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Serotonin Receptors and Drug Abuse
Jones knows the ins and outs of the ups and downs. Each time he uses, it's the same thing. First, he pulls out a little vial and taps a spot of white powder on his palm. Then, he sniffs the powder up his nose and feels the familiar numbing effect of this chemical powder extracted from the leaf of the Erythroxylaceae coca plant. Molecules of cocaine hydrochloride—a powerful psychostimulant—are absorbed into Jones's bloodstream through his nasal tissues. Once inside the bloodstream, they travel to his brain, where these lipophilic molecules readily cross the blood-brain barrier and widely infiltrate even the most deep brain structures. There, the cocaine molecules interfere with the normal regulation of dopamine, a neurotransmitter released in the brain's reward system. By blocking the transporters that normally remove dopamine from the synaptic cleft, the major clearance mechanism for this neurotransmitter is disabled. The dopamine levels in Jones's brain skyrocket to two to three times normal levels. His pupils dilate. His heart rate and blood pressure increase. Now Jones really starts to feel it. The build-up of dopamine in his brain's pleasure center produces a euphoric feeling—a quick rush that hits him after a few seconds and lasts several minutes. And when it wears off, Jones snorts another hit of powder and another after that. Jones continues to resupply his brain with cocaine molecules over the next 12 hours as he continues his binge. The cocaine keeps the dopamine levels in his brain elevated. But then Jones runs out of cocaine. His high wears off. The dopamine levels in his brain drop. Not only are they down from the high levels they reached with cocaine, but they decrease to below normal levels. That's when the bad feelings set in: depression, anxiousness, and craving. Jones has been through acute withdrawal before. He is familiar with the downside to using. A Major Public Health ProblemJones is a fictional character—a sketch drawn from descriptions of cocaine use and withdrawal intended to illustrate that cocaine, like several other drugs of abuse, is a major public health problem in the United States today. According to the National Institute on Drug Abuse (NIDA), nearly 2 million people regularly use cocaine, and cocaine is the leading cause of heart attacks and strokes for people under 35. A White House Office of National Drug Control Policy study issued in the mid-1990s says that Americans spend more on cocaine than on all other illegal drugs combined. It estimates that $38 billion was spent on cocaine in the years 1988 to 1995 alone. These costs are a small wedge of the total pie. Cocaine's secondary costs to society due to emergency room visits and other healthcare costs, lost job productivity, lost earnings, and costs to society through cocaine-related crime, incarcerations, investigations, and social welfare are estimated to be in the billions of dollars annually. The problem of cocaine use is exacerbated by the cravings, propensity for relapse, and affective disorders like depression that often accompany coming off the drug. Finding ways to address cocaine addiction is a compelling societal problem. Understanding how drugs like cocaine induce these effects is an intriguing scientific problem as well. Loren Parsons, an assistant professor in the Department of Neuropharmacology at The Scripps Research Institute (TSRI), thinks that one of the keys to understanding addiction lies in the fluctuations of serotonin levels in the brain. He is looking at the role of serotonin and serotonin receptors in drug abuse and addiction, and is trying to reconcile the neurochemical effects produced by illicit drugs with the intense motivation for continued use that underlies drug dependence. A Famous NeurotransmitterSerotonin, like dopamine, is a neurotransmitter produced in the central nervous system from amino acids. Serotonin, the chemical 5-Hydroxytryptamine, is derived from the amino acid tryptophan and plays a big role in a wide range of physiological states, such as sexual behavior, intestinal functions, and affective states like depression. As a chemical, serotonin has been launched to celebrity status in the past two decades because of its known involvement in depression, anxiety, and obsessive–compulsive disorders. A whole class of antidepressants known as the selective serotonin reuptake inhibitors (SSRI)—including Prozac and Zoloft—work by raising serotonin levels. During the last two decades, scientists like Parsons have also come to recognize that serotonin levels are affected by alcohol and illegal drugs and that this may account for affective disorders similar to depression and anxiety often seen during withdrawal. "When ethanol, cannabinoids, opioids, or psychostimulants are taken into the body, serotonin levels in the brain are elevated," says