GLIA:NEUROSCIENTISTS EPIC BLUNDER FINALLY GETS A SEAT ON THE DOPAMINE ADDICTION SHUTTLE

I am not a scientist, but I have been inordinately lucky to have been exposed to some brilliant ones.
Approximately five years ago when my good friend and mentor, John, was moving to Virginia for health
reasons, I visited him. Seeing John put the image of Charles Darwin in your mind, with his unkempt
beard and his mad-scientist persona. However, when you got to know him, he had a humanistic quality
that when interspersed with his savant underpinnings, made you believe that you were in the presence
of Andy Griffith’s congeniality (who he sang in the choir with at Chapel Hill) coupled with Einstein’s
brain. Having won the Sputnik scholarship in the early sixties he had masters of physics from Princeton
and masters of biology from Brown. At the ripe old age of sixty-five he went and got an MSW and with
the luck of happenstance, I met him during a political campaign and we struck up a conversation and he
became my therapist. John’s passion for exploring the brain mechanisms behind addiction was
intoxicating for anyone with a curiosity about science. And he had a special affinity for discussing the
addiction process in the mesolimbic pathway-he referred to it as: the Dopamine Addiction Shuttle.

Going to John’s office/study in his home was like having tea with Socrates: voluminous books on the
shelves and biological and ecological artifacts strewn everywhere made you feel like you were in a
philosopher’s shrine. I especially liked the whale vertebrae and bear skeleton he picked out of the
garbage at Brown University. Although eighty-five and stricken with Prostate Cancer, John did not lose
one bit of passion. When he saw me walking up his drive-way he shouted out: “KEN WE WERE WRONG:
ADDICTION IS ABOUT GLIA-NOT JUST DOPAMINE AND GLUTAMATE!

One problem with John, with his Mensa brain he assumes everybody is as smart as he is-but that is what
makes him so likeable. He treats everybody like they were a professor. His deep empathy always made
you feel welcome; and even when I sometimes showed up blitzed 15 years ago, he never judged me
and I often would feel like Otis, the Mayberry drunk, when he invited me to sit down to a meal with him
and his late wife, Sally. But what the hell is GLIA? I asked him as we exchanged bear hugs. He replied
“they are the non-neuronal immune cells that are supposed to provide homeostasis in your brain-they
provide myelination, clean up insults and nourish and communicate with the neurons. But you better
not piss them off with unwanted toxins, like drugs or they will play havoc with your body and brain-
causing inflammation, friendly fires and all sort of untoward damage”. He then rattled of something
like “his damn cancer was caused by the inflammation of these bad glia cells that turned on mutant
genes”. Then without a pause he said “what are you doing tomorrow” and I said, “I had plans” and
disappointed, he uttered “Shoot, my son Charley is doing a simulcast from some major university on glia
and cancer”. Confused, I replied”Charley is a physicist(world renowned),what does that have to do with
cancer? “Charley is studying the evolutionary workings of genes with a bunch of other scientists, trying
to look at cancer from different angles-he got a big grant from a cancer institute” he replied.

Though I felt terrible about John’s health, his enthusiasm to see me made me feel great and when I told
him I was” clean “his passion was heightened. He was responsible for getting me to that exultant
plateau with his love and the unending lectures he gave me on the science of addiction. His use of
Bibliotherapy (book reading) and every cognitive behavioral therapy imaginable empowered me to
develop a foothold on the subject-which made it easier to own up to my own problem. I was someone
who always viewed my recovery from an intellectual plane, and John gave me that in spades.

John was relentless with his tutelage of the science of addiction. He was constantly drawings pictures of
the brain on napkins in pizza parlors-and the resultant indigestion was a small price to pay for the
ensuing new dendrites you grew listening to his always interesting take on brain science and
addiction(and they were just as good, whether you had regular or Sicilian). But the recent finding that
“glia” was a major culprit that brain science overlooked was a Eureka moment for him in the study of
addiction. Right then he took a pen and found the nearest napkin and started drawing his new
construct of what he always referred to as the “dopamine addiction shuttle”- only this time, glia was
onboard. After seeing John off, I realized what a renaissance man he was and how fortunate I was to
have been invited into his world all those years.

