Features
Addiction and
The dopaminepathway is helpingresearchersfind their way through
the addictionmaze
ur flourishing knowledge of
the brain is in large part the
product of research on ad-
diction. Identifying what happens in
the brain when a drug is inhaled,
injected, or eaten, why it leads to
compulsive drug seeking, and learn-
ing how to disrupt that process has
seemed like the last best hope for a
permanent fix for addiction. Which
is why, according to Alan Leshner,
director of the National Institute on
Drug Abuse (NIDA), researchers
know more about drugs in the brain
than they know about anything else
in the brain.
Among the revelations: addiction
is now seen to be a brain disease
triggered by frequent use of drugs
that change the biochemistry and
anatomy of neurons and alter the
way they work. Scientists have de-
veloped a basic model of addiction
that presents these changes as the
desperate attempt of the brain to
carry on business-as-usual-to make
neurons less responsive to the drugs
and so restore homeostasis-while
under extreme chemical siege.
But the adaptations the drugs force
on the brain can be long term or even
permanent. With sustained drug use,
the brain adapts to this saturation
bombardment, and giving up drugs
leaves it bereft and demanding a re-
turn to the new homeostasis. Thus,
even the brains of people who have
quit using drugs and urgently wish
to stay clean remain vulnerable to
relapse. Deprived addicts are no
longer seeking to get high, they just
want to feel normal.
Genetic factors, environmental
factors, and-most important-the
intricate and still mysterious inter-
by Tabitha M. Powledge
July 1999
the brain
action of the two are assumed to be
fundamental to the addiction pro-
cess. But a great many critical details
are emerging from studies of events
in the brain.
The common pathway
The most compelling revelation
about addiction and the brain may
even deserve that tattered encomium
"breakthrough." The discovery that
startled the scientists? Although each
drug employs it in a somewhat dif-
ferent way, addictions center around
alterations in a single pathway in the
brain: the "reward" circuit whose
chief centers of action lie in the an-
cient part of the brain known as the
limbic system.
This pathway is involved in drug
addictions of all kinds-not just ad-
diction to illegal drugs such as heroin
and cocaine, but also addiction to
alcohol, tobacco, and even caffeine.
Marijuanaappearsto employ this path-
way too. And perhaps-a big perhaps
because addiction experts are divided
on this point-the pathway also fig-
ures in "addictions" that do not in-
volve drugs, for example, the com-
pulsive and destructive pursuit of
eating, exercise, gambling, or sex.
The addiction pathway is the brain
system that governs motivated be-
havior. When the pathway was first
discovered, almost a half-century
ago, people called it the pleasure
center. Scientists now call it the brain
reward region and have confirmed
its role as the addiction pathway in
countless animal studies (mostly with
rats and mice) and many brain-imag-
ing studies of human addicts.
The pathway is hidden deep within
the brain (see illustration page 514).
It begins at the ventral tegmental
is collaborating with JSTOR to digitize, preserve, and extend access to
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area in the midbrain, which sits on
top of the brainstem. In evolutionary
terms, this region is very old; it be-
gan with the vertebrates, which ap-
peared 500 million years or so ago.
The pathway extends to the nucleus
accumbens, toward the front of the
brain. This area is a traffic hub for
signals to and from the addiction
pathway and other parts of the brain.
The nucleus accumbens is centrally
located at the intersection of the stria-
tum (where motion is begun and
controlled) and the limbic system.
The limbic system is a collection
of primeval brain structures that form
a ring around the brain stem. Among
those structures are the hippocam-
pus, the brain's center of learning
and memory, and the amygdala, the
postulated site of, among other
things, our emotional responses to
experience. These are ancient cen-
ters of cognitive processing, but they
still guide our behavior, sometimes
to our woe. They long antedate the
neocortex, where (among other tasks)
rational thought processes are be-
lieved to take place. The limbic sys-
tem is also closely connected to the
hypothalamus, a tiny area in the cen-
ter of the brain that controls many
hormones, and with them, hunger,
thirst, and sexual desire.
In short, the addiction pathway
has been around a lot longer than
humanity and is situated within easy
reach of ancient brain centers that
control many basic functions, most
of them unconscious, that people
share with other animals.
Drugs and the dopaminepath
Chemicals called neurotransmitters
pass messages from one neuron to
another across the gaps (synapses)
513
University of California Press
BioScience ®
www.jstor.org
 mine. Too little, and people will de-
Prefrontal velop the tremors and characteristic
cortex stoop of Parkinson's disease. Too
much may be responsible for the
..~..
