Download Drugs - The Ramirez Group

Limitless:
Your brain on
neuromodulators
Tufts Ex College
February 25, 2014
This week in preview
I. Limitless – discussion of Eddie Morra’s plight
II. Enhancing Cognition
I.
II.
Nootropics: Ritalin, Adderall, Modafinil
How they affect the brain: Synaptic Plasticity &
Neuromodulation
III. Hazards of stimulant use
IV. Discussion:
I.
II.
Limitless representation – realities and fictions
Off-label Adderall: Caffeine substitute or academic doping?
III. Impulsivity = one aspect of ADHD and addiction
I.
II.
Stanford Marshmallow test
Impulse control, serotonin and nootropics
Eddie Morra, Superhuman
Enhanced Cognition:
• Enhanced learning and memory (glutamate)
• Enhanced alertness and vigilance
(norepinephrine)
• Enhanced motivation and attention (dopamine)
• Decreased impulsivity (serotonin)
• Other observations: enhanced sensory
perception, memory recall, logical reasoning
Neurons communicate
…
Neurotransmitter
Neurons communicate
via neurotransmitters and receptors
Neurotransmitter
Six major neurotransmitters
…
• Glutamate
• GABA
 excites  synaptic plasticity
•
•
•
•
 modulates
 modulates
 modulates
 modulates or excites
Norepinepherine
Dopamine
Serotonin
Acetylcholine
 inhibits
Six major neurotransmitters
and where to find them
Glutamate producing neurons
GABA producing neurons
Neuromodulatory neurons and
their axonal projections:
Norepinephrine
Dopamine
Serotonin
Acetylcholine
Six major neurotransmitters
and where to find them
Glutamate producing neurons
GABA producing neurons
Neuromodulatory neurons and
their axonal projections:
Norepinephrine
Dopamine
Serotonin
Acetylcholine
Eddie Morra
Sudden Genius, Instant Polyglot
• http://www.youtube.com/watch?v=tiHWc2w8
-aY (landlady)
• http://www.youtube.com/watch?v=mieoUSD
NpFg (speaks italian)
Eddie’s ability to learn at lightening speed?
Synaptic Plasticity (LTP at glutamate synapses)
Eddie’s ability to learn at lightening speed?
Synaptic Plasticity (LTP at glutamate synapses)
Glutamatergic
Synapses
Eddie’s ability to learn at lightening speed?
Synaptic Plasticity (LTP at glutamate synapses)
(US)
(UR)
Eddie’s ability to learn at lightening speed?
Synaptic Plasticity (LTP at glutamate synapses)
Eddie’s ability to learn at lightening speed?
Synaptic Plasticity (LTP at glutamate synapses)
(CS)
(CR)
Six major neurotransmitters
and where to find them
Glutamate producing neurons
GABA producing neurons
Neuromodulatory neurons and
their axonal projections:
Norepinephrine
Dopamine
Serotonin
Acetylcholine
Eddie Morra
Sudden Genius, Instant Polyglot
• http://www.youtube.com/watch?v=tiHWc2w8
-aY (landlady)
• http://www.youtube.com/watch?v=mieoUSD
NpFg (speaks italian)
Eddie Morra, Kung-Fu Master
• http://www.youtube.com/watch?v=swOuQBj
biLU
Six major neurotransmitters
and where to find them
Glutamate producing neurons
GABA producing neurons
Neuromodulatory neurons and
their axonal projections:
Norepinephrine
Dopamine
Serotonin
Acetylcholine
Eddie’s ability to learn at lightening speed?
Synaptic Plasticity (LTP at glutamate synapses)
(CS)
(CR)
Eddie’s ability to learn at lightening speed?