Parsons. Significantly, he adds, this elevation in serotonin plays a role in the motivation to continue taking drugs. Early studies in the field showed that when serotonin receptor cells were removed or when the receptors themselves were blocked, drug intake increases in laboratory models. Early studies showed that the opposite was also true. If you increase the amount of serotonin in the brain, by giving an SSRI for instance, drug intake decreases. "The conclusion [from these early studies] was that serotonin produced an inhibitory effect on drug intake," says Parsons. "If you increase the serotonergic component, you make the drugs less attractive. However, now that we have better pharmacologic tools for studying serotonin neurotransmission we're finding a much more complicated picture." The main thrust of Parsons' laboratory is to investigate the function of individual serotonin receptors—proteins that sit on the surface of neurons and bind serotonin. He is interested in the mechanisms whereby these receptors influence drug intake: how they modulate the behavioral effects of alcohol, cocaine, amphetamine and opioids; the neurochemical processes through which these effects are produced; how these receptor mechanisms change with long-term drug use, and how these alterations in function may contribute to addiction. These are not easy questions to answer. The Difficulty of Studying Serotonin ReceptorsSerotonin and the serotonergic system of receptors are widespread in the brain. There are at least 14 different serotonin receptors, which are differentially expressed throughout the central nervous system and elsewhere in the body. Because many of these receptors have only recently been discovered, selective drugs for studying their function are often unavailable. This makes them hard to study, and not all of them have been well characterized. "There's a lot left to be learned," says Parsons. Experimental approaches that broadly activate or block the 14 different receptors can only take scientists so far, because these different receptors are distributed unevenly throughout the brain and affect various neural circuits differentially. Serotonin-1B receptors, for instance, affect one subset of neural circuits, whereas serotonin-6 receptors affect a completely different subset. Things become complicated quickly since some circuits under the control of a particular receptor contribute to the positive or euphoric effects of drugs, while circuits under the control of another receptor inhibit drug-induced euphoria, or even produce aversion. There are also regional differences in the serotinergic response to a drug. Cocaine and alcohol both increase the levels of serotonin in the brain, but cocaine does it broadly and potently across many parts of the brain by blocking the reuptake of serotonin. Alcohol, on the other hand, produces much more subtle changes in serotonin in a more regionally selective manner. And some receptors may interact selectively with some drugs and not others. If you block serotonin-6 receptors, for instance, you greatly increase the reinforcing effects of amphetamines but not cocaine, even though both drugs are in the same class of psychostimulant compounds that increase dopamine. Further complicating the picture are the differences in how individual serotonin receptors respond to long-term drug use. Even if you consider a single receptor subtype, like the serotonin-1B receptor, there may be different responses in different parts of the brain. For example, during abstinence from extended cocaine use serotonin1B receptors in the nucleus accumbens area of the brain are upregulated, while these receptors are simultaneously downregulated in the ventral tegmental area. So, different drugs can cause regionally different serotonergic responses, and the subsequent activation of different serotonin receptor subtypes can either enhance or inhibit the pleasurable effects of that drug. What's more, the balance between these facilitory and inhibitory mechanisms can be altered by long-term drug use. If you want to understand the detailed interactions of serotonin, serotonin receptors, and drugs of abuse, the picture is extraordinarily complicated. Nevertheless, Parsons and his colleagues in the Department of Neuropharmacology are sorting out these questions. Parsons, whose background is in chemistry, came to TSRI in the early 1990s as a postdoctoral fellow after completing his Ph.D. at Emory University. During his postdoctoral fellowship with Associate Professor Friedbert Weiss and Professor George Koob, he began correlating the neurochemical responses to cocaine with the behavioral effects produced by this psychostimulant. In the course of this work it was found that drugs that selectively activate serotonin-1B receptors increase the reinforcing properties of both cocaine and alcohol. In other words, serotonin-1B receptors appear to contribute to the pleasurable effects produced