,.L?. :..........??..
............ . .... .
visions and delusions of schizophre-
nia. But the right amount of dopa-
mine, scientists think, creates our
subjective feelings of enjoyment, de-
--Ventral light, even rapture-not just from
Nucleus

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aNucleums
accumbens
tegmental drugs, but when we are eating ice
area cream, or making love, or getting a
compliment. Defined biochemically,
bliss is what we experience when
that bolt of dopamine lightning
strikes in the nucleus accumbens.
Addictive drugs share one pivotal
characteristic: they all increase brain
levels of dopamine. Many of the ef-
Brain stem fects of the stimulants amphetamine
and cocaine can be explained by their
Addictions center around alterations in the brain's mesolimbic dopamine pathway,
also known as the rewardcircuit, which begins in the ventral tegmental area (VTA) ability to elevate synaptic levels of
above the brain stem. Cell bodies of dopamine neurons arise in the VTA, and their dopamine and block the dopamine
axons extend to the nucleus accumbens. This centrally located hub connects with transporter, observes Marina Wolf,
many other brain structures, such as the limbic system (the so-called emotional who studies addiction in rats at the
brain, in evolutionaryterms very old). Some dopamine fibers also projectto a much Chicago Medical School in North
newer structure, the prefontal cortex, which is involved in cognitive tasks such as Chicago. "So it was logical to go
memory, planning, attention, and social behavior. Illustration courtesy of the from the importance of dopamine
National Institute on Drug Abuse, National Institutes of Health. systems in the acute actions of these
drugs to proposing that the adapta-
that divide them. Dopamine is among ecule and stored for reuse by the pre- tions that occur when the drugs are
the most common of the more than synaptic cell that released it. given chronically-from the cellular
100 neurotransmitters that have been After dopamine has been ejected level all the way up to a behavioral
identified so far, although it is made into a synapse, it normally doesn't level-might be attributable to
in perhaps fewer than 100,000 nerve remain there long; the presynaptic changes within the dopamine sys-
cells out of the brain's 100 billion. neuron's transporter sucks it right tem," she says.
Dopamine is also the chief neuro- back up. But addictive drugs inter- Opioids also stimulate release of
transmitter in the brain reward path- fere with normal dopamine handling, abnormally large amounts of dopa-
way. From cell bodies in the ventral prolonging its sojourn in the syn- mine, employing one of nature's in-
tegmentum, electric commands go apses and so its agreeable sensations. tricate jury-rigged contraptions.
out, leaping along the cells' cablelike Some drugs do this by forcing the Dopaminergic neurons in the ventral
axons to their terminals in the nucleus presynaptic cell to release more than tegmentum are regulated by other
accumbens, where dopamine is ejacu- the usual amounts of dopamine, oth- neurons that keep them from releas-
lated into the synapses. ers by preventing re-uptake by the ing too much dopamine. Those regu-
Once in the synapse, neurotrans- transporter; some may even do a latory neurons are studded with
mitters swim across it and attach little of both. Cocaine, for example, opioid receptors; when drugs such as
themselves to receptors on the sur- imitates dopamine so well that it can morphine lock on to those receptors,
face of the receiving (postsynaptic) bind to the transporter and block they inhibit the inhibitory neurons.
cell. Depending on the neurotrans- dopamine re-uptake. Amphetamines That is, they prevent the neurons
mitter, the attachment commands the reverse the transporter's normal func- from doing their normal job of hold-
postsynaptic cell to either do some- tion, preventing re-uptake while also ing down dopamine production, re-
thing or not do something. (The na- using the transporter to pump addi- sulting in the release of large amounts
ture of the "something" also depends tional dopamine into the synapse of dopamine.
on the neurotransmitter.) Once it from the presynaptic cell. Nicotine probably activates both
has carried out its task, the neuro- As with the other substances in its the dopamine and opioid overpro-
transmitter is broken up by enzymes chemistry set, the brain usually keeps duction systems, but the details are
or vacuumed up by a transporter mol- strict control over supplies of dopa- not yet clear. Ethanol, too, appears

514 BioScience Vol. 49 No. 7

to employ the opioid method of
disinhibiting dopamine neurons (in
addition to its many other activi-
ties), but also increases their firing
rate in the ventral tegmentum.
