High and hooked

A better understanding of how addictions work could provide benefits for  
science, for medicine and for recreation [header in bold on top of the  
article --wonko]

	In 1964 Aryeh Routtenberg stuck electrodes into the brains of his  
experimental rats.  The electrodes were so positioned that current flowing  
though them caused a particular pleasure.  For one hour a day, each rat  
could control this current by means of a lever in its cage.  Another  
lever, which also worked for just that one hour, controlled the food  
supply.  There was no contest between the levers.  The rats, too busy  
mainlining current to stop for food, wasted away to ecstatic death.
	The link between pleasure and addiction is not always so extreme,  
but more mundane addictions have brought about millions of less dramatic  
deaths outside the laboratory, and caused untold misery and pain.  The  
substances to which people get addicted, though, also bring great pleasure  
to billions--some addicted, some not.  They are the basis of several  
multi-billion dollar industries around the world.  Some 60m Americans  
smoke tobacco; three-quarters of West European adults drink alcohol; no  
one knows how many people around the world consume caffeine in tea, coffee  
or cola.  Figures for illegal drugs are harder to come by, but around 2m  
Americans are thought to take cocaine, and many more than that have smokes  
	Not all the people who indulge in these tastes are addicts--that  
is, they do not depend on their habit in a way that seems clearly abnormal  
to the bulk of people who do not share their tastes.  Though almost  
everyone who smokes tobacco is hooked, drinkers are not necessarily  
alcoholics and not all heroin users are hopeless junkies.  Pleasure and  
the addiction need not come together--either can be present without the  
other.  yet the two are obviously connected.  Neuroscientists are now  
using the tools of molecular biology to find the links between them, deep  
in the recesses of the brain.

The kick from cocaine [boldface paragraph header --Wonko]

