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Levers and Learning
Dr. Kalivas and colleagues tested the medications using an animal behavioral protocol that simulates human relapse to addiction. To begin, they trained rats to press a lever to self-administer heroin or cocaine. Once the animals became steady drug takers, after about 2 weeks, the researchers deactivated the lever. Over the next 15 days in the heroin experiment (21 days in the cocaine experiment), the animals reduced the frequency with which they pressed the lever, which no longer delivered a reward. On the 16th day (22nd in the cocaine experiment), the researchers showed the animals a cue that had previously signaled drug availability. All the animals reverted to lever pressing, a response that parallels human cue-induced relapse to drug abuse.
To assess the medications' effects on drug-seeking, the researchers treated some rats in the heroin experiment with acetylcysteine, some rats in the cocaine experiment with ceftriaxone, and others with an inert substance. Each medication or inert substance was injected daily for 5 to 15 days starting on the day the lever was deactivated. The results showed that:
The rats that received acetylcysteine learned that the lever no longer delivered heroin more quickly than the control rats. The difference was particularly striking during the first 5 days following deactivation.
Rats that received either medication pressed the lever less often than the control animals in response to a cue or a low-dose priming injection of drug (see graph).
The rats that received acetylcysteine also pressed the lever less often than control rats when retested 40 days after lever deactivation.
"The team's finding that acetylcysteine can attenuate rodents' drug-seeking for longer than a month is unique and astounding," says Dr. Nancy Pilotte of NIDA's Division of Basic Neuroscience and Behavioral Research. "Our results suggest that acetylcysteine may help abstinent substance abusers learn lessons from behavioral therapy more easily, as well as prevent them from relapsing. This would be a powerful double benefit for these patients," says Dr. Kalivas.
Glutamate Restoration Is Linchpin of Medications' Promise
In recent years, scientists have found that as occasional drug abuse evolves into addiction, and compulsion supplants pleasure as the primary motive for drug use, glutamate rather than dopamine becomes the neurotransmitter most closely tied to drug-seeking. Dr. Peter Kalivas and colleagues at the Medical University of South Carolina (MUSC) in Charleston were among the first to call attention to glutamate as a factor in addiction some 15 years ago.
Glutamate is the brain's primary excitatory neurotransmitter, and it participates in most aspects of normal brain function. The MUSC researchers observed that glutamate signaling in key brain areas is altered when rats self-administer drugs and then undergo withdrawal. Following up on these findings, the MUSC researchers showed that chronic drug exposure upsets the balance between glutamate used as a synaptic signal between neurons and glutamate used to signal between glia and neurons. The disturbance is greatest in a neural circuit that includes the prefrontal cortex (PFC) and the nucleus accumbens (NAc), areas that affect learning, memory, and reward-seeking.
The drug-induced perturbation of glutamate signaling induces a variety of neurobiological changes that appear to influence the transition from occasional drug abuse to addiction. These include:
Alterations in the shape and density of the tiny knob-like structures, called dendritic spines, on which neurons receive neurotransmitter signals from other neurons;
An increase in the abundance or activity of receptors that receive glutamate signals from other neurons;
A decrease in a receptor that limits the amount of glutamate released as a signal;
A decrease in receptors that control neurons' ability to alter the strength of their communication in response to experience—the basic molecular mechanism of learning.
Dr. Kalivas says that the alterations in neural activity resulting from glutamate imbalance limit a chronic drug user's ability to adapt to new information—for example, to stop taking drugs in the face of adverse consequences. "Drug-induced changes in glutamate distribution strengthen the power of learned associations surrounding drugs," he says. "These associations become so strong that they take over the addicted individual's world view, obscuring the pleasure and heightening the compulsion."
Experiments by Dr. Kalivas and colleagues have implicated glutamate imbalance in the hyperresponsiveness to drug cues that is a hallmark of addiction. They showed that drug cues prompt cells in the PFC to release a surge of glutamate into the NAc of a chronically drug-exposed animal. The NAc, which has reduced extracellular glutamate, responds with heightened intensity that may trigger drug-seeking.
"Dopamine triggers reward and is critical in the early stage of addiction, but glutamate is crucial in maintaining addiction and inducing its long-term effects," says Dr. Jerry Frankenheim of NIDA's Division of Basic Neuroscience and Behavioral Research. "However, the picture is quite complex. For example, dopamine and glutamate seem to modulate each other. NIDA is supporting several researchers who are examining the dopamine-glutamate relationship."
