Blocking specific neurons in the nucleus accumbens may effectively dissolve
the neurological association between cocaine-related cues and cocaine's
effect, a hallmark of addiction, according to a study published online in
Nature Neuroscience on July 20.
Behavioral and brain research has shown that chronic addiction rewires
certain brain circuitry, so that seeing such cues as photos of other people
using drugs or drug paraphernalia can evoke strong cravings and drug-seeking
behaviors. This neurological process is one of the reasons for persistently
high risk of relapse even after years of abstinence.
In this study using a rat model, Eisuke Koya, Ph.D., and colleagues at the
Behavioral Neuroscience Branch of the National Institute on Drug Abuse (NIDA)
revealed an important mechanism with which the brain learns to associate
environmental cues and the effect of cocaine.
Scientists previously established a rat model to study the effect of
cocaine by quantitatively measuring rats' locomotor activity (that is,
distance traveled) in a chamber (see photo) after a cocaine injection. If
cocaine injections are repeatedly paired with a specific surrounding outside
of a rat's home cage, the rat will exhibit a much higher level of response
after a cocaine injection in this environment than it would in a strange
surrounding, even if the same dose of cocaine is given. The higher level of
response is indicated by a longer cumulative distance traveled by the rat in
the locomotion chamber.
The environmental cues in these experiments were chambers with varying
setups, such as smooth versus woodchip-covered floors and a square cage versus
a round bowl. Other cues may include odors and sounds.
The phenomenon of enhanced response, or context-specific sensitization, is
believed to be the result of learned association. Like Pavlov's dogs that
learned to associate food with the sound of bells ringing, the sensitized rats
learn to associate environmental cues with the effect of cocaine injection and
have a response to cocaine beyond the cocaine's direct pharmacological
"Pavlov always thought the food stimulus and the bell stimulus merged
and bonded somehow in the brain, but it was all a black box," Bruce
Hope, Ph.D., the senior author of the study and a senior scientist at NIDA,
told Psychiatric News. "I was trying to find how this [type of
learned association] was stored in the brain and how we could identify it, so
that we can specifically find and manipulate those particular cells. That's
what led up to the [current] experiment."
Researchers have known for a long time that many addiction-related
behaviors have roots in neurons in the nucleus accumbens. Hope and colleagues
suspected that the learned association between environmental cues and cocaine
injections may lie in only 2 percent to 3 percent of the cells in the nucleus
accumbens. However, finding these neurons was like looking for a few people in
a country of hundreds of millions. They needed a high-resolution map.
Previous research showed that some neurons in the nucleus accumbens are
activated after the context-specific, cocaine-induced sensitization, marked by
expression of the c-Fos gene in the nucleus. The difficulty was to prove a
causal effect, not mere correlation, between cell activation and behavior.
With conventional methods, it would be difficult to manipulate scattered
neurons without damaging other neurons nearby and contaminating the
experiment. The study authors found an elegant solution to this problem.
First, they took a unique breed of transgenic rats that are genetically
engineered to have a beta-galactosidase gene immediately attached to the c-Fos
gene. Whenever the c-Fos gene is transcribed, beta-galactosidase, a bacterial
enzyme, is also produced in the cell. Meanwhile, these rats are sensitized by
repeated cocaine injections in a specific environment. Next, the rats had a
prodrug known as Daun02 injected directly into the nucleus accumbens. Daun02
is a prodrug of daunorubicin, which is inactive but can be converted into the
active drug under certain conditions. Beta-galactosidase, however, can turn
the prodrug into daunorubicin, which is a cytotoxic drug used in cancer
treatment. Thus, when a neuron is activated (that is, transcribing the c-Fos
gene), it begins to make daunorubicin and soon inactivates itself. Neurons
that are not activated in sensitization remain intact.
Hope noted that it has not been proven whether daunorubicin actually kills
neurons in the experiment, but it clearly inactivates them. As expected, this
selective inactivation erased rats' context-specific response to cocaine. In
other words, the environmental cues no longer provoked their heightened
response to cocaine. In fact, the rats acted as if they had received cocaine
in an unfamiliar environment.
Based on this observation, Hope and his team concluded that activation of a
particular "constellation of neurons" in the nucleus accumbens is
the cause of context-specific sensitization to cocaine. To make this
experiment work, "it took seven years of tweaking," he said.
This model allows the researchers to pick out a few needles in a very large
haystack using a magnet. Conventional methods require killing the animals and
examining brain changes under a microscope. With this model researchers can
manipulate selected neurons in live animals and directly observe any
In humans, there are addictive behaviors analogous to the animal model of
context-specific sensitization. Why do certain environmental cues, such as
sights, sounds, and smells associated with drug use, remain in the brain so
vividly and persistently? Hope believes that a key factor is large amounts of
dopamine released during drug use, which "stamps in" the memory of
associated stimuli more efficiently and deeply than average learning
experiences. This memory can overwhelm other memories and become long lasting,
he explained. In the rat model, the environment-cocaine association remains
for at least six months after the last cocaine injection, which is a quarter
of a rat's lifespan.
Bruce Hope, Ph.D., of the Behavioral Neuroscience Branch of the National
Institute on Drug Abuse has been hunting for the brain cells responsible for
the association between drug abuse and environmental cues.
Credit: Jun Yan
"On top of the pharmacological effects of cocaine itself is the
effect of learning," said Hope. "In my opinion, it is the learning
that leads to associating the effects of drug of abuse with stimuli in the
environment.... Those learned associations probably play a stronger role than
the pharmacological effects in the eventual addiction in
If drug-related cues are coded in human brains in the same way as
demonstrated in the rat model, it is theoretically possible to devise ways to
find the responsible neuronal "ensembles" and inactivate them,
Hope speculated. By erasing the association between cues and cue-induced
memories and behaviors, abstinence may become much easier.
The implication of this study goes beyond addiction, Hope and colleagues
pointed out. The findings open one of the doors to the mystery of memory: what
it is, where it is located, how it is moved from one place to another in the
brain, and how fluid it is. If learned associations can be modified or
inactivated by targeting a specific "constellation of neurons,"
such modifications can guide treatments of trauma-related psychiatric
disorders or symptoms.
Hope cautioned that despite the exciting implications of this research, a
lot of empirical research must be done to understand how memory and addiction
work within and beyond the nucleus accumbens, but he is optimistic that he and
his colleagues are on the right track. Next, his group plans to study whether
this neuronal inactivation method affects drug-seeking behaviors such as
self-administration of cocaine in animals and whether these neurons can be
temporarily inactivated. They also plan to test this method in the amygdala
for conditioned fear responses.
An abstract of "Targeted Disruption of Cocaine-Activated
Nucleus Accumbens Neurons Prevents Context-Specific Sensitization" is