This morning, Dr. Koob
will discuss the effects of alcohol on the female
brain. Thank you, Dr. Koob. [applause] Thank you, Deidra.
It's a pleasure to be here. I really want to thank Deidra
Roach and Cora Lee Wetherington for organizing this. I mean, I know it was an
enormous amount of work. I know -- Deidra didn't
tell you how skeptical I was that she would be
able to pull this off, but she did pull it
off and in a major way, and we were very pleased,
and kudos to both of you for this major effort. I also want to thank the Women,
Drinking, and Pregnancy Workgroup for their
contribution to this. So, and Andrea Barthwell, I
mean, you set me up perfectly, but what I haven't figured
out is how I advance the slide, so here we go. So, alcohol is a
growing women's health issue. You heard about this. I'll just emphasize a couple
of points that have struck me. Oh, and I want to mention that the reason Aaron
White is on this slide -- Aaron, where are you?
Wave your hand. Come on -- is that he did all the work on
this presentation, all right? And he did a
yeoman's job because he had to do it in a
very short time frame. But it is an area that
I've been quite interested in, and I'll explain to
you why as we move along. So over the last century, the
gaps between males and females have narrowed for
prevalence in drinking, total amount consumed,
frequency, binge drinking, early onset drinking,
having an alcohol use disorder, drunk driving, and
self-reported consequences. These are all facts. In the last decade, differences
have narrowed further for current drinking,
drinking days per month, past use of
DSM-IV alcohol abuse, and driving under the influence,
and women are more likely now, we know, to experience
blackouts, liver inflammation, brain atrophy, cognitive
deficits, and certain cancers, as you just heard
in elegant detail. In 2016, I was
charged by Michael Gottesman, who's in the Office
of the Director at NIH and directs all the
intramural programs at NIH, to do a review on what we
know about the neurobiology of sex differences in general, but that was way too
much beyond my pay grade, so I decided with Jill Becker that
we would do it on addiction, and the paper was published in Pharmacological
Reviews last year. But one of the
things that we noticed is a pattern that
evolved from this, and if you take the three
stages of the addiction cycle, which I will go through in
a minute, and as to what -- why they're relevant, but
binge intoxication, withdrawal, negative affect,
preoccupation, anticipation, or the craving stage, you
see definite patterns that overlap with the animal work,
and that is that in humans, the females take less alcohol,
although that's changing, but they escalate
the use more rapidly, as you already
heard, from Andrea. Now withdrawal/
negative affect stage, it's pretty
clear that in humans, females have a greater
response than males, and in stress and anxiety-induced
relapse it's the same thing, and I hope to give you a
little bit of neurobiological insight on why this may be the
case in the next few slides. But the bottom line is
that there's very little data, all right? At this point. So this was a review article, "Sex disparities and substance
abuse research: Evaluating 23 years of structural
neuroimaging studies." It's a really good article, but out of 230
structural neuroimaging studies on substance abuse, only 79
percent included both sexes, but only 26 percent of
those evaluated sex effects, and 85 percent of the studies
that did stratify by sex reported different effects
of substances on brain volumes, indicating the
importance of sex comparisons. So we're just at the beginning,
and I want to emphasize to you that when I joined NIH, you
know, the NIH in general, and Francis Collins, decided that
sex as a biological variable had to transcend all
elements of NIH's research. So, those of you who don't
do rat studies or mouse studies probably haven't noticed because
in human clinical studies we've been
including females all along, but now you are more or less
required to include females as a biological variable when
you do any research at NIH, whether it's a cell
line derived from stem cells all the way to, you
know, primate work, and so you're going to
see, as a result of this, an enormous increase
in our understanding of differences
between males and females. What I want to do is just very
quickly I want to talk about a couple of things relative to
sex differences in the brain, so I am gonna
focus on the brain. So the motives for alcohol use, the
reinforcement for alcohol use, the impact of alcohol on
brain anatomy and function, and then withdrawal and relapse. So in the paper that Jill and
I did, we identified four ways that males can be
different from females and females can be
different from males, okay? So there can be
qualitative differences. Obviously courtship
behavior in mammals, who takes care of the babies, all of these are qualitative
differences in behavior that are mediated
presumably by the brain. There can be
quantitative differences. As I know from rat studies,
female rats, for example, take a lot more cocaine
or drink a lot more alcohol than male rats. There can be
population differences. It could be the percent of males
that like a sweet solution versus the percent of females
that like a sweet solution, but what I'm going
to focus on today is the underlying
mechanisms can differ, and they can differ
in many different ways. They can be
completely different circuits, or I remember hearing of
a beautiful presentation just a couple years ago at the American College
