects of drugs and their reinforcing potential." More studies are needed, both in animals and humans, to better understand these sex differences and to use this knowledge to improve treatment options.

Sources

Campbell, U.C.; Morgan, A.D.; and Carroll, M.E. Sex differences in the effects of baclofen on the acquisition of intravenous cocaine self-administration in rats. Drug and Alcohol Dependence 66:61-69, 2002. [Abstract]

Cosgrove, K.P.; Hunter, R.G.; and Carroll, M.E. Wheel-running attenuates intravenous cocaine self-administration in rats: Sex differences. Pharmacology Biochemistry and Behavior 73:663-671, 2002. [Abstract]

Volume 17, Number 6 (March 2003)