Lori Knackstedt, professor of psychology, is seven years deep into research that’s yielded some surprising results: in cocaine-addicted rats, an antibiotic reduces their drug-seeking behavior and may prevent relapse. The drug Ceftriaxone appears to increase reuptake of glutamate, a neurotransmitter that regulates dopamine, the crux of the reward system. Knackstedt’s team wonders why.
Early addiction science pinpointed excess dopamine as the culprit, and it's no surprise, as dopamine does promote the reward response in the brain. However, dopamine is a short-term response and entails much more than addiction, including the "yum" feeling after eating. The memory aspects of addiction are now understood to stem from the role of glutamate, especially in the nucleus accumbens.
Excessive extracellular glutamate is toxic to neurons and can cause strokes, a potential side effect of long-term drug abuse.
Cocaine, an extract of the coca plant (Erythroxylum coca) inhibits the reuptake of serotonin, norepinephrine, and dopamine, causing an unusually high concentrations of each. While this inhibition has the effect of increased happiness, energy, and pleasure in the user, it also increases the likelihood of cardiovascular and psychological illness.
Cocaine also increases the protein ΔFosB, and each subsequent dose boosts it more, with no cap for tolerance. ΔFosB is a "master control switch" in the nucleus accumbens. Once on, it is overexpressed and creates addiction. Its long half-life means addicts are likely to relapse.
There are two places where glutamate can be in the brain: in the glia (glial) or in the space between neurons (extracellular). In non-addicted brains, normal uptake by GLT1 keeps excess glutamate from going to extrasynaptic receptions. Long term drug use down regulates GLT1’s efforts, so extracellular glutmamate overflows the junction of synapses (the cleft) and stimulates those receptors. This leads to AMPA signaling that supports reward pathways. The spillover makes synapses stronger and the dendritic spines larger, which contributes to cellular memory. In other words, neurons remember drug effects, and stimuli associated to those effects are likely to cause relapse if excessive glutamate is not capped.
Knackstedt's latest paper, published online May 11 in the Journal of Neuroscience, has identified novel mechanisms of how Ceftriaxone (abbreviated “Cef”) reduces cocaine seeking. However, they also found that Cef is not directly increasing gene expression of two key glutamate transporters, GLT-1 and xCT. “We do find that this antibiotic changes things in the brain,” she says. “We’re just not sure how it’s doing it.”
Knackstedt’s fascination with behavior motivates her research. Her neurobiological approach stems from her undergraduate education in biology, where a neuroscience course piqued her interest in how cellular brain processes affect behavior. Now, she’s concerned with the practical aspects of behavior modification. The Ceftriaxone research examines how an antibiotic is disrupting the reward pathway in the nucleus accumbens — the reward center of the brain — and now that they know it’s not acting directly on DNA, the team is one step closer to understanding how Cef reduces excess glutamate that supports continued addiction and encourages patients to relapse.
Cocaine joins heroin as one of the top "triple whammy" drugs: higher addictive potential and increased dependence, increased likelihood of serious physical harm, and higher capacity to harm psychological health and interpersonal relationships, as well as increase the likelihood of arrest and incarceration.
Next, the team will expand their perspective beyond the nucleus accumbens, but that requires a broader approach: proteomics, a portmanteau of “protein genomics,” involves the use of a mass spectrometer to analyze tissue. An emerging body of research shows that “listen to your gut” has some neuroscience behind it; a reduced gut microbiome has been linked to cocaine relapse, as well as anxiety and depressive disorders. Cephalosporin antibiotics such as Cef have been shown to reduce these behaviors, but their role in the gut–brain axis is not well understood.
Nevertheless, overuse of antibiotics has its own set of side effects. Thus, Knackstedt’s side project is to get the best of both worlds: “I’m interested in developing a drug with reduced side effects to treat addictive behaviors,” she says. “Ceftriaxone is a real contender.”