Neurotransmitters

This is your brain on drugs, naturally.

“Just Say No” doesn’t apply to these drugs. Neurotransmitters are built-in drugs. You have to have them to make interconnections between neurons.

If the activity within a neuron is primarily electrical (though battery driven), the connections between neurons are typically chemical. Once a neuron’s depolarization reaches the terminal buttons, calcium channels are activated to release neurotransmitters into the synapse.

300+ types

• Most Common In Brain
  • Glutamate 90%
  • GABA 9%
• Other 1%
  • Monoamines
    • Dopamine
    • Norepinephrine
    • Epineprine
    • Serotonin
  • Acetylcholine

• 1. Catecholamines
  • Most abundant catecholamines
    • Epinephrine (adrenaline)
    • Norepinephrine (noradrenaline)
    • Dopamine
  • Molecules with a catechol nucleus
  • Benzene ring
    • 2 hydorxal side groups
    • Intermediate ethyl chain
    • 1 side-chain amine
    • Catechol
  • Dopamine
    • Derived from tyrosine
      • Dopamine
      • Nor-epinephrine
      • Epinephrine (adrenaline)
    • Tyrosine eaten or synthesized
      • Sent to catecholamine-secreting neurons
      • Water-soluble
      • 50% bound to plasma proteins
        • circulate in bloodstream
    • In blood, half-life of a few minutes
    • Degraded either by COMT
      • • (catechol-O-methyltransferases)
      • Or degraded by MAO
        • (monoamine oxidases)
        • Amphetamines and MAOIs bind MAO
        • Inhibit its action
        • Stops or slows breaking down
        • Why amphetamines have longer lifespan than cocaine
    • 5 types of receptors (D1….D5)
      • Also acts as a hormone
      • Released by hypothalamus
      • Inhibits release of prolactin from pituitary
    • Main source
      • Dopaminergic neurons
      • in midbrain
    • Dopamine level modulated by two mechanisms
      • tonic and phasic transmission
      • Tonic release
        • Small amounts are released
        • Independent of neurons
        • Regulates other neurons and neurotransmitter reuptake
        • Regulates intensity of phasic dopamine response
        • Sets background level
        • Sustained release
      • Phasic release
        • Neurons firing
        • Short-term activation
        • single spikes, and rapid bursts
        • 2-6 spikes in quick succession
    • Impacts
      • Cognition and learning
      • Motivation and voluntary movement
      • Sleep, mood, reward, punishment
    • If it’s addictive, it’s dopamine!
    • Controls flow of info
      • Frontal lobe to other areas of brain
      • Metacognition (memory, problem solving)
    • Maybe
      • Teaching signal?
      • Reward-anticipation?
      • Low Levels
        • Parkinson’s
          • Can’t give dopamine
            • (blood-brain barrier)
          • Give L-Dopa (levodopa);
          • Hope it’s turned into dopamine
      • High Levels
        • Euphoria
        • Orgasm
        • Reward
        • Drugs
        • Nicotine
          • increases dopamine in mesolimbic reward pathway
        • Addicts have altered pathways?
        • Cocaine
          • Blocks re-uptake
            • Takes very little stimulation to activate post-synaptic neuron
          • Cocaine blocks dopamine transporter
          • Cocaine also blocks norepinephrine transporter
            • (increase of up to 150 percent)
        • Cocaine vs. Meth
          • Both inhibit reuptake
          • Use different methods
        • Amphetamines
          • Structure similar to dopamine
            • Fool system
            • Get reuptaken instead
          • Force dopamine out of terminal buttons
            • Transporters work in reverse
            • Pump dopamine out
          • Schizophrenics
            • Reduced tonic dopamine release
            • Over time, causes subsequent phasic dopamine release
            • Abnormally large responses
            • Antipsychotic Drugs
              • Reduce dopamine
              • Reduce concentration, motivation, pleasure
              • Increase weight gain, fatigue, stroke, sexual dysfunction
  • Norepinephrine (NE)
    • Also called noradrenaline
    • Synthesized from dopamine
    • Both hormone and neurotransmitter
    • Stress Hormone
      • Released from adrenals into blood
      • Fight or flight response
      • Increasing heart rate
      • Increasing glucose
      • Increasing blood flow to muscles
      • Increases muscle tension
      • Increases vascular tone
      • Triggers compensatory reflex that drops heart rate
      • Reduce brain inflammation
    • In Brain
      • Stored in synaptic vesicles
      • Binds to adrenergic receptors
      • Impacts top-down perceptual processing
    • Signal termination by
      • Degradation
      • Reuptake by norepinephrine transporter
    • NT for sympathetic neurons
      • Regulates the heart
      • Increase in NE, increases contraction rate
    • Impact
      • Top-down perceptual processing
      • Attention
      • Low levels in ADHD
    • ********************
    • To Increase dopamine levels
      • Ritalin/Concerta
      • Dexedrine
      • Adderall
    • SNRI (selective norepinephrine reuptake Inhibitor)
      • Strattera (for ADHD)
      • Doesn’t also impact dopamine
    • Antidepressants
      • Increase NE and Serotonin
        • Effexor
        • Cymbalta
    • NE transporter might also reuptake some dopamine
    • *************************