Well 5 years have passed since John and I said our goodbyes and I had recently heard from his son that
his cancer was in remission and he was doing well. I was feeling very guilty that I hadn’t touched base
with him, but that quickly changed after reading one of those scientific journals in the waiting room of
my neurologist’s office. I come across a tiny article in one of those sections, similar to “What’s New in
Medicine” or “New Frontiers in Pharmacology” and before me was a paragraph by some Australian
scientist purporting to the fact that glia inflammation was a major culprit in Alzheimer’s disease.
Immediately my mind went to John and that day 5 years ago when he was spewing his delight about glia
being the holy grail for understanding the brain-especially addiction This article caught more than my
attention when they mentioned that patients were experiencing a large reversal of Alzheimer’s with
spinal injections of the glia attenuator, Enbrel. Coincidently , I am on Enbrel for psoriasis and although I
knew that it was an auto-immune disease caused by the body turning on itself, it never occurred to me
that, Alzheimer’s, the dreaded brain insult is caused by the same friendly fire that my skin disease is.
But most intriguing for me was I had forgotten all about John’s passion for the salience of glia being a
major addiction modulator on that fateful day 5 years earlier.

I immediately called John in Virginia and shared with him my magazine encounter with glia. He laughed
and said, “they now are calling it gliosis-the study of glia inflammation- He told me,things were starting
to percolate in the Gliologist’s world” and he blurted out: “Damn, Ken you like to write about science,
especially about addiction. This construct is still in its embryonic days and its omission in the post-
modern scientific circles is clearly an epic failure of Homeric proportions and would provide an
interesting read, to say the least”. He then used a baseball analogy to say: “its (glia) glossing over by the
establishment is akin to ignoring the great talent of the Negro Baseball league in the early part of this
century. What were we thinking that we evolved with 90% glue in our brain and only 10% was useful?

Informing people that glia might very well be the missing link to the often spoken dopamine addiction
shuttle(as he always called it), might be your ticket to waking up some hell-bent scientific dogmatists
who refused to surrender their cognitive dissonance-heck I was hoodwinked too!. With this almost
boyish enthusiasm I asked him, if he wanted to co-write a piece and he said in a way only a friend of
John could appreciate:” Shoot I am too busy trying to figure out which is the mother lode of these 89
genes they just isolated as addiction perpetrators”. Once again the mad scientist is in front of the field
at 90, I thought! He then quipped: “get your hockey skates sharpened and bring me up to speed on
glia”. Enough said!

With my mission sending me into a seemingly foreign world: I started from the beginning with the
etymological meaning of “Glia”. The word can be traced back to a pathologist who in 1856 who named
glia after the Greek meaning of “glue” in what “Discovery magazine” referred to as a “frozen
mistake”: in that scientists erroneously thought that they were “merely passive support players” in the
brain-kind of like bubble wrap-and since the name, glia, is still used today( although it is anything but
glue) it fits the bill for this scarcely used euphemism. Glia’s diminutive role was upgraded over the years
to sort of a maintenance custodian, or using another hockey reference: similar to a Zamboni machine
that is used to clean up or repair any insults to the ice- so the integrity of the brain’s infra-structure was
stable. For purposes of my contextual addiction argument, the two most important types are microglia
and astrocytes. These glia cells are the non-neuronal component of the brain came to be known as
immune cells and they outnumber neurons by a 9-1 margin and also are vital in their protection of the
brain blood barrier and preventing toxic buildup at the synaptic clefts.

A major reason why glia was thought to be insignificant was because unlike neurons, they did not light
up when scientists employed electrodes and later MRI’s. As a psychiatrist friend joked to me:
“scientists are no different than anyone else-they like to see pictures light up”. That all changed in
1990- when a Yale researcher injected calcium into glia and all of a sudden they lit up. Quickly it was
discovered that astrocytes (the most numerous glia type) communicate with neurons through charged
calcium waves. In radio frequency lexicon it can said that: neurons are digital and glia represents
analoge encoding. This revelation was described by many as one of “sciences top blunders of all time”.