of Neuropsychopharmacology. You can actually have the
same behavior manifested, but if you
actually image the brain or look into the
circuitry of that behavior, you'll find that females
get to the same place as males, or males get to the
same place as females, but they may be
using different circuits, or emphasizing
different circuits, or using a different transmitter
within that circuit. So we're in for some really
fascinating neurobiology, but then I'm a neurobiologist,
so I think it's fascinating. But let me give
you one quick example of the difference
between male and female brains, and that is that females develop more
interhemispheric communication, so it's maybe a little
difficult to see in this slide, but the male
communication within the cortex stays in the cortex, but the female
communication from the cortex, as you can see in
the bottom panels here, actually distribute themselves
into subcortical areas. So you can read into
this however you want. We're going to
ultimately have to figure out what exactly this
means about development. Those of you that
raise teenagers know that raising male
teenagers and female teenagers is a different ball of wax, so you can think
about this in that context. There's widespread differences
in morphology in adulthood that are being elucidated
with brain-imaging studies, and I just want to point out to
you two that may be relevant, and keep that in
the back of your mind, but in females
there's more gray matter in the medial prefrontal cortex, and in males
there's more gray matter in the anterior
cingulate cortex. This is without
drugs, and you can say, "Well, what on
earth does that mean?" Well, your medial
prefrontal cortex is the brake on your
reptile brain, okay? It's important for putting
the brake on executive function and making sure that you
don't make impulsive moves, so there may be something there, whereas the anterior
cingulate is more involved in hedonic activities and
releasing impulsive activity in your reptile brain. And it may be, indeed,
that these two differences illustrate what
I'm going to show you about the effects of
alcohol on the brain. So now you're going to
get a little Koob lesson on how the brain
works in addiction. This actually comes from a
paper that Nora Volkow and I published just last year in I
think it's Lancet Psychiatry. It's a further elaboration
of the neurocircuitry work that we've been
summarizing and integrating over the last 10
years, and the argument is -- and this was not handed
down on Mt. Olympus to Moses, and don't criticize my -- you
know, I had -- I said that once. It's obviously an oxymoron. I said that once and somebody
actually wrote me an email and said I should take religious
studies, but in any event -- [laughter] You know, this is heuristic. That means it's
something we use as a guide. So we know that addiction
follows a binge stage. It's a big problem in
alcohol use disorders. We know that when you're not
binging you're in withdrawal, and I want to emphasize
to you I'm talking about motivational withdrawal,
not physical withdrawal. I don't think alcoholics drink because they get
tremor, all right? And many of you
heard me say that before, and then in between there's
a craving that develops. It can develop
from many sources, but we call that the preoccupation/
anticipation stage, and you can make a
pretty good argument that the bits of the
brain that are involved in these stages are also
involved in functional domains. So for example,
incentive salience is a binge/intoxication domain. It's mediated largely
by the basal ganglia, the blue bit there in the brain, and it involves reward
and the linking of rewards to the environment, all right? And then the negative
affect stage is generally kind of the downer stage
where there's a reward deficit, but there's also a -- and you
heard Andrea talk about this -- a stress surfeit, an
activation of stress systems, and that's mediated largely
by amygdala, extended amygdala, a part of your brain that's
critical for fear-responses, fight or flight, and then
the craving is frontal cortex, as I alluded to earlier, and there's a bit of the frontal
cortex that can drive craving, and there's a bit
of the frontal cortex that can inhibit craving, and those can be
affected by drugs of abuse. And so you put this all
together, you can come up with neurotransmitters
that we know are involved, and so the questions are, do females start
drinking for different reasons? Do the reinforcing effects
of alcohol differ by sex? Does alcohol cause different
brain adaptations in females? Do withdrawal symptoms occur? Are they different
in males and females? And do the causes
of relapse differ? And we're only at the beginning,
only at the tip of the iceberg in trying to understand sex
differences in these domains, but I can assure you
that our portfolio at NIAAA, and I'm pretty
sure NIDA's portfolio, we are going to have
lots of data coming in in grants that
are currently funded. So just a couple
of quick things. We know that females
show smaller increases in sensation-seeking
during adolescence than males. This is something
we've known for a long time, that males are more likely to
show sensation-seeking behavior, and the same goes for
impulsivity in males, and this is, of course, a
component of taking that risk of engaging in over-drinking
or over-drug-taking in the binge/intoxication stage. And we also know that
females may be more motivated to drink alcohol for negative
reinforcement than males, and so this is a quote
from the Kuntsche paper where they say the results from the largest drinking