	The cerebral nooks and crannies of interest are those between  
nerve cells--synapses.  To jump over the gap between two cells, a nerve  
impulse has to be translated from electricity to chemicals and back.  The  
first cell releases a chemical called a neurotransmitter into the synaptic  
gap.  These molecules are then picked up by receptor proteins on the  
surface of the second cell.  The neurotransmitter fits the receptor as a  
key fits a lock.  The unlocking of the receptor leads to the creation or  
suppression of a nerve impulse in the second cell.
	There are many different types of neurotransmitter, and thus of  
synapse; different pathways in the brain need their different properties.   
It is by subverting some of these synapses, and thus some of the brain's  
pathways, that drugs produce pleasure.  it is through changing them in a  
more fundamental way that the drugs cause addiction.
	The first evidence for this is almost 20 years old.  Recently it  
has started to pile up quite quickly.  In 1975 Solomon Snyder, at Johns  
Hopkins University in Baltimore, Hans Kosterlitz of the University of  
Aberdeen in Scotland and John Hughes of Parke-Davis, and English  
pharmaceuticals company, found out how heroin, then drug-du-jour for  
worried policy-makers, works.  Dr. Snyder discovered there was a receptor  
protein in mammalian brains which heroin would stick to.  Dr. Kosterlitz  
and Dr. Hughes reasoned that nature was unlikely to have produced such a  
lock without also evolving a key.
	Working independently, they found a chemical in the body that  
fitted into the same receptor as heroin; Dr. Kosterlitz named it  
"endorphin".  This type of neurotransmitter (there are, it turns out, at  
least three different endorphins) damps down pain by suppressing the  
signals which transmit it; it also provides feelings of well-being.   
heroin acts as an ill-fitting key which can open the lock but cannot then  
be withdrawn.  The synapse is over-stimulated.  Unusually pleasurable  
sensations result.
	If you replace heroin and endorphins with nicotine and the  
neurotransmitter acetylcholine, or with caffeine and adenosine, or Valium  
and gamma-amino butyric acid, or marijuana and anadamide, the same story  
can be told.  Other drugs work in slightly more subtle ways.  Alcohol does  
not mimic a neurotransmitter, but at least some of its effects come from  
messing up the same synapses that heroin works on.
	Cocaine, which has replaced heroin as the drug of concern in  
America, and has thus been extensively researched, works on nerves that  
use the neurotransmitter dopamine.  These nerves are found in, among other  
places, the mesolimbic system--the part of the brain which seems to  
generate emotion.  Cocaine subverts the pathway not by binding to dopamine  
receptors, but by sticking to a molecule called, inelegantly, the dopamine  
re-uptake transporter.
	Nerve cells, canny little things, recycle their neurtransmitters.   
Receptor molecules spit out their neurotransmitters once they have served  
their purpose, and the cell whence they came mops them up for reuse.   
Block this re-uptake, and the transmitters will just sit in the synaptic  
gap, stimulating the receptors again and again and again.  Another  
strategy is to jam the re-uptake system open, so that dopamine flows  
though it the wrong way all the time, keeping the gap suffused with the  
neurotransmitter.  That is what amphetamines do.
	The fact that amphetamines and cocaine work in similar ways will  
come as no surprise to anyone who has tried both.  The nature of the high  
a drug provides depends on the type of neurotransmitter it interferes  
with.  but the brain is a complex place; the separate systems within it  
that use different neurotransmitters all interact.  A drug acting on one  
set of synapses can have secondary and tertiary effects all over the  
place.  That is why drug experiences are so varied.
	The range of things that can be addictive, though, is wider even  
than the range of available drugs.  Foreign bodies in the synapses are not  
an absolute prerequisite for an addiction.  Something as straightforward  
as healthy exercise can, in the extreme, hook.  In the case of exercise it  
appears that the body becomes addicted to the endorphins it produces to  
ameliorate the pain and stress.
	Other behaviours that carry an intensity with them--and thus  
presumable overstimulate some parts of the brain's wiring--can produce  
similar effects, though the synapses involved have yet to be charted.   
Gambling has many of the characteristics of drug taking--a euphoric high,  
and a craving in the addict.  Some people believe themselves addicted to  
sex; lawyers in England recently convinced a jury that a teenage hacker  
was addicted to computing. [OH MY GOD!  NETNEWS IS ADDICTIVE!  QUICK, GO  
	It is easy to see some such "addictions" as excuses, especially as  
the term resists strict definition.  But addiction to chemicals is clearly  
real, and there seems no reason to believe that compulsive chemical-taking  
is necessarily in a different class from other acquired compulsive habits.   
Anyway, chemical dependency is easier to study than other sorts.  That is  
why it has been possible to locate the roots of pleasure in the  
synapses--and why it has been possible to find the roots of withdrawal  
there, too.

Cold turkey [boldface header --Wonko]

