A single exposure to cocaine or methamphetamine can cause a powerful reaction in the brains of mice, shutting down the neurons that generate pleasure, according to new research that has also discovered that these cellular changes lasted for at least a week.
The findings suggest this may be a protective, anti-addiction response, say the researchers, who theorize that it might be possible to mimic this response to treat drug addiction.
“It was stunning to discover that one exposure to these drugs could promote such a strong response that lasts well after the drug has left the body,” says Paul Slesinger, an associate professor at the Salk Institute for Biological Studies.
“We believe this could be the brain’s immediate response to counteract the stimulation of these drugs.”
Slesinger and Christian Lüscher, a long-time collaborator at the University of Geneva, have been investigating the cellular changes in the brain that occur with drug abuse.
They do know that drugs such as methamphetamine and cocaine disrupt the “reward pathway” in the brain, altering the brain’s response to dopamine, a primary neurotransmitter that increases in response to sex, food, and drugs.
The scientists note that previous research has shown that cocaine and methamphetamine enhances excitatory connections to dopamine neurons in mice. They instead looked at the neurons that inhibit dopamine transmission, and found that one injection of cocaine or methamphetamine changed inhibitory GABA neurons. The neurons were not able to control how they fired, so they released more than the usual amount of inhibitory neurotransmitter.
The Salk researchers identified a change in the biochemical pathway in inhibitory GABA neurons that led to this protective effect. It involved a change in the activity of a protein, known as a phosphatase, that controls the levels of a receptor important for controlling the electrical activity of the GABA neuron.
“This particular pathway — involving a GABA type B receptor and a particular type of potassium channel — was affected by psychostimulants in these inhibitory neurons,” Slesinger says. “We noticed a dramatic reduction in the strength of this signaling pathway, which we showed was due to a decrease in the activity of the GABAB receptor and the potassium channel on the neuron’s membrane surface.”
“If we could tap into this pathway — enhance the ability of inhibitory neurons to control the activity of dopamine neurons — we might be able to treat some types of drug addiction,” Slesinger says.
What is not known is how long the drug response lasts. This study only looked at the brains of mice at two time points: 24 hours and seven days, after drug use. What is also unknown is why addiction ultimately develops with chronic drug use. These are questions Slesinger and his colleagues are now investigating.
Source: Salk Institute