motive study conducted to date suggests that
gender-specific prevention should take differences
in the motivational pathways toward heavy
drinking into account. That is, positive reinforcements
used to be more important for boys and negative
reinforcement for girls. Now most of you
are very well aware of the construct of
positive reinforcement, so, you know, go to
Sea World in San Diego, watch the dolphin jump through
a hoop, and watch carefully, and you'll see the
trainer slip it a fish, okay? So that's positive
reinforcement, but negative reinforcement is a neglected
construct in psychology, and what it really
refers to is the fact that you are trying to
remove an aversive experience. So if you're
having an anxiety attack, and you're drinking to
suppress that anxiety attack, which is more frequent
in females than in males, that's negative reinforcement. You're trying to get rid
of something aversive, okay? And some of you have heard
this called self-medication. That came out in an earlier
talk, but one of the things we know is that drinking for
negative reinforcement really, in my opinion, is often
where you cross the line to what I would
consider a moderate to severe alcohol use disorder,
or what we used to call alcohol dependence, all right? And then anxiety and depression
symptoms and alcohol use among adolescents is
a study that was done, a cross-sectional study in Norwegian secondary-school
students, and, you know, increasing of the severity
of anxiety symptoms primarily associated with
alcohol consumption measures among girls, and so there may
be a link, as Andrea hinted at in her presentation,
between what I would call these negative affective
states and excessive drinking, and, as we'll
see, the telescoping that's associated with
women's substance abuse. And so I just said
this. I'll read the quote. "We proposed that males and
females have different pathways of vulnerability
to substance abuse. In adolescent boys, sensation-
seeking and impulsivity may drive drug and alcohol use, while stressful experiences in
comorbid internalizing disorders may mediate substance
use in adolescent girls." Those of you who
are as old as I am remember a guy named Bob
Cloninger, and, actually, Cloninger
proposed that there were two types of
alcoholics at the time. He proposed a type 1 and a type
2, and the type 2 alcoholic was the top part of this quote,
which would be impulse-seeking, sensation-seeking alcoholics,
and the type 1 alcoholic would be the relief alcoholic, and that fits more at the
bottom or the female phenotype. And I might add that Cloninger
predicted even back then, 40 years ago, 50
years ago now, that, in fact, his categorization
of type 1 and type 2 were indeed loaded
differentially for sex. So the exact differences
in why females and males drink are unclear, but
it certainly does appear that alcohol affects the
reward areas of the brain differentially in the two sexes, and this is a nice study done
by John Krystal's group at Yale -- I think it
was John Krystal -- which is that alcohol
induces less dopamine release in females than males, and
there's a linear relationship; you can see it there
between dopamine release and the subjective effects
in men but not in women. Dopamine is released in both males and
females when you drink. This was equivalent
of about three drinks, as I recall from the study, and some of you are going
to look at this and say, "Wait a minute. It looks
like there's less dopamine on the alcohol
side," and that is correct. It's actually
what you're measuring, dopamine D2 receptor
binding, so a decrease means that your
endogenous dopamine has bound to the receptor and decreased
that signal, all right? So low means high. You know? Sorry about that, but
it's a PET study. And even more intriguing
is that the ventral striatum is larger than controls
in binge-drinking females but smaller than controls
in binge-drinking males, and, you know, we don't really
know what this means as of yet, but it is in the
ventral striatum, and this is the basal
ganglia, and this is, we know, the structure that mediates the
rewarding effects of alcohol. You can interpret this
in many different ways. One would be that
females are protected here, but it could also mean that maybe
this is the beginning stages of suppression of
activity because of maybe an active neural inflammatory
mechanism, so, you know, I think the mechanism for
this remains to be determined, but there is a difference
between males and females in this reward pathway. And then females show a smaller
response of the amygdala to alcohol and corticosterone
in males as well. Could this prompt more drinking? And this is a fairly complicated
slide for my colleagues at the Scripps Research
Institute, Marian Logrip, who's now assistant professor
at Indiana University, but, you know, the difference,
there are differences. In the males,
ethanol or corticosterone reduced the activity of
these glutamatergic neurons. In both the lateral and
central nucleus, the amygdala, these are key
structures in fight-or-flight and stress responses,
but in females they reduce this activation produced by
glutamate less than in males. And so, you know,
it's the beginning of -- and this was just acute
binge-equivalent administration of alcohol and
measuring actually how these cells
fire in the amygdala. So the central nucleus to
the amygdala receives input from the basal lateral amygdala, which receives
input from the cortex, and so this is the way you -- when you go into a
freezing response when you're dodging a taxi at one of