In short, each drug makes use of
the dopamine pathway in a different
way and recruits other brain chemi-
cals (includingother neurotransmit-
ters) to help. What follows is a selec-
tive and much-simplifiedaccount of
some consequencesof the dizzyingly
complicated process of addiction.
The evolutionof motivation
Researchershave amassed a moun-
tain of reasons to explain drug use.
Leshnersays that 72 "risk factors"
have been defined, from the street
price of a drug to the drug habits of
the people one hangs out with. But
the basic reason people use drugs
isn'tcomplicatedor mysterious.They
like the way drugs make them feel.
Scientists believe, however, that
therewardpathwayexists for reasons
more fundamentalthan fun. It does,
after all, contain receptors, trans-
porters,andothermoleculesthat nor-
mally hitch up not with drugs but
with the chemicals that evolution
hasdesignedfor them. Scientistshave
known that the brain producesthese
"natural"psychoactivedrugssincethe
1970s, when the enkephalins,the first
of the opioid peptides, were discov-
ered. Since then, researchers have
identified the natural brain-analogs
of all of the major drugs of abuse.
Scientistsbelieve activation of the
rewardpathway is an essential spur
to motivation, an incentive to learn
and repeat adaptive behavior that
they call reinforcement.Eating may
be pleasurable, but its underlying
purpose is to sustain life; the plea-
surethat accompaniesdelightful fla-
vors and full bellies is an enticement
that encourages creatures to make a
habit of it.
The brain contains other circuits
that interact with the reward pathway
to encourage adaptation and survival,
circuits that deal with emotion and
learning. These circuits assign signifi-
July 1999
Using PET (positron
emission tomography)
scanning,researchersat
theNationalInstituteon DL
DrugAbusedetectedthe
activation of brain re-
gions implicatedin cer-
tain forms of memory
k
whenhumanvolunteers
who abusecocainewere
exposedto drug-related
cues (drugparapherna-
Downloaded from https://academic.oup.com/bioscience/article/49/7/513/236613 by guest on 15 August 2021
lia and a videotape of
cocaineusers).Brainac-
tivation(increasedneu-
ralactivity)wasdetected
as anincreasein glucose
metabolism, as indi-
cated by the color scale
at the lower right. The
drug-related cues did
1
2.
1
8,
not producebrainacti-
vation in control sub-
jects(scansnot shown),
but volunteerswho ex-
perienceda highlevelof
cue-induced cocaine
craving showed brain
activationin the dorso-
lateral prefrontal cor-
tex (DL; upper scans),
which is importantin short-termmemory, and in the amygdala(AM; lower scans),
which is implicatedin emotional influenceson memory.When these volunteerswere
exposed to neutral(non-drugrelated)cues, this activationwas not seen (scansat left).
Image republishedwith permission from Grant S, et al. 1996. Proceedingsof the
National Academyof SciencesUSA 93: 12040-12045.
cance and meaning to experience- be less to produce pleasure directly
to individuals, things, and events in than to focus attention on events
the world. Doing so requires calcu- that portend reward (such as the
lating, for example, whether some- dinner bell) or perhaps even distress
thing is hazardous,or edible, or sexy, (such as nausea) to facilitate learn-
and then adjusting brain function to ing and remembering.
generate adaptive tactics, such as
flight, approach, or courtship. The anatomyof addiction
Assigning significance and mean-
ing to experience also requires stor- With enough reinforcement, drug
ing memories of those tactics-suc- users move on to the stages of addic-
cessful and unsuccessful-as a guide tion known as craving and depen-
to adaptive behaviorin the future. In dence. Dependence is an ambiguous
short, it requireslearning. As an aid word, sometimesused to mean physi-
to this learning,the brain links expe- cal and sometimes psychological de-
riences with emotions; we tend to pendence. Yet these are very differ-
remember best the experiences that ent states, and-perhaps not
are accompanied by strong sensa- surprisingly-they employ different
tions such as the euphoric rush from parts of the brain.
that dopamine zap in the nucleus Drugs can cause a host of changes
accumbens. In fact, researchersnow to partsof the brainthat control body
think that dopamine'schief role may functions, especially the brain stem
515
 for addiction,theyfoundthatpergo-
lide, which occupiesboth kinds of
receptors,reduceda dozen heavy
coke users'subjectiveexperiencesof
beinghighandeventheirheartrates,
but it had no effecton self-adminis-
tration of cocaineand actuallyin-
creasedcraving.Thegroupalsostud-
ied ABT-431, another possible
therapeuticagent,whichselectively
control morphine morphine occupiesthe D1 receptor.Thisdrug

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+ BDNF also significantlyreducedfeelingsof
being high in nine cocainesmokers
andhadno effecton self-administra-
A natural brain compound called BDNF (brain-derivedneurotrophic factor) can tion. But its effect on cravingwas
"rescue" dopamine-producingneurons from alteration by morphine. At left is a moreambiguous.Therewas a trend
normal dopamine-producingneuron in the ventral tegmental area of a rat's brain. for ABT-431 to decrease cocaine
Repeated administration of morphine shrinks the neuron perceptibly (center).
