Craving (6 page)

Over the last ten years or so that I have spent treating people who are prey to their cravings, I’ve discovered that it is critically important for people to believe they are in control of their actions, that it seems impossible for them to accept that they might be influenced by circumstances beyond their control. Years ago I met an alcoholic who told me, “Dr. Manejwala, every drink I ever took made perfect sense to me
while I was taking it.
”

Nevertheless, what we know about how the brain seeks reward and reinforcement suggests that these influences are mostly
not
under our conscious control. In fact, most of the structures involved in reward and reinforcement (such as food and sex) lie deep within the brain, in what scientists call the subcortical regions. These subcortical areas are not under our conscious control. In response to survival drives (food, sex, sleep), the brain’s reward systems activate behaviors associated with strong emotions, such as bulimia and gambling, and using intoxicating substances like alcohol and marijuana. This means that when we engage in activities that are designed to be rewarding because they are integral to our survival, these parts of the brain activate, ensuring that we continue to do what we need to in order to survive (eat) and propagate our species (sex).

Cravings as a Biological Phenomenon

We now have conclusive and overwhelming scientific evidence that cravings are, in part, a biological phenomenon. Here’s a recent example. UCLA’s (University of California, Los Angeles) Marc Cohen had cigarette smokers perform three tasks: watch a video that induced cigarette cravings, watch a neutral video, or watch no video at all. He and his team instructed the smokers to resist their cravings. Purely by analyzing the functional brain scans, the team could tell which video the subjects were watching.
Using the same technique, they were able to predict whether or not the subjects were resisting their cravings.
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This is another way that functional brain imaging can be used along with certain mathematical tools to essentially “read” a person’s mind. It also suggests that the distinction between the mind and the brain is largely an artifice related to our current imperfect understanding of neurobiology and the science of mind.

Of course, cravings are much more than responses to reward and reinforcement. Cravings involve emotions, memories, sense of loss of control, reward, and reinforcement. Each of these primary characteristics of cravings results from the activities in specific regions of our brains. Some cravings appear to be related to reward, others to the pursuit of relief, and still others to obsession.
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The reward-related cravings may primarily involve the neurotransmitters dopamine and gamma-aminobutyric acid (GABA), the relief-related cravings may involve glutamate, and the obsessive cravings may be more related to serotonin.

But let’s review the simplest phenomenon first: the phenomenon of reward. To understand this simple but powerful survival drive, we’ll need to explore some basic aspects of the anatomy and biology of the brain.

The Brain’s Reward System

Several key regions of the brain are involved when the brain experiences reward. These regions are located along an area of the brain called the median forebrain bundle (MFB). The first is a deep brain structure called the ventral tegmental area (VTA). The VTA, located at the base of the midbrain, consists of many nerve cells, some of which contain dopamine, a neurotransmitter involved in various brain functions, including reward. We’ll be talking a lot more about dopamine, which is a catecholamine neurotransmitter, later. Actually, the VTA has been connected to several important brain functions, such as motivation, cognition, and even love. In 2005, Helen Fisher of Rutgers University and her colleagues Arthur Aron from the State University of New York-Stony Brook and Lucy Brown from Albert Einstein College of Medicine published a landmark study on this very subject. Using a technique called functional magnetic resonance imaging (fMRI), the researchers found a correlation between romantic love and intense activity in the right VTA. This research suggests that romantic love, distinct from the sex drive, is closely related to the brain’s motivation system. This connection allows people to focus their energies on a particular mate, thus conserving energy and facilitating their ability to select a mate. Many of my own patients have described a feeling of love toward their drug of choice, and this may be due to some overlap between the neurobiology of romantic love and the neurobiology of addiction. Some of the neurons in the VTA will release dopamine only when a reward is greater than expected.

The VTA neurons connect (or project, as neuroscientists like to say) to many brain regions, including the prefrontal cortex (the part of the brain that Phineas Gage lost), the amygdala, and the nucleus accumbens. The “amygdala” (the Greek word for almond, because in humans it is about the size and shape of an almond) is responsible for processing emotions related to survival. In particular, the amygdala lights up in response to intense pleasure, fear, and anger. One particularly important role of the amygdala is to signal the emotional significance of an event. This means that the amygdala decides how intense an emotional reaction should be in response to a particular event. In cravings, this signal is amplified, so that the person’s emotional response to the craving is much more than it “should” be. And that increased emotional intensity leads to an amplification in the person’s response behaviors as well (for example, drug use, sex, food, or gambling).

The VTA also projects to the nucleus accumbens (NA). One of the most interesting regions of the brain, the nucleus accumbens is responsible in part for pleasure, reward, and, according to some recent research, even joy and laughter. In 1954, James Olds and Peter Milner of McGill University in Montreal published a study that was to become one of the most famous studies in the history of addiction research.
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This study dramatically transformed our understanding of the brain science of reward and reinforcement. Olds and Milner implanted silver wire electrodes into the brains of fifteen male rats and then measured the effects of stimulating various parts of their brains. (Rat brains are actually remarkably similar to human brains. This was a major ego blow to me when I learned it in medical school.) Their experiments, and many more refinements over the ensuing decades, have demonstrated that when rats are permitted to press a lever that delivers an electrical stimulus to their NA, it is extremely reinforcing. These rats would rather stimulate their NA than eat, to the point where they will die of starvation, just for the chance to press the lever one…more…time.

