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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 Therapies

Parsons 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."