This unearthing of glia as formidable accomplices of neurons, sent a shockwave through the neuro-
science world. It was not long before researchers begin deciphering the surprising multi-tasking actions
of glia in the brain and central nervous system. In the early 90’s researchers isolated the TLR4 (toll like
receptors) that showed that not only did glia nourish the neurons, but that its immune role was
staggeringly larger than thought. The TLR4 were bunches of “watch dog” glia that alert the immune
system to any unnecessary intruders and when activated it sends out hazmat teams to access and fix
any abnormality. The problem is when glia is overloaded with stressors: they morph into double
agents where it no longer is putting out the fires and instead is pouring accelerant on them and create
egregious destruction that result in auto-immune diseases. Most importantly from our addiction stand-
point, they rewire the brain and make it fertile territory for exacerbating addictive behavior. This type
of pro-inflammatory behavior by glia is now referred to as gliosis.

Although a new window opened up in brain research with the TLR4 construct, it wasn’t until a decade
later that the realization that this “glia activation” not only caused a host of auto-immune disorders, but
made addiction researchers curious about its effect on drug addiction. However, glia as a major
participant evolved slowly and even today dopamine gets all the celebrity status in the science world,
with glutamate a distant second and glia an afterthought or mentioned in generic declarations such as:
“synaptic expression of spraying excitatory chemicals to boost dopamine liability in the reward
pathways” or “unknown involvement of non-neuronal cells, which fuel the firing of glutamate
pumps”,etc. While these explanations are correct in describing the glia processes, there is a certain
apprehension in using the words glia activation or gliosis and if you are lucky you might find the
“G”word hidden in the footnotes- similar to looking for: “baggage handler” or “assistant transportation
director” in the credits of a feature film. Although, there are a multitude of articles that talk about glia’s
hyper-expression in the promotion of drug and alcohol abuse-they tend to be presented in a vacuum
and do not elucidate on the dynamic interaction between these cells and neurons. Moreover, the
journal articles that do incorporate the entire “shuttle addiction construct” are subject to “peer review”
and their scientific jargon make it inaccessible to even savvy lay people. However, having said that, the
sheer intensity and complication of describing the interaction of glia with the pertinent
neurotransmitters involved in “the addiction shuttle” in one cogent accessible argument would be
painstakingly hard for even “Strunk and White”.

However, do not worry, here is where my many scientist friends do pro bono work for the good of
someone” writing about science”(like me) and not a “science writer” . So I was advised to start with the
simplistic shuttle argument without glia and then anecdotally fill you in on glia’s machinations. Let’s
begin: the dopamine shuttle starts in the Ventral tegmental area (VTA)loaded up with dopamine. Then
it travels upward into the Nucleur acumbus( NAC),where more dopamine is taken on as well as
glutamate(which triggers the release of dopamine and the anti-anxiety transmitter GABA),which further
primes the dopamine shuttle until it winds up flooding the Pre-frontal Cortex( PFC) with more
dopamine- thus wiping out the executive function and producing drug-laden behavior. Then the
glutamate gets resupplied and further excites the dopamine sending them back to the midbrain to
complete the dance and do it all over again. The essential point to remember is- dopamine gets you
addicted but glutamate keeps you addicted”

What about glia’s role? Now you’re talking my language! By using a NASCAR analogy I will show you
that glia is energizing the dopamine and glutamate at their respective receptors or pit areas throughout
the mesolimbic pathway, where fueling takes place along the synaptic cleft . Consequently glia serves
as a sort of “Pit Stop “where glutamate and dopamine neurons are sprayed with accelerant chemicals
and proteins then the glia pit-crews regroups for next addiction promising shuttle. The problem from
a public relational standpoint is dopamine almost always gets the most exposure on the proverbial “race
of the week”,Glutamate would make the nightly ESPN highlight real and glia would be lucky to get a
sound bite at the box-car derby. Fortunatly, as Douglas Fields, pioneering author of the Other Brain
repeatedly states, it is just a matter of time before scientists realize that glia needs to be fully integrated
as “partners that make the whole system work…,you can’t say one is more important than the other.
The important concept is that glia contribute something new something different”.