However, when BDNF is administeredalong with morphine, no shrinkageoccurs craving,althoughit failedto achieve
(right). Photos: Eric Nestler.
statisticalsignificance.
"Thus, D2 activationincreased
drugcravingwhileD1 activationdid
and spinal cord. These alterations ogy of craving.Therearetwo major not," Haney acknowledges.She is
producephysicaldependenceon the classes of dopaminereceptors,ac- not, however,convincedthat Self's
drug.Whenthe drugsupplystops, cordingto David Self, of Yale Uni- hypothesisis correctbecauseshesus-
the result can be a sicknesscalled versity.He calls them D1-like and pectsthat,at the low dosessheused,
withdrawal. Withdrawal fromheroin D2-like.Selfandhiscolleagues,who pergolideactedselectivelyat the D2
is a ghastlyexperience,and alcohol study addictionin rats, reportthat receptor,yet, like ABT-431,it did
withdrawalcan actuallybe fatal. the two receptortypeshave certain not affectself-administration.
Historically,withdrawal illness structuralsimilaritiesand that their But Selfsays Haney'sfindingsfit
hasbeenregardedas thetelltalesign within-cellsignalingsystemsaresimi- the hypothesisthat the two recep-
of anaddictivedrug.Manyresearch- lar,buttheyhavedifferentanatomi- tors,althoughtheyseemto be doing
ers, however, now reject physical cal profiles:They tend to be in the similarthingsin stimulantandrein-
withdrawalsymptomsas a defining same brainregions,but sometimes forcing effects, are doing opposite
characteristicof addictionbecauseiton differentcell types. thingswith regardto appetitivever-
turnsout that a drugcan be power- Selfandhiscolleagueshavefound susconsumatory behavior."Ithinkit
fully addictivewithoutcausingseri- evidencethat these two classes of between
is usefulto makea distinction
ouswithdrawalsicknesses.Twosuch dopamine receptorsalso function reinforcement andreward,appetitive
drugsmuchinevidencetodayarecrack differentlyin addictionin rats.Crav- versusconsumatorybehavior.Those
cocaineand methamphetamine. ing and relapseseemto involveD2 terms are often interchanged,and
All addictivedrugsalterneurons. activation almost exclusively, al- they shouldn'tbe," he says.
Someof thesechangesappearto con- thoughboth receptorsare activated
tributeto signsof psychologicalde- duringreinforcement.Self hypoth- Addictionandthe
pendencewhenthe drugis stopped, esizesthat eachreceptoris involved
dopaminetransporter
suchasdepressionandcraving.These in a differentmotivationalphaseof
two sensationsin particulararenow the reinforcement process,whichhe Althoughthe detailsmayhavebeen
believedto spur addictson in their calls appetitive (D2) and con- disputed,the centralrole of dopa-
compulsivepursuit of drugs. This sumatory(D1). "I like to use the mine in addiction nevertheless
irresistibledesirehas replacedwith-terms 'seeking'and 'having.' You seemedfirmlyestablished.Andthen
drawalsymptomsas the new hall- can thinkof D2 receptorsas stimu- last May came research that appeared
markof addiction. latingseeking,whereasD1 receptors at first glance to contradict the no-
stimulatehaving,"he says. tion that dopamine underlies addic-
Addictionand Self'sanimalstudieshave gotten tion. "The leading hypothesis for
confirmationof a sort fromstudies how cocaine works in the brain ap-
dopaminereceptors on humansby MargaretHaneyand pears to be wrong," said The New
Studiesof dopaminereceptorsare her colleaguesat ColumbiaUniver- York Times. The headline in Nature
helpingto shedlighton the physiol- sity.Lookingforpossibletreatments Neuroscience asked: "Hard knocks

516 BioScience Vol. 49 No. 7

for the dopamine hypothesis?"
