High Price

hundred. Furthermore, we now know that there are specific receptors—or specialized structures that recognize and respond to a particular neurotransmitter—for each neurotransmitter, and most neurotransmitters have more than one type of receptor. For example, dopamine has at least five receptor subtypes—D1–D5. We also now know that hormones like oxytocin and testosterone can act as neurotransmitters.
    But despite these ever-intensifying complexities, our theory about dopamine’s role in reward has not been appreciably revised since it was originally proposed. And, as you will see later, a growing body of evidence casts doubt on this simplistic view of reward.
    Nonetheless, when I started studying addiction, I was a true believer in the dopamine hypothesis. I thought that dopamine probably drove sexual and gustatory excess, that it made crack cocaine addicts crazed with cravings. Many of the researchers I worked with were convinced; my heroes were people like Olds and Milner and Wise and Koob, who had made key discoveries through animal research on brain mechanisms involved in reward. I thought that if we could just understand how drugs of abuse interacted with this neurotransmitter, we’d easily develop better treatments—perhaps even a cure—for addiction. The answers were in this one chemical in this key circuitry of the brain.
    Soon, however, certain research findings began to make me skeptical of this idea. These included some of my own. For example, my master’s research involved studying how dopamine was removed from the pleasure-linked nucleus accumbens after nicotine was administered. At the time, some researchers were claiming that cocaine and nicotine acted similarly on dopamine in this area, even though data also suggested that rats pressed levers far more times and would work much harder for cocaine than they would to get nicotine.
    Indeed, trying to get rats to press levers for nicotine was one of the most difficult experiments I ever tried. I didn’t succeed and I’m not alone. Plenty of researchers also failed at this task. (Incidentally, trying to get rats to press for THC, the active ingredient in marijuana, is even more difficult.)
    In my master’s work, I looked at how nicotine affected dopamine’s action in the nucleus accumbens. But what I was seeing was unexpected: nicotine wasn’t acting at all like cocaine. Some of the behavioral effects might be similar in some situations, but in this brain region, the two drugs actually had opposite effects.
    The oscilloscope that I monitored displayed a line representing how quickly the dopamine activity rose or fell after a drug or saline solution was given. And those lines looked very different when you compared what happened with cocaine to what was seen with nicotine. With nicotine, the line would go up and then fall off more quickly than with saline. 3 But with cocaine, it would go up and stay up much longer than with saline. 4
    This meant that nicotine was increasing the rate at which this brain region “mopped up” dopamine—in other words, nicotine was taking dopamine out of the connection between brain cells (the synapse) where it has its effect, faster than would occur naturally. But cocaine was acting in the opposite way. It was keeping dopamine active in the synapse for longer.
    Because this finding contradicted the conventional wisdom and threw a bit of a monkey wrench into the neat story that was being told about dopamine and drugs, there was some resistance to it at first. Charlie Ksir, my PhD preceptor, and I published the first two papers detailing this research in 1995 and 1996. Some researchers did not want to believe that we were correct. Antismoking activists didn’t like it, either, because it got in the way of the useful rhetorical claim that cocaine acted similarly to nicotine in the brain, which claim had allowed them to amplify arguments about nicotine addiction by implying that it was just like the nefarious crack.
    Soon, however, our findings were replicated and expanded on by other researchers. 5 Years later, in fact, I was approached by tobacco companies, whom I turned down on more than one occasion. They, of course, wanted to enlist me in their efforts to stress the differences between their drug and cocaine. The distinction that we found, however, didn’t mean that nicotine wasn’t addictive or even that it wasn’t ultimately increasing dopamine’s activity.
    But it was one clue that the dopamine story