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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."
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