by these drugs. Further neurochemical work revealed that serotonin-1B activation potentiates the effects of cocaine and alcohol on both dopamine and GABA in brain regions involved in drug reward. Interestingly, the influence of serotonin-1B receptors is altered by long-term drug use. According to Parsons, when a person takes a drug like cocaine, serotonin levels increase throughout the brain, and this, in turn, activates serotonin-1B receptors. During heavy cocaine use, the increased serotonin in the brain will bind to and activate these serotonin receptors beyond normal levels. The effect of this increased activation can be profound. Receptors can change based on how much they are activated, and, if they are activated all the time, they trigger mechanisms that are designed to restore balance. These mechanisms might downregulate serotonin receptors by decreasing their number on the surface of cells, or they might do so by changing the way that they interact with other proteins to which they must couple to be active or by inducing the action of endogenous peptides that naturally interfere with the function of the receptors. In any case, what Parsons and his colleagues observed was that serotonin-1B receptors are downregulated during extended cocaine use. Then, during withdrawal, the opposite happens. There is a significant depletion of serotonin in the brain during the acute stages of withdrawal. Parsons and his colleagues observed it to fall to half the normal level or less, and they found that this effect becomes even more pronounced with longer histories of cocaine use. Starved for stimulation because of the decrease in serotonin during withdrawal, the serotonin receptors can become significantly upregulated in number or function. This upregulation is persistent, says Parsons, and the increase in serotonin receptor activity may be behind the notable decrease in serotonin levels for a number of days during acute withdrawal. Experimentally, it lasts for at least three weeks in laboratory models. A whole bank of symptoms are associated with withdrawal, including depression, anxiety, impulsivity and drug craving. Many of these symptoms are most severe during the early stages of withdrawal, when the brain is most disturbed. However, some symptoms, most notably drug craving, can persist for months and even years. "Serotonin-1B receptors have been implicated in the etiology of depression, anxiety and impulsivity," says Parsons, "and there's growing evidence that they could play a role in drug craving. Each of these symptoms have been implicated in the relapse to drug taking often encountered during withdrawal." Interestingly, Parsons and his colleagues have subsequently found that serotonin-1B receptors exert a similar influence on a variety of other drugs. These receptors enhance the reinforcing effects of amphetamines, alcohol, and opiates, and this effect does not seem to depend on how the drugs are taken (intravenously, orally, etc.). This observation is significant because Parsons has studied other serotonin receptors and found that this was not the case. For instance, the serotonin-3 receptors seem to exert a strong effect on behaviors associated with alcohol. Blocking them will cause the self-administration of alcohol to decrease in experiments with laboratory models. These same receptors, however, do not change in response to cocaine or amphetamine use, and they seem to exert no influence on behaviors related to those drugs. Blocking them has no effect on the self-administration of cocaine or amphetamines. A similar dichotomy exists with the serotonin-1A receptor—despite its similarity to the serotonin-1B receptor. Other serotonin receptors, such as the serotonin-2C subtype, affect both cocaine and ethanol reinforcement, but in a negative or inhibitory way opposite to serotonin-1B receptors. Possibilities for TherapiesParsons seeks to characterize these mechanisms because such knowledge will set the groundwork for developing new therapeutics for drug addiction and other diseases. For instance, since serotonin-1B receptors may be involved in the negative aspects of drug withdrawal such as depression, anxiety, impulsivity and perhaps craving, it might be beneficial to specifically block these receptors with a medication while a patient is experiencing withdrawal. Research in this area may also provide insights that reach beyond drug abuse. "Although our work tends to focus on addiction-related phenomena," adds Parsons, "many of the mechanisms we study have relevance to psychiatry in general. Depression, anxiety and aggression are often associated with addiction, but not exclusively so. Hopefully by dissecting out the influence of different serotonin receptor subtypes in these withdrawal-related dysfunctions we might identify good therapeutic targets for these disorders in non-dependent individuals as well."
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