Marc Caron, of Duke University
Medical Center, and his colleagues
had genetically engineered mice that
completely lack the transporter for
clearing dopamine out of its syn-
apses and thus have perpetual high
levels of extracellular dopamine.
These knockout mice should not have
been interested in cocaine. But they
were; the researchers were able to
teach the mice to self-administer the
drug. Caron's group suggested that
cocaine interacts with targets other
than the dopamine transporter, and
that the serotonin transporter could
possibly initiate and sustain cocaine
self-administration in the mice.
Caron points out that pharma-
cologists have known for a number
of years that many psychostimulants
are capable of blocking not only the
ability of the dopamine transporter
to re-uptake dopamine and there-
fore increase extracellular dopamine
concentration, but also the ability of
the norepinephrine transporter to re-
uptake norepinephrine and the abil-
ity of the serotonin transporter to re-
uptake serotonin. Previously, the
effects on other neurotransmitter
systems were not thought to be im-
portant because many of the reward
mechanisms can be blocked by block-
ing the dopamine system.
What the study suggests, Caron
says, is that addiction does not de-
pend solely on the ability of cocaine
to raise the concentration of dopa-
mine. "It's probably much more that
cocaine interacts with many other
systems," he says, noting the possi-
bility that norepinephrine might also
be involved.
In normal mice, Caron says, co-
caine probably also raises levels of
serotonin, which in some way is ca-
pable of modulating the dopaminer-
gic responses. The genetically engi-
neered mice are allowing researchers
to tease out the contribution of the
serotonin system to the regulation of
the dopamine system. Pharmacologic
studies, which are often plagued by a
drug's lack of selectivity, have yielded
ambiguous results on how-or even
July 1999
whether-serotonin interacts with
the dopamine system. By contrast,
Caron notes, one of the advantages
of genetic manipulation is that it
permits researchers to be highly se-
lective in the effects that they choose
to investigate.
Of the dopamine transporter
knockouts, Haney observes, "I don't
think the Caron study alone negates
the dopamine theory of addiction;
there are too many data supporting
it. It seems possible to me that knock-
out mice have different brains-dif-
ferent neuronal adaptations have
taken place to compensate for what
is missing." She points out that most
of the data implicating other neu-
rotransmitters and neuromodulators
in the addiction story, including
glutamate, GABA (gamma-amino-
butyric acid), and endogenous can-
nabinoids, still support the notion
that these substances exert their ef-
fects via the dopamine system.
Addiction and glutamate
However glutamate exerts its effects,
it is playing an increasingly promi-
nent role in the addiction story. Ad-
dictive drugs commandeer cells in
the amygdala and hippocampus to
construct intense emotional memo-
ries of drug experiences. These
memories link the powerful plea-
sures of drug highs to the people,
places, and paraphernalia associated
with them. Thereafter these associa-
tions can by themselves trigger
cravings. Indeed, one way in which
alcohol and drug treatment programs
help users abstain is by trying to
sever these associations, creating a
fresh social circle and new friends,
supportive and abstinent, as a sub-
stitute for their former drinking bud-
dies or fellow drug users.
The latest brain-imaging tech-
niques offer visual evidence of why
recovering addicts may need this sort
of behavior modification to replace
old habits with new ones. PET
(positron emission tomography)
studies by researchers at NIDA's in-
tramural research program in Balti-
more reveal that when cocaine ad-
dicts watch videos of coke users, not
only do they feel craving for the
drug, but also the parts of their brains
that light up are those involved in
memory, including the dorsolateral
prefrontal cortex (probably the site
of "working" memory) and the
amygdala. This finding suggests, the
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researchers say, "that a distributed
neural network, which integrates
emotional and cognitive aspects of
memory, links environmental cues
with cocaine craving."
Because craving and reinforcement
are aspects of learning, it is not sur-
prising that addiction researchers are
interested in glutamate, the neu-
rotransmitter most associated with
the learning process. Indeed, as the
chief agent of fast neuron stimula-
tion, glutamate is at the core of nearly
all brain physiology and biochemis-
try and is central to the most sophis-
ticated cortical processes. Glutamate
receptors in the hippocampus ap-
pear to trigger the complex cascade
of biochemical reactions that con-
vert short-term memories into per-
manent ones, a process called long-
term potentiation.