Even more interesting is the following: after they have been stimulating their NAs for a while, if the electricity to the experiment is unplugged, something very peculiar happens. First, the rats press the stimulation lever even more intensely and rapidly. This is called an extinction burst and represents the desperation of wanting additional stimulation. Eventually, however, the rat “realizes” that no more stimulation is forthcoming (the electricity has been turned off). You would then expect the rats to give up and press on the lever for the food and begin eating instead. But that’s not what happens. Instead, the rats curl up in a corner and die of starvation, in the face of all the food they could want or need! Why would the rats refuse to eat after overstimulating their own NAs?

The answer is critical to our understanding of craving and has to do with a concept neuroscientists call downregulation. When one neuron is communicating with another, a neurotransmitter is released by the first neuron, and it attaches to a protein on the surface of the second neuron, called a receptor, which can be thought of as an antenna. These receptors then change shape as a result, and the second neuron is activated. The outcome is that the first neuron has communicated with the second neuron. The “talking” neuron releases the chemical neurotransmitter (in our case, dopamine), and the “listening” neuron waits for its receptor to be activated by the dopamine. Many of the neurons in the NA have these dopamine receptors and are just waiting to be activated so they can send their signals to other parts of the brain, signals that say, “I’m experiencing reward, and even more than I had expected!”

The number of dopamine receptors that get activated determines the strength of the signal—the intensity of the reward. When these cells are overstimulated (which is what happened to the rats in which Olds and Milner implanted the electrodes), they recognize that with so much dopamine flooding their cells, there is no need to manufacture so many dopamine receptors. As cells like to conserve energy, they will only manufacture dopamine receptors if they need them.

So what explains why the rats curl up in a corner and die once the stimulation to their NA is turned off? The answer is that the number of dopamine receptors has been dramatically reduced, or downregulated. This affects the rat’s ability to experience reward. Nothing is rewarding, including food. The reward system is burned out. The rat then dies of starvation. Now the tremendous implications of the classic Olds/Milner experiment become clear. When humans experience overstimulation, as in, for example, cocaine addiction, their NA becomes flooded with dopamine, and the dopamine receptor density decreases (downregulation). Eventually, the addict becomes unable to experience reward or pleasure from anything without the drug.

There have been some fascinating studies about this phenomenon. For example, certain rats have been bred to “prefer” alcohol. In 2004, Dr. Panayotis Thanos and colleagues at the Brookhaven National Laboratory showed that they could use a viral vector to deliver the gene for a specific type of dopamine receptor (D2) into the core of the rat nucleus accumbens and actually affect how much alcohol preferring (and nonalcohol preferring) rats drink for up to twenty days. They basically controlled how much alcohol these animals drank by infecting them with a specific type of genetically altered virus. When I mentioned this book to Thanos, he noted that he had completed a more recent study that showed a similar effect in rat cocaine self-administration. Some very recent optogenetic research has shown similar results with food-seeking behaviors.

The Brain Science of Craving

Over the last ten years, I’ve been asking drug addicts why they use. The answer is almost universal: “Doc, I wasn’t using to get high. I was just trying to feel
normal.
” Well, “normal” is complicated, but it’s at least in part related to the dopamine receptor density in the nucleus accumbens. Actually, many changes in the brain occur as a result of decreased dopamine activity.
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One thing is clear: a low dopamine receptor density in the NA feels miserable.

Of course, this is a grossly oversimplified explanation of the brain science of craving. So far we’ve learned about neurotransmitters that activate or increase activity in the brain. There are also chemicals that inhibit or reduce brain activity. Research shows that the brain’s primary inhibitory neurotransmitter, GABA, is involved, as are serotonin, enkephalins (which are related to endorphins), and norepinephrine. One currently popular theory is that intense rewarding behaviors increase serotonin in the hypothalamus, which then activates opiate receptors in the hypothalamus. This results in the release of enkephalins into the dopamine-rich VTA, as I described above. The enkephalins reduce GABA activity in the nucleus accumbens, and that results in an increase in dopamine release in the VTA. A recent small study also showed that people with a certain serotonin transporter genetic variation are much more likely to crave alcohol.
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Many other studies have shown a relationship between serotonin function in the brain and alcohol use disorders.
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Other researchers have shown that injecting GABA-inhibiting substances into a rat’s hippocampus (a memory-related structure that is also part of the brain’s emotional/behavioral limbic system) causes the rats to drink more alcohol.
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There are many other hypotheses about how these neurotransmitter pathways operate, but one thing is clear: craving is about much more than just dopamine.
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My professional experience confirms that addicts are not simply trying to relive the experience of their first high. That’s really only a very small part of the story. Most of the people I work with who struggle with craving aren’t seeking reward—they are seeking relief.
The overwhelming biological process in addictive craving is really a complex set of desperate, survival-based drives to feel “normal.”

I mentioned above that some cravings appear to be related to reward, others to the pursuit of relief, and still others to obsession. The reward-related cravings may primarily involve dopamine and GABA; the relief-related cravings may involve the GABA/glutamate balance; and the obsessive cravings may be more related to serotonin. Thus it’s possible that naltrexone (an opiate-blocking medication that probably works, in part, through regulating GABA and dopamine) is a better choice for cravings directly related to intense rewards such as gambling. Acamprosate, and even some newer medications such as baclofen (a muscle relaxant that affects GABA), may be better choices for relief-related cravings, the kind of cravings that are distressing or uncomfortable (as they affect the GABA/glutamate balance). We do definitively know that drugs that affect serotonin, such as Prozac (fluoxetine), are better choices for obsessive cravings (such as in obsessive-compulsive disorder [OCD] and bulimia), but seem to show no benefit in “pure” alcoholism.
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