Habitual users of addictive drugs are apt to call themselves “addicts” even years after stopping their actual drug use. And with reason: The long-term use of psychostimulants such as cocaine or methamphetamine leaves deep marks on the brain, with associated chronic symptoms that can range from anxiety and impaired memory to intense drug cravings.
Some researchers have described this addiction process as the flipping of a neurochemical “switch,” in which repeated drug use forces key synapses in the brain to undergo a more or less permanent change from one state to another. A big part of this switch is a set of circuits connecting areas of the cortex to the striatum, a region known to be involved in motivation, movement and habit formation. Previous research has shown that these “corticostriatal” circuits can be significantly less active following drug addiction and may remain so even after many months of drug withdrawal.
A report in the April 10 issue of Neuron describes in detail how this corticostriatal depression appears to occur.
Researchers led by Nigel Bamford, a pediatric neurologist at the University of Washington in Seattle, used cutting-edge electrophysiological and fluorescent-imaging techniques to probe and to photograph the fine workings of still-living brain tissue harvested from mice. The mice had been given methamphetamine for 10 days and then had the drug withdrawn. Bamford and his colleagues found that the repeated doses of meth depressed the corticostriatal circuits in the mice essentially by disturbing the complex system of regulatory sensors that normally govern those circuits.
“When you have this many interactions it’s very difficult to summarize them briefly,” says Bamford. The affected neurons in the striatum, known as medium spiny neurons, are influenced not only by corticostriatal nerve terminals, which come in from parts of the frontal and motor cortex, but also by two other major sets of terminals, one from striatal “interneurons” and the other from dopamine neurons in the midbrain, near the brainstem. These terminals are in turn regulated by their own activity, via feedback receptors that sense the ambient levels of relevant neurotransmitters.
Usually, the midbrain terminals become active when the brain receives an unexpected stimulus. The dopamine molecules they release bind to feedback receptors on nearby cortical terminals, silencing those that have been relatively inactive. This effectively filters out corticostriatal activity that isn’t related to the new stimulus, allowing the brain to focus better on the situation being presented. When a psychostimulant drug is used chronically, though, this complex filtering system switches into a new state—working only when the drug is present in the system.
Such drugs typically provoke a flood of dopamine from midbrain terminals, and none does this more copiously than methamphetamine. Bamford and his colleagues were able to show, in their meth-injected mice, that these chronic surges of dopamine adversely affected feedback sensors on the interneuron terminals, apparently dialing down the activity of those terminals and keeping them down even after the dopamine surges subsided. The lowered level of the neurotransmitter these interneuron terminals secrete, acetylcholine, in turn led to reduced stimulation of cortical terminals, keeping the cortical terminals depressed.
In other words, a mere 10 days of drug use in these mice more or less shut down one of the corticostriatal system’s primary regulatory components, the interneurons. Bamford and his colleagues demonstrated that when this regulatory circuit was missing, only a readministration of the drug could jolt the cortical terminals out of their depressed state—and this “renormalization” of corticostriatal activity lasted only until the drug-induced rush of dopamine subsided again. The corticostriatal systems of the mice had come to depend on the drug.
Bamford and his colleagues found that this drug-induced dependency in the corticostriatal system lasted for at least 140 days in the mice, roughly equivalent to decades for a human.
“It’s still early days for addiction research,” says Julie Kauer, a Brown University pharmacologist who has published extensively on the neural mechanisms of addiction. “But to see a change that’s persistent four months later, and that can be reversed by a drug, is very important.”
Peter Kalivas, an addiction researcher at the Medical University of South Carolina, notes that the Bamford group’s results represent a strong and detailed confirmation of the role of corticostriatal depression in addiction. “The major contribution is the trademark of this research group, which is outstanding new technology allowing verification at a synaptic level.”
Switching it back to normal
Both Kalivas and Kauer emphasize the importance of the findings for potential addiction therapies. “Showing how [terminal] receptors can regulate this process is new and opens the door to future studies,” says Kalivas.
If these receptors could be hit the right way with pharmaceuticals, then in principle the corticostriatal pathway could be reset to normal, effectively making that part of the brain forget about its drug dependency. “We’re interested especially in these interneurons because they seem to be the gatekeepers of this synaptic switch,” says Bamford.
He and his colleagues are focusing their attention on an interneuron-terminal receptor known as an M4 muscarinic receptor. “We think the repeated drug exposure drives the amount of acetylcholine down, and that M4 receptor gets used to that reduction in acetylcholine and locks that in place,” Bamford says. Blocking M4 sensors for a while with an M4 antagonist might induce an interneuron into relaxing its abnormal, drug-induced restriction on the flow of acetylcholine.
Other research has shown that M4 autoreceptors are more specific to these striatal circuits than the other known regulatory sensors. So the use of a compound that blocks only M4 receptors “might allow one to target those interneurons specifically without significant untoward effects,” adds Bamford. “M4 is a big target.”