The overwhelming reality is glia becomes even more problematic in substance abuse, especially in
opiate use where the TLR4 toll receptor views all opiate drugs as neuro-toxins and after each
indulgence the potentiation factor of astrocytes and microglia attacks increases in severity and quantity-
thus compromising their analgesic effects and increasing the dopamine shuttle that originates in the VTA
and then floods the pre-frontal cortex. Consequently, a double whammy takes place where the
opiates pain relieving properties are mitigated and the pleasure-seeking component is heightened
with each glia activation. In other words, if you look at the TLR4 as the military base for inflammatory
glia and the commanding officer alerts the glia soldiers of incoming enemies (opiates), they are
dispatched to neutralize their weaponry(inhibiting the pain fighting properties) and call in their allies,
the dopamine/glutamate brigade, to further hype up the the dopamine shuttle by spraying them with
even more dopamine producing chemicals and to make sure they come back again- they are
“brainwashed” and imprinted at the various receptor sites to not forget how wonderful the party was!

No wonder, even legitimate users can quickly became addicted when the pain-relieving properties are
greatly undermined causing ensuing tolerance and adding insult to injury by heightening the pleasure
seeking components of opiates. This orchestrated dance might even seem like a dirty trick for those
legitimate users, who are just looking for analgesic efficacy and instead are hood-winked by immune
cells who were originally designed to aid in the injury quotient. What happened that glia cells who are
defined by the National Institute of Drug Abuse as: “cells that provide protective function to the brains
main cells (neurons)”would trigger adverse inflammation in the brain when confronted with drugs? Dr.
Linda Chang of the University of Hawaii answer is: when glia are confronted with molecules potentially
harmful to the brain, such as opiates or methamphetamine, glia mount a response resembling the
inflammation and scar tissue formation associated with immune responses in other parts of the body
leading to an increase in regional volume analogous to the swelling in immune responses.
Subsequently, continued abuse results in damage that is manifested in decreased cognitive
performance. In other words glia mistakenly sees these drugs as harmful invaders and excretes
chemicals to neutralize them as they would any other instigator-thus leaving tissue and neuron
damage in the process”.

Chang like most scientists feel that continued exposure to drugs like methamphetamine and morphine
actually leave structural changes in the brain from malfeasant glia reactions. While, the literature
suggests it is the heavy or moderate user that is at risk many other aspects and gene expressions are at
work to actually change and modify the brain’s plasticity. However, this “glia gone bad” construct can
be seen in almost all autoimmune diseases, especially those involving the TNF factor. The Tumor
Necrosis factor is a form of this sabotage where pro-inflammatory cytokines (form of microglia) go
haywire and over produce an inflammatory response that can cause cell death and disease. Such
diseases as Parkinson’s ,Altzheimers,multiple sclerosis, psoriasis and even Chrohn’s - to name a few are
implicated by this glia bombardment.

This author, who has suffered from psoriasis for years(as previously disclosed) owes a debt of gratitude
to Dr. Bruce Beutler for his working in isolating TNF and paving the way for TNF inhibiting drugs to
mitigate my pain-he was awarded the 2011 Medical Noble Prize for his efforts . While this class of
drugs, known as biologic response modifiers, have not been used to treat addiction brain liability
caused by excitatory glia ,unearthing the TNF construct has made it possible for ongoing
pharmacological therapies to explore inhibiting TNF in drug abuse. But, one side note that is
remarkable and unsettling at the same time: that scientists have revealed through understanding the
inflammatory effect of the glia, that Alzheimer’s is an auto-immune disorder. Correspondingly, it would
not be such a revolutionary thought, that addiction at the very least has components of an auto-
immunity? While this concept might be a bit of a reach it certainly should make anyone think twice,
before they start binging on any drug for a short-lived high.

It is important to mention that most gliosis research has been down with methamphetamine and
opioids, there have been recent studies that show alcohol, other psycho-stimulants and perhaps most
interesting “overeating” has implicated glia as a culprit. In the prestigious journal ,”Nature”scientist
Daniel Lee and colleagues were surprised to find mature glia, tancytes dividing in the hypothalamus-an
area of the brain not known to have mature neurons. After studying these dividing cells they were
shocked to find that the brain had been rewired and their food circuitry was “amped up” to respond to
the greater food intake (especially higher fat) that modern day humans pursue-they went on to suggest
this might explain how high diets in adolescence leads fat to obesity in adults.