Wolf thinks that the introduction
of glutamate as a player in addiction
is logical, not just because glutamate
underlies learning, but also because
the dopamine system is regulated by
glutamate-containing neurons. "For-
get about drugs of abuse and just
think of the dopamine neurons in the
ventral tegmental area. One very
important way that they get excita-
tory drive is through glutamate-con-
taining nerve terminals that synapse
on them. So on that end glutamate is
very important in driving the cells,"
she says.
On the other end of the dopamine
pathway, dopamine terminals center
in the nucleus accumbens. "And the
other major synaptic input that those
accumbens cells get is glutamatergic.
There are a lot of transmitters in the
accumbens, but two of the major
transmitters determining the output
of the accumbens are dopamine and
glutamate," Wolf points out. "The
517
glutamate connection makes very
good anatomical sense because it's
working together with dopamine at
the level of the accumbens to deter-
mine what the response to dopamine
really is."
In the last decade, Wolf and her
colleagues have shown that glutamate
receptors participate in behavioral
sensitization, the frenetic activity seen
in lab animals that researchers ac-
cept as a model of drug craving.
Long-term changes that occur with
chronic drug administration, she
says, seem to be dependent on
glutamate systems, although each
drug interacts with glutamate in a
different way.
Despite her concentration on
glutamate, Wolf says, "I don't think
that anybody would suggest that we
abandon the idea that the dopamine
cells are the core of the reward path-
way. I wouldn't move to describing
glutamate as the primary transmit-
ter, I would stick with dopamine."
She also points out that research on
the role of glutamate in addiction is
still in its early stages.
There is, she says, a growing con-
sensus that addiction is simply an-
other form of neural plasticity.
"Glutamate seems to be important
in just about every form of neural
plasticity, but in each case its spe-
cific role is a little bit different, and
I'm sure that's going to be the case
for drug addiction too."
In fact, glutamate may be just as
central to learning to become drug
free as it is to becoming a user. Self
and his colleagues have recently
found that addicted rats that are no
longer given drugs and eventually
abandon their search for them, a
phenomenon known as extinction,
show changes in glutamate receptors
in the nucleus accumbens. The sub-
sequent brain changes, Self says, are
not caused by the fact that the rats
have been cocaine users, because the
researchers don't see those changes
in rats that continue to use cocaine.
And the changes are not caused by
withdrawal from cocaine because
they are not seen in rats that have
518
gone through withdrawal but not
the extinction process.
His conclusion? "[The brain
changes are] caused by the experi-
ence of extinction," he says. "This is
another type of neural adaptation.
There are changes in the brain that
are direct pharmacological effects of
the drug. There are other changes in
the brain that are the result of expe-
rience. Learning, in short. And these
interact."
Indeed, Peter Kalivas and his col-
leagues at Washington State Univer-
sity at Pullman have proposed that
whereas pharmacology is largely re-
sponsible for producing paranoia in
cocaine users, craving and relapse
are mostly the result of learning.
"It's sort of a circular thing," Self
says. "Taking drugs changes the brain
through both learning and direct
pharmacological effects. How then
do those changes affect motivation
for subsequent drug taking or, in the
absence of the drug, drug seeking
and drug craving?"
Addiction inside neurons
Some researchers hope that knowl-
edge about the interaction of phar-
macology and learning will emerge
by paying less attention to what goes
on between brain cells and more to
what goes on inside them. The new-
est frontier in addiction research is,
therefore, signal transduction: the
process by which events on the out-
side of a postsynaptic neuron influ-
ence events inside it. Binding to a
dopamine receptor, for example,
unleashes a chain of events in the cell
that culminate in an order to a cell's
genes to modify what they're doing.
Neuroscientists of all sorts have
paid intense attention to a crucial
link in this chain, an intracellular
signaling chemical called cyclic ad-
enosine monophosphate (cAMP),
because it turns genes on and orders
them to make some very consequen-
tial proteins. These are the proteins
that help form new synaptic connec-
tions between neurons-the basis for
long-term potentiation.
Addiction researchers have inves-
tigated cAMP's role in various re-
gions of the brain, including the
nucleus accumbens, where chronic
exposure to morphine accelerates
activity in the cAMP pathway. One
outcome appears to be increased lev-
els of a molecule nicknamed CREB
(short for cAMP response element
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binding protein)-the molecular
switch that governs production of
synaptic proteins and so converts
short-term into long-term memories.
CREB and the cAMP pathway al-
most certainly play a role-perhaps
a central role-in forming the memo-
ries that researchers suspect are fun-
damental to craving and relapse.