Clinically, addiction can be characterised by two things: craving and  
withdrawal.  Craving is still the subject of a certain amount of  
scientific handwaving.  The best the psychologists can do is describe the  
process as one of positive re-inforcement--which means that if you like  
something, you will tend to do it again.  Having their receptors  
overstimulated is something people tend to like a lot.  How this "liking"  
translates into neural circuitry is not yet clear.
	Withdrawal, the physical and mental turmoil that follows when an  
addiction is interrupted, is proving more tractable to experimental  
analysis.  A suggestive picture of how it works can be pieced together, as  
long as you do not mind taking the pieces from different studies of  
different drugs: work on cocaine by Nora Volcow at Brookhaven National  
Laboratory, among others; on cocaine and amphetamines by Bruce Cohen of  
McLean Hospital in Boston; on heroin by Zvi Vogel at the Weizmann  
Institute in Rehovot in Israel and Antol Shofelmeer at the Free University  
in Amsterdam; an on benzodiazepines (such as Valium) by Erick Sigel at the  
University of Berne.
	Again, the synapse is the scene of the action.  Most biological  
systems have feedback mechanisms that help smooth out the little  
fluctuations that life throws at them.  Synapses are no exception.  The  
receiving cell can adjust itself to changes in the behaviour of the  
transmitting cell in two ways.  It can finetune the signal the receptors  
pass on, and it can change the number of receptors.
	The receptor molecules are conduits for information, with one end  
outside the cell and the other inside.  When a neurotransmitter attaches  
itself outside, the part on the inside changes its shape.  In this new  
shape, it can accommodate molecules called G-proteins, which hang around  
inside the cell.  These G-proteins are, themselves, also shape-changers.   
Interacting with the receptor activates the G-proteins; these then head  
off to spread the word via yet more molecules, called second messengers.
	the second messengers tell the cell about the signal from the  
neurotransmitters.  One part of the cell that listens is the system which  
sends out and suppresses nerve impulses.  Another avid audience is made up  
of the enzymes which add phosphate groups to proteins, some of which help  
in the production of impulses.  More messages make them more active, and  
more likely to add phosphate to receptor molecules.  A phosphorylated  
receptor is an unhappy receptor.  It is reluctant to accommodate  
G-proteins and thus to bring information in from the outside.
	The nucleus, which controls the production of proteins, and also  
listens to the second messengers.  Lots of chatter from them suggests to  
the nucleus that there are too many receptors at the synapse, so it brings  
their manufacture to a halt.  Insert an addictive drug into the system and  
the din from the second messengers becomes deafening.  The result is fewer  
receptor molecules.
	Both the phosphorylation of receptors and their absence means that  
it takes more of the drug to obtain the same effect.  Those high doses, in  
turn, lead to even less sensitive synapses.  And they also lead to  
synapses that can no longer function without the drug.  The cell gets used  
to damming the flood of drug-induced noise in order to be able to deal  
with the faint whispers of reality that float on top of it.  Remove the  
drug, and the normal signals can no longer get over the barrier that has  
been erected.  The system goes from getting too much of the  
neurotransmitter's effects to not enough; heaven turns to hell.
	Put this way, the molecular picture seems obvious.  It fits with a  
common experience of addiction, that of needing to do more and more of the  
drug just to keep from feeling bad.  Of course, it cannot be that  
simple--after all drugs that work on the same neurotransmitter may vary in  
their addictiveness.  And people vary, too, in their susceptibility to  
addiction.  Then again, addictions to substances that affect different  
types of synapse can be quite similar--and some people seem to be prone to  
addiction per se, rather than just to have a weakness for a particular  
substance.  And the fact that addiction remains after withdrawal has  
ended--a fact attested to at Alcoholics Anonymous every day--suggests  
there is a more general problem to look at.

Dopamine heads [boldface header --Wonko]