To fully understate the pervasive nature of glia as a brain plasticity modulator, it is Important to realize
that glia kinetic energy is always at work through our lives by the process of pruning good and bad
neurons, in direct proportion to our age and health of our brains. Subsequently, how healthy we are
emotionally and the quality of nutritional substances that are brain are exposed to will determine from
birth the amount of toxic expressions our brains will encounter in life. I great example of this is research
done by Duke University and the University of Adelaide in Australia when they examined the immune
anti-inflammatory cytokine molecule (glia), Interleukin 10(which will be discussed in greater detail later)
in newborn mice to see how morphine exposure to this integral part of the reward center would play
out in relationship to the amount of nurturing they were given by their moms. They found the more
nurturing the pups received the greater amount of anti-addicting gene expression these mice
developed. By this programing of infant mice brains through nurturing researcher Mark Hutchinson
said: “one we have proven a mother’s touch changes brain function and two, we have demonstrated
an exciting way to intervene in the cycle of drug abuse. While this is just one example of glia’s role in
the nature vs nurture construct, it is safe to say that glia has a great memory.

Thankfully, there is now a great effort to find a better mousetrap to minimize gliosis as one NYU
neurologist says, “will be the holy grail of brain work for the next few years”. The money will be chasing
the buzz-phrase, “glia attenuator”, to find ways to reduce the hyper toxic effect of glia.

One major marker for down regulating or eliminating unwanted glia activation is focusing on the
previously mentioned,TNF Inhibitor ,interleukin 10: that lessens or knocks out the expression of pro-
inflammatory cytokines found in methamphetamine and opioid use which has the effect of greatly
minimizing drug craving. While this therapy is no being used in other glia cytotoxic diseases such as,
Parkinson’s and Multiple sclerosis, it is hopeful that the current interleukin- 10 studies being evaluated
on substance abusers will be successful.

Without question the most exciting and researched drug trying to harness the interleukin-10 properties
is Ibudilast(MN166), a 20 year old drug synthesized and used in Japan for the treatment of bronchial
asthma. The drug is in stage 2 clinical human trials with the company,Medici –nova, a small biotech in
California. The drug has a wide range of utility for attenuating TL4 signaling as well as TNF with what the
company says is an enhanced producer of Interleukin 10. According to the the graduate textbook,
MICROGLIA IN HEALTH AND DISEASE, co-editors Trembly and Sierra discuss its far reaching therapeutic
value for drug abuse: “This CNS directed anti-inflammatory, Ibudilast, has potential use in the improved
efficacy and safety of opioids and methamphetamine as it decreases drug reward, dependence,
withdrawal and reinforcement.

Aside from some other fringe compound/drugs that have proved some muster in some animal trials,
clearly the gold standard in glia suppression in addiction are the brother and sister of naloxone and
naltrexone. Both are opioid antagonists and both have a high affinity to the mu opioid receptor.
Naloxone, as we are all aware of has done some heroic lifesaving work, by reversing the opioid
intoxications within minutes-completing its job by blocking the microglia on the TLR4 receptor and
commandeering the u-opioid receptor and destroying the morphine inside. Since 98% of naloxone is
metabolized to an inactive metabolite it must be administered intravenously, subcutaneously or
intramuscularly.

Naltrexone, while similar to Naloxone it is used to maintain long term alcohol and opiate sobriety. FDA
approved Naltrexone for treatment of alcohol dependence 1994. The standard dose is 50 mg tablet per
day and judging by The Sinclair Method, which is a diagnostic tool quantifying drinking behaviors, it has
shown while people tend to lower their drinking amounts-complete abstinence was hard to achieve.
While the mechanism for action seems to be the mitigation of the dopamine conduit they are not
exactly sure of the extent of the buzz that is knocked out with alcoholics, but it does seem to lessen the
cravings.

Naltrexone also is used in opioid dependence to block the high the user gets. However, unlike alcohol
therapy, Naltrexone does not have much efficacy in mitigating the craving profile that exists with the
opiates. Naltrexone is administered in a daily pill form, which hinders its therapeutic value, because
opioid users become non-complaint due to the craving factor. Consequently greater efficacy is found
when a 30 day coverage product of Naltrexone, called Vivitrol, which is an injectable time-released
product. In fact, success has been so good with compliance during this current heroin epidemic, that
many people do not understand why it wasn’t used earlier (it was originally approved in 1984 for this
very reason) and more pervasively-especially upon release from rehab and prison, when the addict is
most vulnerable. Hopefully, this will become a reality in the near future.

