We all heard this refrain; drug addicts kicking the habit, only to go through a lifetime of a constant battle to stay clean.

Why is it so hard? Why is it getting progressively harder within days after quitting? Who is the “devil that made them do it”?

The received wisdom for many years was that the reward system in the brain, which is the seat of all manners of addiction, is driven exclusively by dopamine receptors. But frankly, this belief had some problems. Here is a big one: The dopamine system is geared to maintaining homeostasis, which is the property of a living organism to regulate its internal environment so as to maintain a stable, constant condition. For example, exposure of dopaminergic neurons to increased concentrations of cocaine results in increased effects inside the cells. To maintain a constant internal environment inside the cell, the neuron responds by reducing the number of dopamine receptors. However, when the drug effect wanes, the addict feels depressed. And to get the same “high” in the face of reduced density of receptors, he’d have to take an even higher dose of the drug, which would, in turn, result in yet another lowering of receptor density on the cell membrane. This is the basis of addiction; progressively elevated doses of the stimulus needed to obtain the same effect. Dopaminergic neurons respond in the same fashion to cessation of the stimulus, only in the opposite direction—the density of receptors increases back to the normal level. If the dopamine neurons were the sole ones involved, then this should be the end of addiction syndrome. But we know that this is not true.

We know that recovered addicts have to constantly battle the urge to go back on the drug. The dopamine receptor system does not explain this behavior.


The neurobiological basis of faltering resistance

Marina Wolff wanted to see if the neurons bearing the glutamate receptor have something to do with the difficulties addicts encounter after withdrawing from the drug. So she and her colleagues examined the glutamate neurons in the nucleus accumbens, which is part of the reward system and is involved in motivation and learning. They trained rats to self-administer cocaine by poking their noses into a hole when given a cue. As expected, the rats’ cocaine-seeking beahvior was more pronounced 45 days after the cocaine supply was cut off than after the first day. Examining the rats’ nucleus accumbens, they found something totally unexpected. Compared with rats in early withdrawal, rats deprived of cocaine for 45 days had incredibly high levels of a glutamate receptor of an unusual composition (called GluR2-lacking AMPA receptors). This unusual receptor promotes an inordinately strong response to glutamate. Indeed, if the new glutamate receptors were blocked in rats 45 days after cocaine withdrawal, their response to drug cues was cut by almost 50%. The conclusion according to Marina Wolff is obvious: The neurons were making new receptors in response to withdrawal, which explains the increased response to cocaine cues.


The implications

The obvious implication is that this receptor should be a powerful target for drugs designed to help in withdrawal from drug addiction.

But did you notice that this craving after withdrawal and the increasing difficulty in resisting cues is also an affliction of serial dieters? Indeed, eating stimulates the reward system just like any recreational drug; and overeating has all the hallmarks of addictive behavior. So, the obvious next step is to examine the levels of this unusual glutamate receptor in animals trained to overeat. It may be the answer to the losing battles millions of people wage every day in a desparate attempt to avoid re-gaining the weight they had lost.

Lastly, one more thought. Until only very few years ago, it was believed that complex behaviors could never be explained by “simple” chemistry. Books and articles were written about the uniqueness of the brain, as if it obeyed different laws of physics. Here, we have a receptor of a known composition, whose level in the brain controls a complex behavioral pattern. Can the day be far when we would be speaking of all human behavior in molecular terms?

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.


  1. That’s why organizations have been set up to help people with these kinds of problems. Honestly this is actually one of the hardest vices to stop and if possible, in the near future, there should be a scientific breakthrough that will solve this.

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