Limitless Your brain on neuromodulators Tufts Ex College

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 • • Norepinepherine Dopamine Serotonin Acetylcholine excites synaptic plasticity inhibits modulates or excites

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=ti. HWc 2 w 8 -a. Y (landlady) • http: //www. youtube. com/watch? v=mieo. USD Np. Fg (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=ti. HWc 2 w 8 -a. Y (landlady) • http: //www. youtube. com/watch? v=mieo. USD Np. Fg (speaks italian)

Eddie Morra, Kung-Fu Master • http: //www. youtube. com/watch? v=sw. Ou. QBj bi. LU

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 • • Norepinepherine Dopamine Serotonin Acetylcholine AMPA, NMDA receptors GABA receptors NE receptors DA receptors 5 -HT receptors ACh receptors

Hyper-energy/focus http: //www. youtube. com/watch? v=l 4 XVLWX 2 c. MQ REDUCED Impulsivity

Hyper-energy/focus http: //www. youtube. com/watch? v=l 4 XVLWX 2 c. MQ Hyper-motivation/attention http: //www. youtube. com/watch? k. Ww. Fl. BI 4

Hyper-energy/focus http: //www. youtube. com/watch? v=l 4 XVLWX 2 c. MQ REDUCED Impulsivity Hyper-motivation/attention http: //www. youtube. com/watch? k. Ww. Fl. BI 4

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 (11 CMe. NER) is displaced by modafinil causing a reduction in the radioactive signal (Madras, JPharm. Exp. Ther 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)

Patience (aka serotonin) is a virtue • • 5 HT neuron lesions increase impulsivity Nucleus accumbens lesions increase impulsivity 5 HT 2 b receptor blockade in NAc increases impulsivity Decreased brain 5 HT increases impulsivity – Through 5 HT restrictive diet – Through 5 HT 2 b receptor variant (making 5 HT 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 100 g 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