Genetics plays a role in drug-seeking behavior

Inbred strains of rats differ in how aggressively they seek cocaine after a few weeks of use, researchers say.

The finding, posted online Jan. 18 by Psychopharmacology, is another piece of evidence that genetics plays a role in the relapse of drug-seeking behavior in humans, says Dr. Paul J. Kruzich, behavioral neuroscientist at the Medical College of Georgia and lead study author.

It also fingers glutamate, a neurotransmitter involved in learning and memory, as an accomplice in stirring the cravings and uncontrollable urges that drive some drug users to use again, he says.

"Given the right environmental stimuli, all persons addicted to psychostimulants can relapse, but potentially some people are a little more susceptible than others … it's all about gene-environment interaction," says Dr. Kruzich.

He took two strains of inbred rats – Fischer 344 and Lewis – with known genetic differences, enabled each to self-adminster cocaine for 14 days, then took the drug away for a week but not the levers the animals used to access it.

During that hiatus, he adminstered a drug that stimulates glutamate receptors, possible targets for drugs of abuse.

He found that the F344 strain worked harder to get cocaine than the Lewis rats following treatment with the glutamate drug, suggesting they were more susceptible to relapse.

"Maybe 12-step programs and faith-based programs will be enough to keep some people from relapsing," says Dr. Kruzich. "For others we may have to come up with medical treatments we can use on top of those to keep them from taking drugs again."

He says there are many different versions of the hundreds of genes that may play a role in increasing the risk of relapse.

It's known that some people become addicted more quickly than others, some literally with their first use, he says. The hardest part is not getting people to stop taking drugs: that happens when they are checked in a clinic or put in jail. The real work is keeping them from relapsing when they are out of such restricted environs, he says.

"Something happens, either they see an old colleague they have used with, they go into an old environment, they have a huge stressor in life and they start to want the drug. They have drug hunger, what we call drug craving," says Dr. Kruzich. "When it gets bad enough, they engage in drug-seeking behavior."

His lab is working to identify the relapse trigger to use as a target for developing ways to curb craving and subsequent relapse.

His studies focus on an area of the brain called the nucleus accumbens core, a target for drugs of abuse long considered a pleasure center, Dr. Kruzich says. Drugs such as cocaine and methamphetamine stimulate release of dopamine in the nucleus accumbens. Dopamine is a neurotransmitter believed responsible for the euphoria that come with drug use. In fact, animals given dopamine blockers won't self-adminster drugs of abuse, and dopamine has long been a focus of drug-abuse studies.

"These drugs impinge upon the reward centers of the brain that normally food, sex, survival and adaptation impinge upon," says Dr. Kruzich. "When you are having that great piece of cheesecake and thinking, 'Oh man,' that is the kind of response these drug of abuse are evoking but much more so than that cheesecake could ever do."

Glutamate, also released in the nucleus accumbens core, may play an equally important role in drug relapse, he says. Drugs such as cocaine appear to alter glutamate neurotransmission in the core, which may contribute to the rewiring of the brain that occurs with drug use. "It's not that these drugs just damage neurons, which they can, but they rewire the circuitry of the brain so no longer is your spouse or your job or other things in your life important to you. Your brain is tricked into thinking that drugs are the most important thing for your survival," Dr. Kruzich says.

Unfortunately, drugs that restore glutamate function also produce seizures, so scientists are looking for an indirect approach to restore the misdirected rewiring.