Heightened Cocaine Addiction and Motivation in Women Linked to Hormones

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Women’s hormonal cycles may make them more prone to cocaine addiction than men, and also increase their susceptibility to typical triggers that lead to relapse, according to the results of a study by scientists at Vanderbilt University. The findings are of particular interest because while most preclinical studies on the mechanisms of addiction are carried out in male animals, women exhibit higher rates of addiction following exposure to men.

This is Erin Calipari, an assistant professor of pharmacology in the Vanderbilt Center for Addiction Research. [Vanderbilt University]
The new studies in rodents suggest that biological mechanisms underpinning addiction may not be the same in men and women. “Women becoming addicted to drugs may be a fundamentally different process than men,” commented research lead Erin Calipari, PhD, an assistant professor of pharmacology at the Vanderbilt Center for Addiction Research. “It’s important to understand this, because it’s the first step in developing treatments that are actually effective.”

The Vanderbilt team reported its findings in Neuropsychopharmacology, in a paper titled, “Cues play a critical role in estrous cycle-dependent enhancement of cocaine reinforcement.”

Epidemiological evidence suggests that women may be more likely to develop drug addiction than men, and they represent “a particularly vulnerable population,” the authors explained. “Clinical studies have shown that women transition from first drug use to addiction faster, have more difficulty remaining abstinent, and have greater cue-induced cravings than men.” Despite this, the vast majority of preclinical addiction studies have focused on males. This is partly to negate the need to disentangle any influence of hormonal cycles. This means that drug development has effectively targeted correcting any dysfunction in men, and may explain why women sometimes don’t respond to therapy in the same way as men.

In recent years that has been what the scientists termed “a push” to incorporate females into existing addiction models, the scientists noted. However, “males and females often have different behavioral strategies, making it important to not only include females, but to develop models that assess the factors that comprise female drug addiction.”

The interaction between cues and motivation in addiction is particularly critical in the case of sex differences, as women exhibit increased cue responses, including craving, and in women the subjective effects of cocaine and craving do change at different times in the menstrual cycle, “highlighting a role for hormonal cycles in the process.”

The Vanderbilt University School of Medicine team developed a rodent model to help untangle the effects of hormonal cycles in addiction, and in the animals’ motivation to dose themselves with cocaine in responses to reinforcing cues. “We developed a new behavioral procedure that combines Pavlovian-instrumental transfer with behavioral economics to isolate the effects of cues on the consummatory and appetitive responses driven by cocaine.”

In the study, male and female rats were first given a series of intravenous injections of cocaine. During dosing a light came on, which effectively represented the environmental cues, such as drug-related equipment, that would be present when humans are taking drugs. The animals were then trained how to self-administer cocaine by pushing a lever, which triggered a syringe pump to release a dose of cocaine that was delivered intravenously.

After training the male and female animals underwent a series of different tests involving lever pressing, and light presentation, to assess estrous cycle-dependent changes in how much cocaine they would administer, and their drive to acquire it. The study results showed that during those periods when their circulating hormones were high, the female rats made stronger associations with the light, and were more likely than male rats to keep pushing the lever to dispense cocaine. “… the animals will press a lever just to get the light—that environmental stimuli,” Calipari explained. “That has value to them.” In fact, the female animals were willing to “pay” twice as much as the male animals, Calpari said in a video interview.

“We find robust cycle-dependent changes in Pavlovian learning,” the authors stated. “In this study, we found no differences in self-administration across the estrous cycle in the absence of cues; however, when cues were introduced, the cues that acquired value during estrus—but not during diestrus or in males—increased motivation.” Interestingly, further studies in the animals’ brains suggested that in females, the estrous cycle-related effects of cues driving their motivation to acquire cocaine appeared to localize in the striatal regions.

Although the studies were carried out in rodents, the results are transferable to humans in terms of behavioral economic analysis, a way of comparing data across species, which uses a calculation to define the values of the most and least that a subject will do to get the desired result, or payoff.

“Estrus females exhibit enhanced vulnerability to form associations between cocaine and Pavlovian cues that later influence volitional drug intake,” the authors wrote. “During estrus, the associations formed between drugs and associated stimuli act to potentiate motivation, even months following initial pairing … Together, these data suggest that fundamental differences in the motivational properties of psychostimulant drugs between males and females are complex and are driven primarily by the interaction between drug-associated stimuli and drug effects.”

“There’s epidemiological data that says women are more vulnerable, but it’s unclear what the factors are,” Calipari commented. “We know they transition to addiction faster and have more problems with craving and relapse. Now, with research like this, we’re beginning to isolate environmental and physiological causes.”