	For more evidence that addictions have something in common in the  
way they act on the brain as a whole, no matter which pathways they  
stimulate, look at the pictures on this page.  [two computer imaged  
pictures with lighter and darker patches, one of the left half of a brain,  
and another of the right half.  The left half has darker blotches.  Under  
the left half is the caption "Your brain" and, as you might expect, the  
right half has "Your brain on drugs" --Wonko]  Edythe London, who works at  
America's National Institute on Drug Abuse, studies glucose metabolism in  
the brains of people with addictions.  Glucose is the body's principal  
fuel, so its use is a good index of how active an area is.  Dr London's  
pictures show that, in certain parts of the brain, addicts use less  
glucose than non-addicts do.  The difference applies regardless of what  
drug is being used, and it is still visible when they are not under the  
	Other clues to a general theory of addiction have led researchers  
to focus on the dopamine system--even when looking at drugs which do not  
affect dopamine receptors.  There is evidence that many, and possibly all,  
addictions affect the dopamine cells in the brain's mesolimbic system.  In  
the case of cocaine this effect is direct, which may account for the  
drug's peculiar potency.  for other drugs it seems to be indirect, brought  
about by connections between the dopamine system and the other  
neurotransmitter systems.
	Inside the dopamine system, the researchers' attention has lighted  
on D2.  it should come as no surprise by now to hear that D2 is a protein  
found in synapses, one of the three different receptor proteins for  
dopamine.  The detailed make-up of these proteins can vary from person to  
person--variation that comes from differences in the gene which describes  
the protein.  So the different variants of D2 are inherited.
	It was inheritance that led the researchers to D2.  In the 1970s a  
series of Danish studies compared the children and step-children of  
alcoholic fathers.  The former proved more likely to succumb to the same  
addiction.  This, and the evidence that identical twins are more likely to  
share an alcoholic fate than are non-identical twins, suggested that genes  
were playing a role.  In 1990, to great excitement, Kenneth Blum of the  
University of Texas at San Antonio, and Ernest Noble of the University of  
California, Los Angeles, announced that they had found a gene peculiarly  
common among alcoholics.  It described a form of the D2 receptor known as  
	This was challenged by several researchers, most notably Kenneth  
Kidd, of Yale.  Dr. Kidd points out that different ethnic groups have  
different frequencies of A1, which could confuse the statistics.  Others,  
convinced by Dr. Blum, Dr. Noble and subsequent work, have suggested that  
A1 frequencies may actually explain differences in alcoholism between  
ethnic groups, though this is far from certain.
	In 1992 George Uhl, of Johns Hopkins, found that a second variant  
of D2, known as B1, seemed peculiarly common in people addicted to  
tobacco, cocaine, heroin, tranquillizers, marijuana and amphetamines as  
well as alcohol--almost the whole list of commonly addictive substances.   
This is at least as controversial as the original finding; its meaning is  
not clear, nor is the nature of the difference between the different D2s.
	To link small variations in a single protein with the existence of  
an all-purpose "addictive personality" is to go a long way too far.  But  
there is evidence in one case for a link between personality and  
withdrawal symptoms--and to link withdrawal symptoms to specific molecules  
is not too farfetched.  About 40% of people prescribed courses of  
benzodiazepines to treat anxiety or insomnia can suffer some withdrawal  
symptoms--souped-up versions of the symptoms the drugs are used to  
treat--after the course of medication is finished.  Peter Tyrer, who  
worked at St. Charles' Hospital in London, has found that the people who  
suffer withdrawal share not a specific protein, but rather specific  
personality traits: insecurity, inability to make decisions, an  
over-reliance on the opinions of others.  Spot them, and you can save  
people from withdrawal.

Better living through chemistry [boldface header... gotta love these  
catchphrases --Wonko]

	The links between proteins, the lowly building blocks of the  
brain, and personalities, the high abstractions of the mind, are  
undoubtedly going to be convoluted--but evidence from both ends suggests  
they are there to be found.  What are the pharmaceutical companies, to  
which this should be of interest, doing about it?
	Some work is going into drugs to treat drug addiction.  Naltrexone  
keeps heroin from activating endorphin receptors, without activating them  
itself.  Methadone works in the same way as heroin, but less effectively;  
it thus provides a way off heroin that minimises withdrawal symptoms.   
Similar approaches to cocaine are being tried.  Drugs which act on  
dopamine pathways in general may have widespread effects on addiction.   
but drugs to defeat dependence are not the only possibilities.
	Some of the damage that comes from drug addiction, especially the  
physical damage, comes from secondary aspects of the drug.  Lung cancer,  
for examples, is caused by the substances that accompany nicotine in  
tobacco smoke, not by nicotine itself.  It might be possible to get rid of  
some of these problems without getting rid of the pleasure, even if it is  
not possible to get rid of the addictions.  Another option is to develop  
tests which could tell people if they were at risk of falling under a  
particular spell so that they could choose their pleasures wisely.
	Eventually, an understanding of neurotransmitters, receptors,  
G-proteins, and second messengers might allow pleasure and addiction to be  
decoupled--or at least allow withdrawal to be suppressed.  Though, on the  
face of it, the effects that cause pleasure in the short term are those  
that cause addiction in the long term, there is a lot of variability in  
the system that might be exploited.  Techniques like those used to target  
specific dopamine receptors in the treatment of Parkinson's disease,  
might, at least in principle, be used to fine tune a drug's effects at the  
synapse and produce low-addiction highs.  And pure substances tailored to  
neurotransmitter sites would have a good chance of being free of  
unpleasant side effects elsewhere in the body.  That would not create a  
brave new world; it might, perhaps, create a slightly happier one.