Synaptic Plasticity (LTP at glutamate synapses)
(CS)
GABA producing neuron
(CR)
Six major neurotransmitters
and their receptors
• Glutamate
• GABA
AMPA, NMDA receptors
GABA receptors
•
•
•
•
NE receptors
DA receptors
5-HT receptors
ACh receptors
Norepinepherine
Dopamine
Serotonin
Acetylcholine
Six major neurotransmitters
and their receptors
• Glutamate
• GABA
AMPA, NMDA receptors
GABA receptors
•
•
•
•
NE receptors
DA receptors
5-HT receptors
ACh receptors
Norepinepherine
Dopamine
Serotonin
Acetylcholine
Hyper-energy/focus
http://www.youtube.com/watch?v=l4XVLWX2
cMQ
REDUCED Impulsivity
Hyper-energy/focus
http://www.youtube.com/watch?v=l4XVLWX2
cMQ
Hyper-motivation/attention
http://www.youtube.com/watch?v
kWwFlBI4
Hyper-energy/focus
http://www.youtube.com/watch?v=l4XVLWX2
cMQ
REDUCED Impulsivity
Hyper-motivation/attention
http://www.youtube.com/watch?v
kWwFlBI4
Nootropics
Enhance Cognition:
• Enhance learning and memory (glutamate)
• Enhance alertness and vigilance (norepinephrine)
• Enhance motivation and attention (dopamine)
• >>Decrease<< impulsivity (serotonin)
• Other observations: enhanced sensory
perception, memory recall, logical reasoning
The wide reach of neuromodulators
Glutamate producing neurons
GABA producing neurons
Neuromodulatory neurons and
their axonal projections:
Norepinephrine
Dopamine
Serotonin
Acetylcholine
Modafinil and norepinephrine
Modafinil blocks reuptake of NE
by binding NE transporter
NET
Modafinil and norepinephrine
Modafinil blocks reuptake of NE
by binding NE transporter
NET
PET (Positron Emission Tomography)
Radiolabeled ligand of NE transport (11CMeNER) is
displaced by modafinil causing a reduction in the
radioactive signal
(Madras, JPharmExpTher 2006)
Modafinil the stimulant
Binds dopamine transporter at cocaine binding site
(Volkow, JAMA 2009)
Modafinil the stimulant
Binds dopamine transporter at cocaine binding site
Dopamine
Modafinil
blocks
reuptake
by binding
DA transporters
• Binds at same site (ie. competes) with cocaine
• Makes more DA available to receptors (ie. Competes with
raclopride)
(Volkow, JAMA 2009)
Modafinil the stimulant
Binds dopamine transporter at cocaine binding site
Dopamine
Modafinil
blocks
reuptake
by binding
DA transporters
• Binds at same site (ie. competes) with cocaine
• Makes more DA available to receptors (ie. Competes with
raclopride)
(Volkow, JAMA 2009)
Patience (aka serotonin) is a virtue
•
•
•
•
5HT neuron lesions increase impulsivity
Nucleus accumbens lesions increase impulsivity
5HT2b receptor blockade in NAc increases impulsivity
Decreased brain 5HT increases impulsivity
– Through 5HT restrictive diet
– Through 5HT2b receptor variant (making 5HT less potent)
• Amphetamine, ritalin, adderall and modafinil decrease
impulsivity
• But not in mice lacking serotonin
Mischel’s marshmallow test
of delayed gratification or impulsivity
• Ability to delay gratification
in 18 years of follow-up,
claimed to be predictor of
success in school, happiness,
popularity
• 40 year follow-up study
found higher median income
among delayed gratifiers but
bimodal distribution among
instant gratifiers
Delay discounting
in animal models
(Louie & Glimcher, 2010)
Delay discounting
in animal models
100g of amino acid mixture:
(Schweighofer… Doya, Jneuro 2007)
Hazards of Nootropics
Ritalin and Adderall
(Amphetamine)
At doses higher than
prescription:
• Potential for abuse,
dependence, withdrawal
• Irregular heartbeat,
hypertension
• Reduced seizure threshold
• Obsessive behaviors
• Insomnia
Modafinil
• Sleep disturbances
• Cardiac problems in cases of
valve irregularities
• Abuse potential (less than
amphetamine,
controversial)
• Allergic reaction in liver
• Dermatological problems
Truism of the day
Off-label use (use by patients not diagnosed as
requiring treatment) has not been subjected to
long-term longitudinal studies.
Absence of evidence (of long-term harm) is NOT
evidence of absence
Public Service Announcement
Stimulation of dopamine
release by cocaine, heroin,
amphetamine, ritalin,
adderall, and modafinil
cause a homeostatic
decrease in dopamine
receptors.
Only thing known to
stimulate dopamine
and INCREASE dopamine
receptors:
EXERCISE
This week in review
• What Limitless gets right
–
–
–
–
Enhanced motivation (dopamine)
focus (norepinephrine)
learning and memory (plasticity at glutamate synapses)
Impact of alcohol, blackouts, tolerance
• Where it takes liberties
–
Exaggerated effects, both good and bad
•
•
•
•
Eddie writes a book in four days and learns languages just by listening;
can recall and bind details from very remote memories;
all but Eddie and Melissa die from the drug
Eddie appears to continue to function at full speed after weaning off the drug
• What it got wrong
–
–
Modafinil, Ritalin and Adderall decrease impulsivity, while Eddie shows
increased impulsivity and risk-taking
Decreased impulsivity by nootropics likely results from enhanced serotonin
action