  • Epinephrine
    • Hormone & Neurotransmitter
    • Also called adrenaline
    • As hormone
      • Associated with fear
      • Arouse body
        • increases heart rate, constricts blood vessels, dilates air passages
    • Given to treat
      • Cardiac arrest
      • Anaphylaxis
      • Superficial bleeding
      • Has been used for
        • Bronchospasm
        • Hypoglycemia
        • Now use
          • Salbutamol (synthetic epinephrine)
          • Dextrose
    • Local anesthetic injections
      • Add epinephrine to retard absorption
      • Bupivacaine
      • Lidocaine
    • Easily binds to most adrenergic receptors
      • Inhibits insulin secretion
      • Stimulate liver and muscles
      • Stimulates pancreas to release glucose
      • Stimulates pancreas to release ACTH
      • Regulates cortisol
    • Epinephrine Path
      • Tyrosine
      • L-DOPA
      • Dopamine
      • Norepinephrine
      • Epinephrine
    • Physiologic triggers
      • Noise & bright lights
      • Physical threat
      • Excitement
      • Hot rooms
    • “Adrenaline junkie”
      • Getting “high” on life
      • Dangerous activities
      • Always overwhelmed
      • Need for emergency
      • Endorphins released too
• 2. Indolamine
  • Tryptamine – also called indolamine
    • Serotonin
  • Serotonin (5-HT)
    • Regulates pain and stress
    • Opiate-like
    • Tryptophan
      • helps body produce niacin (B3)
    • Needed to produce serotonin
    • Serotonin is converted into melatonin
    • Stored in intestines
    • Released by liver into blood
    • Binds to platelets
      • When platelets bind to a clot, give off serotonin
    • Vasoconstrictor
      • Regulates clotting
      • Wound healing
    • In Brain
      • 5-HT released from varicosities
      • Not terminal buttons
      • Varicosities
      • Axon can have long chains of swellings
      • Near terminal branches
    • Receptors
      • At least 9 types
      • 5-HT3 is ion gate
      • All others are G-protein regulated
    • Impact
      • Regulate release of insulin
      • Mating behavior of males
      • Regulate growth
      • Regulate intestinal movements
      • Regulate mood, sleep, appetite
      • Serotonin regulates intensity of mood
      • Not change mood itself
      • Change perception of depression
      • Change perception of phobia
    • Too Much
      • In peripheral areas
        • Sudden increase is painful
        • Venom of wasps and scorpions
      • In Brain
        • LSD
        • Visual hallucinations
        • Psychedelic drugs increase serotonin
        • Psilocin-Psilocybin, DMT, Mescaline, LDS
        • MDNA (ecstasy), Mephedrome release serotonin
    • Low Levels
      • Depression
      • Prozac increases serotonin
      • Inhibits reuptake of 5-HT
      • Sudden Infant Death Syndrome (SIDS)
        • Defective serotonin signaling?
        • Not enough serotonin in brain stem, drop in heart rate?
      • To Increase
        • Stop from breaking down
          • Inhibit MAO wth MAOI
        • Stop reuptake
          • Inhibit reuptake with SSRI
        • Tricyclic antidepressants
          • Inhibit reuptake
            • Serotonin
            • Norepinephrine
    • Problems?
      • Chronic use of SSRI
      • Might lover baseline levels
      • Even if increase serotonin
      • Worse than when started
      • Switched meds usually resets it
    • Serotonin Syndrome
      • Extremely high levels
        • toxic and potentially fatal effects
      • To avoid too much of one:
      • SSRI & MAOI taken together
• Acetylcholine (Ach)
  • First neurotransmitter identified
    • small molecule substances
    • similar to amino acids but structurally different
  • Activates muscles
  • Impacts
    • Peripheral nervous system (PNS)
    • Central nervous system (CNS)
    • Major neurotransmitter in autonomic nervous system (ANS)
  • Inhibitory neurotransmitter
    • Slows heart rate
  • Excitatory neurotransmitter
    • Neuromuscular synapses
  • Activates Muscles
    • Binds to receptors
    • Opens sodium channels
    • Sodium ions enter muscle cell
    • Starts sequence that produces muscle contraction
  • Inhibits Heart Muscle
    • Different receptor
    • muscaninic
  • In CNS
    • Neuromodulator
    • Impact plasticity, arousal, reward
    • Enhances senses when wake up
    • Help us pay attention
    • Promotes REM sleep
    • Impacts short term memory
    • Increases response to sensory $
    • Facilitates transmission from thalamus to cortex
    • Reporting expected uncertainty?
  • Low Levels
    • Alzheimer’s disease
  • Two main receptor types
  • 1. Nicotinic Acetylcholine Receptors (AChR)
    • Ionotrophic
    • Sodium, potassium and chloride
    • Muscle and neuron types
      • Curare blocks muscle type
        • Stops quick effects
      • Myasthenia gravis
        • Muscle weakness and fatigue
        • Body produces antibodies against acetylcholine nicotinic receptor
        • Inhibits acetylcholine signal transmission
        • Destroys motor end plate
  • 2. Muscaninic Acetylcholine Receptors (mAChR)
    • Metabotrophic
    • In heart, lungs, sweat glands
    • Blocked by atropine
      • Deadly Nightshade
        • Poison-tipped arrows
        • Increases pupil size
          • For attractiveness in past
    • Sometimes used in cataract surgery
      • Causes pupil constriction
      • Miochol-E (CIBA Vision)