Serotonin Receptors and Drug Abuse
By Jason Socrates
Bardi
"You
know I'm gonna miss you now that you're gone..."
——Lou
Reed, Berlin, 1973
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 Problem
Jones 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 Neurotransmitter
Serotonin, 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 Receptors
Serotonin 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.
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