People who have used cocaine for a long time report a paradoxical-seeming experience: The pleasure they get from taking the drug decreases even as the drug intensifies its hold over their behavior.
A recent NIDA-supported study sheds light on why this might be. Researchers shows that, in mice, a cocaine-induced imbalance in the activity of two key populations of neurons in the reward system persists for a longer period after repeated exposure to the drug. For long-term users, the researchers suggest, this change could both weaken the cocaine “high” and strengthen the compulsion to seek the drug.
A Distorted Ratio
Drs. Congwu Du and Yingtian Pan and colleagues at Stony Brook University in New York and at NIDA injected two groups of mice with a single dose of cocaine (8 milligrams per kilogram of body weight). One group of mice had already been exposed to the drug daily for 2 weeks, and the other, a control group, was receiving the drug for the first time. Using a novel dual-imaging and measurement technique*, the researchers tracked the drug’s impact on activity levels of two populations of medium spiny neurons (MSNs) in the striatum of the two groups of mice.
One of two MSN populations observed by the researchers interacts with dopamine via receptors called D1R. When activated by dopamine, striatal D1R MSNs give rise to pleasurable feelings, motivate an animal or a person to repeat the experience that yielded these feelings, and promote the conversion of such motivation into action by stimulation neurons in the brain’s motor cortex. The other MSN population interacts with dopamine via a different receptor, called D2R. When activated, D2R MSNs counter the effects of the D1R MSNs. They attenuate euphoria and drug seeking and inhibit the motor cortex.
In the experiment, Drs. Du and Pan found that immediately after the cocaine injection, D1R MSN activation increased and D2R MSN activated decreased, both in the mice that had been exposed daily to the drug and in those being exposed for the first time. As a result, in both groups, the ratio of D1R MSN to D2R MSN activation shifted sharply in favor of the D1R MSNs and their reward- and motivation-promoting effects.
At 5 to 7 minutes post-injection, however, the D1R to D2R activity ratios diverged between the two groups of mice. In the control mice, D1R activation rapidly fell back to its baseline level, causing the D1R to D2R ratio to also return to near baseline. In the mice that had been exposed daily to cocaine, in contrast, the cocaine-induced D1R activation increased steadily over the entire 30 minutes that the animals were observed. As a result, D1R to D2R rose higher and remained elevated longer in the daily-exposed mice holds in people as well, it could help explain why long-term users of cocaine report less euphoria from taking the drug.
The researchers propose that the drawn-out time course of cocaine-induced D1R to D2R MSN activation following repeated exposure will also enhance an animal’s or a person’s drive to seek the drug. Dr. Pan explains, “Dopamine both activates and inhibits brain circuits, and normally this dual action produces healthy behavioral outcomes. Cocaine upsets this balance. It enhances the D1R MSN signaling that normally puts a brake on those behaviors. In our experiment, we showed that this imbalance is short lived in mice when they are exposed to the drug for the first time, but long lasting in mice that have already been repeatedly exposed.”
More Research is Needed
“The research field had not put much effort into separating how these two dopamine receptor systems are involved in rewiring the brain exposed to chronic cocaine use, or their effects on compulsive intake of the drug,” says Dr. Nora D. Volkow, NIDA Director and a collaborator on the study. “This work highlights the importance of the relative participation of D1R versus D2R signaling.”
Drs. Du and Pan have more work to do to show that their observations account for long-term cocaine users’ reduced enjoyment and increased compulsion to use the drug. As a first step, they plan to examine whether increasing the D1R to D2R MSN activity ratio indeed increases animals’ drug-seeking behavior. This will be very challenging, says Dr. Du, because it will require adapting their imaging technique to monitor MSNs in awake and moving animals. To date, they have used it only with anesthetized and restrained animals.
Another outstanding question is whether long-term cocaine use actually changes the time course of D1R MSN activation in people as it does in mice. Dr. Pan notes that although research has not yet addressed this question, imaging studies conducted in Dr. Volkow’s laboratory have shown that cocaine dampens D2R signaling in people as well as mice. If further investigations confirm the researchers’ hypotheses, says Dr. Volkow, “treatments that strengthen D2R signaling could help people stop using cocaine.”
Park, K.; Volkow, N.D.; Pain, Y.; Du, C. Chronic cocaine use dampens dopamine signaling during cocaine intoxication and unbalances D1 over D2 receptor signaling. The Journal of Neuroscience, 33(40):15827-15836, 2013.
*To achieve their observations, Drs. Du and Pan developed a dual-imaging technique based on a novel microprobe that was used for visualizing individual neurons deep within the brain. The technique enabled them to distinguish the populations of D1R and D2R MSNs, and to track moment-to-moment changes in each one’s calcium levels. Calcium levels directly reflect a neuron’s level of activation.