In fact Naloxone success has been so strong, that in February University of Colorado researchers under
the leadership of gliosis pioneer,Linda Watkins, reported strong success in blocking the TLR4 capacity
as a dopamine agonist in cocaine abuse studies. Dr. Watkins further indicated that “it is likely to be
beneficial in treating a wide range of drug abuse”.

Quietly, while much of the opiate conscious world has its eyes and ears for the imminent release date of
the ultra-potent painkiller, Zohydro, another painkiller, Targinig ER, which will to my knowledge the first
opiate drug in the U.S. that combines oxycodone and naloxone in one pill. The efficacy here is what is
called by the company, a co- infusion: where the ultra-low dose Naloxone blocks the pro-inflammatory
cytokine and glutamate expression while preserving the full effect of the morphine. In other words,
the patient’s pleasure center award is blocked and the IL-10 modulator will preserve the full drug effect
and not have the tolerance problem. While, I cannot find much on this drug the FDA approved it
several months ago, but it has been available in other countries for some time. One question I have:
how will the blocking of the dopamine/glutamate reward pathway effect the drug user from a
physiological and psychological perspective? Theoretically, if you’re shutting off the glutamate receptor
that mitigates the GABA response and thus take some of the muscle relaxing/anxiolytic qualities that
have been known to help with pain, wouldn’t you be compromising the analgesic effect? Even if that
theory is dead wrong, isn’t Pavlovian cueing patterns at play: whereby once the thought that you
wouldn’t get a “buzz” from the opiate is eliminated, wouldn’t the placebo factor also cease?

I can’t deny that the study of Gliosis reads like a low-budget horror flick if you are still using drugs or
abused them in the past. As for myself I have to say after thinking about my history of abuse, I got all I
could out of the defense mechanism, denial, pretending my self-medication years where just an
innocuous way to put off joining the human race. In fact as I write, my conscious mind is entering a
cavern of those dark days; where that macabre public service commercial on TV of the egg in the frying
pan with the voice of a man saying: “this is your brain on drugs”. While back then I thought it was a
useless publicity stunt to mock my intelligence, today I give it credence: since it is still playing in
syndicated reruns in my audiovisual library in my head, digitally categorized under the heading Long-
term guilt. However, will I petition the Brain Library of Congress to re-list it under Miscellaneous Self
Pardons.

Lastly, I will leave you with some thoughts about how I feel about my life as a recovering addict after my
glia odyssey. First, my gratitude for being clean is greater than ever. Second, I am shocked that it
doesn’t take much to do a lot of brain degradation with drug use. Next, it is amazing how scientists
overlooked the importance of glia for so many years, just because it didn’t light up like neurons do. No
wonder we are addicted to computer screens? Finally, it is surreal that many people are not aware that
for all these years; the mythical justification for saying that we only use 10% of our brains originates
from the fact that scientists deemed glia, worthless glue. What a bummer because I am sure there
were some unlucky souls who thought they had almost eighty- nine eggs left before it made sense to get
clean. I just pray they turn off the frying pan before they are just left with toast.

I would like to thank my good friend, John and all patient reader’s for allowing me to be a gliologist
during this longer than expected period of trying to put a jigsaw puzzle together. For those scientists
out there: I want to apologize if I erred in the depiction of any construct or if integrity was lost by
simplifying the gliosis theory. Moreover, I hope I didn’t insult your intelligence with street vernacular
instead of proper nomenclature. After all, the relative dearth of existing robo-algorithmic abstracts- or
cognitive-crutch aids such as” Glia for Dummies” were scarce to none when I needed an accessible
reprieve from some intractable scientific concept, that made me hanker for a short vignette on the” life-
span of amoebas” . Fortunatly,as I said in my opening statement: “I am not a scientist ,but I have been
inordinately lucky to have been exposed to some brilliant ones-and once again they were as ubiquitous
as glia.

Kenneth Gaughran