Chapter 4

Electrical to Chemical Signal to Electrical/Psychopharmacology

The players:

a) Ion channels:

1) Signals that __transduce__ (change from one signal type to another)

a)Ligand Gated

  1. Ligand = a chemical that attaches to a binding site on a receptor
  2. Found in dendrites, cell body and axon terminal

b)Mechanically Gated

  1. Found in sensory systems (example: skin)

2) Signals that ___propogate___

c)Voltage Gated

  1. Found all throughout neuron membrane
  2. Propagate post-synaptic potentials and action potentials

b) Receptors:

NT receptor location? / Directly/indirectly opens channel? / Speed of action? / Length of action?
Ionotropic (ligand receptor) / On channel / Directly
- via NT / Fast / Short
Metabotropic (g protein coupled receptor) / Coupled to G-protein / Indirectly
- via alpha subunit / Slow / Long

c) Neurotransmitters; their lifecycle:

  1. Biosynthesis
  2. Differs for each neurotransmitter but each begins with precursor + enzyme = NT
  3. Storage
  4. Vesicles are created in the golgi apparatus
  5. Precursors, enzymes, and vesicles are transported down the axon to the terminal (microtubules)
  6. Once in the terminal, NT are synthesized and packaged into vesicles
  7. Release (See below)
  8. Receptors [See above (iono vs. metabotropic) ]
  9. Inactivation
  10. Destruction (enzymes break NT down)
  11. Diffusion (the process by which molecules spread from areas of high concentration, to areas of low concentration)
  12. Reuptake (by presynaptic receptors). For a picture: pg. 61

c.2) For specific neurotransmitters, see chart below

d)Regulation of axon terminal activity (how does a neuron know its fired too much or too little)

  1. Autoreceptor:
  2. Definition: Metabotropic receptors on the presynaptic neuron that respond to the neurotransmitter that they themselves release
  3. Purpose: to regulate the synthesis and release of the neurotransmitter; mostly inhibitory effects that is the presence of that NT causes a decrease in the rate of synthesis or release of the NT
  4. Picture: pg. 113, more information in chapter 2 pg. 63
  1. Heteroreceptor:
  2. Definition: Activation of neuron 1’s terminal button causes presynaptic inhibition OR facilitation of the neuron 2’s terminal button. The second neuron contains heteroreceptors that are sensitive to the NT released by neuron 1.
  3. Purpose: also to regulate synthesis and release of neurotransmitter possibly through regulating Ca++
  4. Example: Endorphins, Picture: pg. 113
  1. Retrograde signaling
  2. Definition: Post-synaptic cell sends messengers back to the presynaptic cell
  3. Example: If a post-synaptic neuron is receiving too much input, they may snip off a NT like 2-AG which resides in the cell membrane of the post-synaptic neuron. The 2-AG NT will float back to the pre-synaptic cell and bindto CB1. CB1 will slow down the entry of Ca++ to the cell.

The Game Plan

WHAT?ACTION?

  1. Action potentialarrives at the ___terminal button_____
  2. Na+ influxcauses opening of voltage-dependent/gated __Ca++__ channels
  3. Ca++ influxsevers__anchoring proteins__ and causes vesicles to fuse with pre-

synaptic membrane

  1. Vesiclesrelease NT via __exocytosis__
  2. NT diffuses across synaptic cleft
  3. Receptorsbind NT
  4. Ion channels open
  5. Ionsmove
  6. Membrane potentialchanges (__EPSP__ if depolarized, __IPSP__ if hyperpolarized)
  7. EPSP and IPSPsummate
  8. Membrane potentialreaches threshold
  9. Action potentialpropagates

Psychopharmacology (routes of administration of drugs and their fate in the body) [i.e. Big picture]

-Psychotropics: drugs affecting perception, mood and behavior

-Pharmacokinetics: the process by which drugs are absorbed, distributed, metabolized, and excreted within the body

  • Administration:
  • Injection (in muscles, underneath the skin, veins and more)
  • Oral (sublingual, inhalation)
  • Topical (directly into the skin, steroids)
  • Measurement:
  • Blood plasma
  • Microdialysis
  • Distribution:
  • Properties that affect absorption
  • Lipid solubility: molecules that are lipid soluble pass through cells easily & quickly
  • pH
  • Impediments to drugs
  • MAO in gut (will break down monoamines and inactivate certain NT)
  • Depot binding
  • Blood albumin: if the molecule is bound to a depot (like albumin) they cannot reach their sites of action
  • Fat cells: another example, most slowly, and less likely to interfere with the initial effects of the drug
  • Blood brain barrier: only lets fat soluble molecules pass; the faster a drug can get pass this the better the “high”

-Psychodynamics: effect the drug exerts

Drug Effectiveness

-How to measure?

