Psychopharmacology aka The Chemical Soup aka Neurotransmitters by linzhengnd


									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 potential                    arrives at the terminal button
   2. Na+ influx                          causes opening of voltage-dependent Ca++ channels
   3. Ca++ influx                         causes vesicles to fuse with pre-synaptic membrane
   4. Vesicles                            release NT via exocytosis
   5. NT                                  diffuses across synaptic cleft
   6. Receptors                           bind NT
   7. Ion channels                        open
   8. Ions                                move
   9. Membrane potential                  changes (EPSP if depolarized, IPSP if hyperpolarized)
   10. EPSP and IPSP                      summate
   11. Membrane potential                 reaches threshold
   12. Action potential                   propagates

* 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     Speed of       Length of action?
                                                opens channel?         action?
Ionotropic        On ion channel                Directly               Fast           Short
                                                - via NT
Metabotropic      Coupled to G-protein          Indirectly             Slow           Long
                  Separate from ion channel     - via 2 messenger
   • 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             I: NMDA,         Transporter           Learning, memory      Everywhere
                         Byproduct of      AMPA
                         Krebs             M: mGluR
             GABA -      Glutamate         I: GABAa         Transporter           Regulate excitation   Interneurons
                                           M: GABAb
Biogenic amines          Sequential        Mostly M         MAO                   Modulation of         Everywhere
                                                            (monoamine            glutamate and
                                                            oxidase)              GABA
     Acetylcholine + Choline               I: nAChR         AChE                  *Help learning        *Basal forebrain 
            (AChR)       Acetyl CoA        M: mAChR                               *Form memories        *Medial septum 
                                                                                  *REM sleep            *Pons 
   Norepinephrine      +    Dopamine          M: alpha 1,2     Transporter,       Arousal               Locus coeruleus (dorsal
             (NE)                             & beta 1,2       MAO                Attention             pons)  EVERYWHERE!
   Dopamine (DA)            Tyrosine          M:               Transporter,       *Movement             *Nigrostriatal:
                       +                      D1               MAO, COMT          *Working              Substantia nigra  striatum
                       -                      D2                                  mem/planning          (basal ganglia)
                                                                                  *Reinforcement/addi   *Mesocortical: VTA C
                                                                                  ction                 *Mesolimbic: VTA  L
         Serotonin     +    Tryptophan        9 types          Transporter,       Mood, social          Raphe  cortex, basal
            (5-HT)                            All M but 1      MAO                cognition             ganglia, hippocampus
Neuropeptides/         -    Amino acids       M                Proteases          Modulation            *Used in combination with
Opioids                     -NT in vesicles                                                             other NTs
  (ex. Endorphins)          before go to                                                                *Interneurons
                            terminal                                                                    *Everywhere, esp. limbic
Gases                  +    Arginine          N/A              Spontaneous        Vasodilation around   Metabolically active brain
  (ex. Nitric oxide)   /-                     Diffusion        oxidation          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 specific membrane 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
Brain chemicals in general are either…
    • Neurotransmitter           if impacts local neurons
    • Hormone                    if in/from bloodstream
    • Neuromodulator             if travels long distances and impacts many neurons

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