the circles here in Washington, that freezing response is
the amygdala getting activated, and the pathway is through
your eyes to your cortex to your basal lateral amygdala
to the central nucleus, which innervates the freezing
response, and so, you know, there may be differences
in how males and females -- how alcohol
affects those responses. So one hypothesis
that I ascribe to is the differences in
neuroadaptation and stress circuitry could lead to differences in
motivational withdrawal, and so the quote here is, "Importantly there
is evidence that while severity of alcohol
withdrawal may not be substantially different
between men and women with similar drinking histories, the qualitative
nature of the withdrawal may be indeed divergent,
suggesting profound differences in neuroadaptation to alcohol
dependence in men and women." So during withdrawal from other
substances, perhaps alcohol, too, stress reactivity and
cortisol levels are higher in females than in males, and
this has actually been borne out with a study on fear-potentiated
starter results. This is a fairly
complicated slide, but the top
right-hand panel shows you that women show a much more
dramatic cortisol response when they are exposed to a
startle stimulus, you know, which is a fear-potentiated
startle stimulus, so where a cue has
been paired with something that makes you jump, all right? And the extinction is
also slower in females, and that's the
bottom left-hand panel. So, you know, there's
beginning to be hints that the brain of
females reacts differentially in the context of drugs of abuse during this withdrawal/negative
affect stage. And then we know that
females exhibit more damage to the hippocampus,
frontal lobes and other areas following repeated chronic
high-dose alcohol exposure than males. Could this be
contributing to larger cognitive deficits in females? Is this part of the escalation? Is this part of the telescoping to a more severe
alcohol use disorder? And it's a
hypothesis, but again, there are thicker
frontal cortex areas in binge-drinking females that are thinner than
in binge-drinking males. The red there is
the frontal cortex that I've been talking about. Again,
an intriguing observation. We're not exactly sure
what it means at this point, but there is a difference
between males and females in the third part of the
brain and in the third domain, which is this craving domain. So what do we know? Just to
summarize what I've told you, we know that females
may be more motivated by negative reinforcement. Males may be more motivated
via positive reinforcement. The reward system seems to be less responsive to
alcohol in females and shows fewer neuroadaptations
with repeated exposure. On the contrast, the stress
areas may be less affected by alcohol in females
initially, but chronic use may lead to greater
rebound increases in activity, may be related to cortisol. One of the little
things that they don't teach in medical school is
that if you have high chronic activation of cortisol, it drives the stress
systems in your brain, and I don't have
time to go into all that, but I'm going to repeat it. High chronic
administration of cortisol, because of chronic stress, it would normally
make you cushingoid, but there's a mechanism
in our brains to shut off the cortisol release
that's in the hypothalamus, and that works fine, but
there's another mechanism in the amygdala that cortisol is driving the
brain's stress responses, and it may indeed be that females
are more sensitive to that. There may be more
damage and inflammation in the female
brain during withdrawal, and chronic drinking
leads to thicker cortical areas in women but thinner in men. What we do not know
-- and there's a lot -- is how these neuroadaptations
in the neurocircuitry change over time versus males. We don't know the implications
yet, as Andrea said, for prevention and treatment, including
medication development, but I think this is a critical
area, as Andrea Barthwell said, particularly the
medications development. I don't know whether you all
know this, but Janine Clayton always uses this
example when she talks about male/female
differences, but if you are someone who takes
zolpidem, that's Ambien, okay, for jetlag, which is
to help you sleep -- it's a short-acting benzodiazepine-
like drug that's very effective in getting you five
hours of sleep, all right? But if you're a
female, you metabolize it at half the rate as a male. So if you actually take
20 milligrams of zolpidem because you're flying
from Europe and want to get a good night's sleep
before you land in Washington, you should not be
driving your automobile when you get out of the airport
if you're a female, because you're going to
metabolize that 20 milligrams a lot less than a male, and in
a lot shorter time, less time. So, you know, keep in
mind, there are differences. You know, it's unbelievable
when you think about it that these differences in medications
for psychiatric disorder are never or very
rarely considered, because they have
become critically important, and, of course, it's an area
that we're going to have to put a good bit of
emphasis on at the NIH. So again, I want to thank
you all for your attention. Special thanks to Aaron
White and Antonio Noronha, Jennifer Hobin, and Trish Powell for helping me get
these slides together. You know, our interest in
sex differences in the brain is a work in progress. Like I said, if I was to
give this talk next year, we'll probably
have even more data, and the year after even more
data. So thank you very much. [applause] I'm right on time.
I'm right on time.