Eric Nestler and his colleagues at
the Yale University School of Medi-
cine have suggested that CREB-me-
diated gene transcription in the
nucleus accumbens serves as a kind
of drug reward rheostat. They
showed that CREB regulates nucleus
accumbens expression in vivo of the
rat gene for dynorphin, an endog-
enous opiate, concluding that opiate
receptors play a role in both cocaine
reward and aversion to it. Repeated
exposure to cocaine, they say, up-
regulates dynorphin expression
through the cAMP pathway-via the
dopamine D1-type receptors. En-
hanced dynorphin release could even-
tually inhibit dopamine release via
opioid receptors on the terminals of
dopaminergic neurons. "Diminished
release of dopamine in the nucleus
accumbens may be aversive, or it
may unmask other actions of co-
caine that oppose drug reward,"
they say. This interpretation could
explain why, over time, human ad-
dicts tend to find cocaine less re-
warding and more likely to cause
anxiety, irritability, and other un-
pleasantness.
Most of the neuronal adaptations
generated by the drugs that have
been studied so far have involved
second-messenger systems, especially
cAMP, but researchers are also in-
vestigating other ways that the brain
remodels its ever-malleable neurons.
This approach has led them to neuro-
BioScience Vol. 49 No. 7
trophic factors. Once thought to be
active only during the earliest stages
of nerve cell growth and develop-
ment, neurotrophic factors are now
believed to be essential to the adult
sdL'aySble Co
for
brain as well, where they are in-
volved in signal transduction and
neuron growth and maintenance.
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Metabolic
Respirometry
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be able to repair a drug-damaged Measurement
Temperature &Control
brain. Nestler's lab has reported that
chronic morphine administration Measurement
Humidity &Control
reduces the size of dopamine-pro- Monitoring
Activity
ducing neurons in the rat ventral DataAcquisition
tegmentum by 25 percent on average
while making no obvious changes in with
other kinds of neurons in that re-
gion. This shrinkage may be one way
in which the rat brain tries to adjust
Unlimited Technical Support
its dopamine supply to a flood of & Three Year Guarantee
opiates, Nestler suggests. But infu-
sions of BDNF (brain-derived neuro-
trophic factor) into the ventral teg-
mentum not only prevent opiates
from shriveling the dopamine neu-
SABLE SYSTEMS
rons (perhaps by ratcheting down
the speedup in the cAMP pathway INTERNATIONAL
that opiates induce), but can even
restore those neurons to their former "ByScentts&,forScin/nts TM

plump state. 1-800-330-0465/1-702-269-4445

The dopaminepathway is
not the yellow brick road
Neuroscientists believe that their re-
search is at last going to enable seri-
ous progress on this ancient human
affliction. The common pathway was
a benchmark revelation, in part be-
cause it offered a unified framework
for studying what for a long time had
seemed like a hodgepodge of unre-
lated behaviors.
Important though it may be for
understanding addiction, the dopa-
mine pathway itself does not seem
likely to yield promising new medi-
cations or other treatments for ad-
diction. The pathway is so essential
to normal functioning, to the every-
day pleasures of life, and perhaps to
learning itself, that it may be nearly
impossible to interfere with it suc-
cessfully. "Whateveryou do to the
dopamine system, you always get
morethan you bargainedfor," Caron
observes. "That's because of lack of
selectivity and our lack of funda-
mental understandingof which pro-
tein of the dopamine system really
mediates the addictive behavior."
And although genes seem more
and more likely to play a key role in
addiction,identifyingthese geneswill
not necessarilylead to treatmentsei-
ther. "There'snot going to be a single
gene that's defective in people that
have more liability to become ad-
dicted. You probablycan have many,
many changes in the brain that will
all eventuallymanifest themselvesin
addictivepersonalities,"Caronsays.
Researchers are hopeful that un-
derstanding the differences in the
way the brain handles the various
psychoactive agents will help them
identify suitable points of attack.
Leshner cautions audiences con-
stantly against the hope of a magic
bullet against addiction. But in the
next few years, there may be real
progress in treating and perhaps even
preventing this peculiarly human af-
fliction, one that is as old as the first
Paleolithic brewers and as new as the
latest mind-bending molecule from
the designer druggist's clandestine
chemistry lab. O
Science writer Tabitha M. Powledge is
the author of Your Brain:How You Got
It and How It Works (Scribner, 1995).

July 1999 519