COGS 17 – Neurobiology of Cognition

Handout #4, Wednesday, October 22nd, 2008

Psychopharmacology aka The Chemical Soup aka Neurotransmitters

From action potential to action potential…:

WHAT?ACTION?

  1. Action potentialarrives at the terminal button
  2. Na+ influxcauses opening of voltage-dependent Ca++ channels
  3. Ca++ influxcauses vesicles to fuse with pre-synaptic membrane
  4. Vesiclesrelease NT via exocytosis
  1. NT diffuses across synaptic cleft
  1. Receptorsbind NT
  2. Ion channels open
  3. Ionsmove
  4. Membrane potentialchanges (EPSP if depolarized, IPSP if hyperpolarized)
  5. EPSP and IPSPsummate
  6. Membrane potentialreaches threshold
  7. Action potentialpropagates

FROM LECTURE:

* Step 4: (the life cycle of a neurotransmitter)

•1. Biosynthesis

•Precursors and enzymes located in soma and transported down axon

•At terminal, precursor ----(enzyme)----> NT

•2.Storage

•Vesicles also located in soma and transported down axon

•At terminal, just-made NT packaged in vesicles via transporters

•Filled vesicles docked (kept in place) by proteins

•3. Release same for all NT

•Na+ influx depolarizes membrane

•Voltage-dependent Ca++ channels open

•Ca++ influx causes vesicles to undock and move to membrane

•Exocytosis: Vesicles fuse and in the process release NT

•4. Receptor Action

•***NT receptor relation to ion channel? ***

•Both channel types are ligand-gated via NT binding to the receptor, versus the voltage-gated Na+, K+ and Ca++ channels

NT receptor location? / Directly/indirecty opens channel? / Speed of action? / Length of action?
Ionotropic / On ion channel / Directly
- via NT / Fast / Short
Metabotropic / Coupled to G-protein
Separate from ion channel / Indirectly
- via 2nd messenger / Slow / Long

•5. Inactivation

•Enzymatic destruction

•Reuptake via transporters

•(Recapture via endocytosis)

Criteria of a NT:

  1. Synthesized from neurons with appropriate biochemical machinery
  2. Released from neurons in response to an electric signal
  3. Produce physiological response in postsynaptic target
  4. Postsynaptic effects should be blocked by known antagonists
  5. Terminated by appropriate mechanisms

COGS 17 – Neurobiology of Cognition

Handout #4, Wednesday, October 22nd, 2008

* Step 5: (see Table 4.4, pp132-133 for drugs and their effect on different NT)

Summary of neurotransmitters, information compiled from lecture and textbook:

NT / Precursor / Receptor type / Inactivation / Function / Brain location/pathway
Amino acids / Sequential / Mostly I / Transporter / Sensory motor / Everywhere
Glutamate / + / Glutamine
Byproduct of Krebs / I: NMDA, AMPA
M: mGluR / Transporter / Learning, memory / Everywhere
GABA / - / Glutamate / I: GABAa
M: GABAb / Transporter / Regulate excitation / Interneurons
Biogenic amines / Sequential / Mostly M / MAO (monoamine oxidase) / Modulation of glutamate and GABA / Everywhere
Acetylcholine (AChR) / + / Choline
Acetyl CoA / I: nAChR
M: mAChR / AChE / *Help learning
*Form memories
*REM sleep / *Basal forebrain 
*Medial septum 
*Pons 
Norepinephrine (NE) / + / Dopamine / M: alpha 1,2
& beta 1,2 / Transporter, MAO / Arousal
Attention / Locus coeruleus (dorsal pons) EVERYWHERE!
Dopamine (DA) / +
- / Tyrosine / M:
D1
D2 / Transporter, MAO, COMT / *Movement
*Working mem/planning
*Reinforcement/addiction / *Nigrostriatal:
Substantia nigra  striatum (basal ganglia)
*Mesocortical: VTA C
*Mesolimbic: VTA L
Serotonin
(5-HT) / + / Tryptophan / 9 types
All M but 1 / Transporter, MAO / Mood, social cognition / Raphe cortex, basal ganglia, hippocampus
Neuropeptides/
Opioids
(ex. Endorphins) / - / Amino acids
-NT in vesicles before go to terminal / M / Proteases / Modulation / *Used in combination with other NTs
*Interneurons
*Everywhere, esp. limbic
Gases
(ex. Nitric oxide) / +/- / Arginine / N/A
Diffusion / Spontaneous oxidation / Vasodilation around brain / Metabolically active brain areas

COGS 17 – Neurobiology of Cognition

Handout #4, Wednesday, October 22nd, 2008

Information on NT receptors and NT action:

Gating of ion channels

–Ligand-gated (activated by NT/drug) in postsynaptic membrane,open after NT bind to receptor

–Voltage-gated (activated by specificmembrane potential) involved in action potential changes

Location of receptors

•Postsynaptic receptors

–Ionotropic

–Metabotropic

•Presynaptic

–Autoreceptor

•Located on the same terminal button that releases the NT

•Bind NT from same terminal button

•Metabotropic

•Do not control ion channels, no change in membrane potential

•Inhibits NT release via negative feedback

–Heteroreceptor (neuron #1  neuron #2  receiving neuron)

•Located on terminal button #2

•Bind NT from terminal button #1

•Also metabotropic

•Control calcium channels in terminal button #2

•If opens them, “presynaptic facilitation” by NT from #1

•More calcium  increases NT from #2

•If closes them, “presynaptic inhibition” by NT from #1

•Less calcium  decreases NT from #2

•Dendritic autoreceptors

–Located on dendrites of postsynaptic neuron

–Binds own NT

–Controls ion channels, causes hyperpolarization of postsynaptic neuron

Modifying the message: various ways…

•NT-related

•1. Biosynthesis

  • Changing synthetic enzyme levels

•3. Release

  • Changing vesicle number, NT number

•4. Receptor action

  • Changing receptor number (up/down-regulation)
  • Changing receptor affinity (low/high)

•5. Inactivation

  • Changing reuptake transporter number/affinity

•Neuron-related

•Axon growth

•Dendrite growth

Competitive binding: the molecule binds to the same site as the NT-binding site on the receptor

•Direct agonist – mimics the effects of a NT by opening the ion channel

•Direct antagonist – does not open the ion channel

Noncompetitive binding: the molecule binds to an alternative binding site on the receptor

•Indirect agonist–facilitates ion channel opening

•Indirect antagonist–prevents ion channel opening

Neuromodulators:

Brain chemicals in general are either…

•Neurotransmitterif impacts local neurons

•Hormoneif in/from bloodstream

•Neuromodulatorif travels long distances and impacts many neurons