Epidemiological clinical studies have shown that females are especially vulnerable to drug addiction and relapse. More specifically, females are more likely to transition to addiction soon after their first drug use and relapse, and they have greater cue-induced cravings for drugs.
Despite these observations, most studies focus on understanding the molecular mechanisms which underlie drug addiction in men.
Erin Calipari and colleagues recently published a paper in Neuropharmacology which details findings from their research comparing cue-induced drug cravings in males and females.
“Women becoming addicted to drugs may be a fundamentally different process than men,” Calipari said, according to ScienceDaily. “It’s important to understand this, because it’s the first step in developing treatments that are actually effective.”
Calipari is an assistant professor in the Department of Pharmacology at the Vanderbilt University School of Medicine. One of the primary objectives of her research is to identify neural circuits which associate positive or negative stimuli with certain actions to dictate future behavior.
Calipari views addiction as an impairment of the associative learning process. Humans and other animals have evolved to learn through association: We can mentally link cues which predict the occurrence of positive and negative stimuli. We assign values to the cues in order to seek out rewarding stimuli while avoiding negative ones. But when that assignment is hijacked, addiction can occur.
Additionally, identifying cues is tricky. Especially in instances where users self-administer drugs, the act of self-administration includes cues, like the spoon or needle used to inject the drug. According to the authors of the paper, since the cues and the act itself are so closely intertwined, it is difficult to parse out the cues, the effects of cue leaning and the effects of the drugs.
Cocaine induces physiological effects by affecting a neurotransmitter called dopamine. Dopamine is a chemical which is involved in transmitting signals from neuron to neuron. Once ingested by the user, cocaine creates a pleasurable experience by blocking dopamine transporters in the brain. When its transportation back into the neuron is blocked, increasing concentrations of dopamine remain in the gap between neurons. High levels of dopamine are implicated in a variety of psychiatric disorders, including addiction.
When females are sexually receptive and fertile (cycles called estrus) higher levels of ovarian hormones circulate throughout their body. Previous work in the Calipari lab showed that during estrus, cocaine has a threefold increase in ability to inhibit dopamine transporters compared to males and females who are not in the midst of estrus.
“We aim to identify the molecular mechanism for enhanced cocaine affinity for the DAT [dopamine transporter] and understand how this underlies cocaine addiction vulnerability in females,” the Calipari Lab website reads.
In the study, Calipari and colleagues studied self-administration in male and female rats. When the rats were administered cocaine, a light (the cue) would flash for 20 seconds. The pairing of the cue and the cocaine would occur either during or after estrus in females.
Then the rats had to self-administer cocaine by pressing a lever. In this phase, the researchers used a behavioral economics approach called threshold procedure to assess the effectiveness of reinforcing training by increasing the price that must be paid for a reward. In this experiment, the cocaine dosage was steadily decreased so that getting the desired amount of cocaine required pressing the lever an increasing number of times. Thus more effort, the price, is required to obtain the reward, cocaine.
“We found that the animals will press a lever just to get the light — that environmental stimuli,” Calipari said. “That has value to them.”
Behavioral economics analysis found that cocaine, even in low dosages, administered with cues to estrus females formed strong associations. Subsequently, the strength of those associations remained independent of the estrus cycle.
Contrary to previous work, the researchers found that in the absence of cues, the estrus cycle stage had no effect on drug consumption. But, they argue, this may be because the task is not suited to measure the direct effects of the estrus stage on cocaine addiction. This shows, according to the paper, that increased vulnerability among females for drug addiction cannot simply be distilled to associative learning. It is the result of a complex interaction among multiple factors.
“Importantly, we show sex differences in vulnerability can be driven by interactions between cycle stage, cocaine effects and cues,” the study reads.
The behavioral economics analysis allows the results to be applied to humans. According to Calipari, this study and others like it are just the beginning in separating environmental and physiological causes of addiction.
Nevertheless, these results can be used in treatment centers to educate female drug users about their increased vulnerability to addiction.