Dose Response Curve:

Sites of Action: What are the many ways drugs can affect you?

Agonist
-chemical that facilitates post-synaptic effects
-example: AChE (acetylcholinesterase) breaks down ACh. In a patient with ACh deficit, can block enzyme so that ACh can continually stimulate a post-synaptic cell. So a chemical that blocks AChE is a ACh agonist. / Antagonist
-chemical that block or inhibit post-synaptic effects
-example: a choline reuptake blocker would prevent choline from re-entering the cell thereby preventing the re-synthesis of ACh / Inverse Agonist
-chemical that binds to the receptor site of an agonist but reverses the activity of the receptor
-example: if a zinc ion binds with the zinc binding site on an NMDA receptor, the activity of that receptor is decreased

Drugs can be either:

Indirect
-chemical that binds to a receptor site other than the primary receptor site or indirectly affects the effectiveness of a drug
-example: benzodiazepines promote the activity of the GABAa receptor and therefore is an indirect agonist / Direct
-chemical that binds directly to the primary binding site and directly affects the effectiveness of a drug
-example: muscimol binds to the GABA binding site and serves as a direct agonist.
Non-competitive binding
-a receptor has a separate neuromodulator binding site. The molecule does not compete with molecules of
-example: GABAa has a separate receptor for specific drugs (benzodiazepine) / Competitive binding
-drug binds at the exact same receptor site as a neurotransmitter
-example: direct agonist
NT / E/I / Precursor / Receptor type / Inactivation / Function / Brain pathway
Amino acids / Sensory motor / Everywhere
Glutamate / + / Glutamine
Byproduct of Krebs / I: NMDA, AMPA, kainate
M: metabotropic glu receptor
[NMDA: 6 binding sites: (glu, gly, polyamine, zinc, mg, PCP), also known as an AND gate= will only open if there is depolarization and glu binds] / Reuptake / Direct excitatory effects in brain and spinal cord raise or lower the threshold of excitation affecting the rate of action potentials / Cortex  cortex
GABA / - / Glutamate / I: GABAa (controls Cl-)
M: GABAb (controls K+)
[GABAa, at least 5 binding sites: (GABA, benzodiazepine, steroid, picrotoxin, barbiturate) / Reuptake / Direct inhibitory effects throughout brain and spinal cord / Cortex  cortex
Biogenic amines / Modulatory / Midbrain  Cortex
Acetylcholine (ACh) / + / Choline
Acetyl CoA / I: nicotinic; in skeletal muscles
-agonized by: nicotine
-antagonized by: curare
M: muscarinic; in smooth muscle
-agonized by: muscarine
-antagonized by: atropine / -AChE (acetylcholinesterase), eventual reuptake of choline / -Primary NT secreted by efferent axons in CNS and 1st discovered
-Help learning (basal)
-Form memories (medial)
-REM sleep (pons) / -Basal forebrain 
-Medial septum 
-Pons 
Norepinephrine (NE)
Catecholamine / + (general) / Tryosine  L-DOPA
DopamineNE / M: α1 & β1-2 (post-syn, excitatory)
α1 (autoreceptor, inhibitory) / Reuptake, MAO (monoamine oxidase) / -Arousal
-Attention
-Increases vigilance / Locus coeruleus (dorsal pons)  EVERYWHERE!
Dopamine (DA)
Catecholamine / +
- / Tyrosine (AA) 
L-DOPA / M:
D1 (post-synaptic)
D2 (pre & post-synaptic) / Reuptake, MAO / -Movement
-Working mem/planning
-Reinforcement/addiction / -Nigrostriatal pathway:
Substantia nigra  striatum (BG)
-Mesocortical: VTA Cortex
-Mesolimbic:VTA Limbic
Serotonin
(5-HT)
Indolamine / + / Tryptophan / 9 types
All metabotropic but 1 / Reuptake, MAO / -Mood, social cognition
-Suppresses certain categories of species-typical behavior / Raphe nucleus (in pons, midbrain, medulla)  cortex, basal ganglia, hippocampus
Neuropeptides/ Opioids
(ex. Endorphins) / - / Amino acids / 3 all Metabotropic:
mu: most analgesic effects
delta: some analgesic effects
kappa: negative side effects / Enzymes (no reuptake) / -Act as both NT and NM
-Modulation of effects of other NT / -Used in combination with other NTs
-Everywhere, esp. limbic