Neurotransmitter Release:

1

• Neurotransmitter Release
• exocytosis and endocytosis

• Transmitter synthesized and stored
• Action Potential
• Depolarization open voltage-gated Ca2 channels
• Ca2 enter cell
• Ca2 causes vesicles to fuse with membrane
• Neurotransmitter released (exocytosis)
• Neurotransmitter binds to postsynaptic receptors
• Opening or closing of postsynaptic channels
• Postsynaptic current excites or inhibits
  postsynaptic potential to change excitability of
  cell

2

• Transmitter Inactivation
• reuptake and enzymatic breakdown

Reuptake by transporters (glial cells)
Reuptake by transporters
Enzymatic breakdown
Neurotransmitter can be recycled in presynaptic
terminal or can be broken down by enzymes within
the cell
3
NT Receptor Binding

• Receptors are large, dynamic proteins that exist
  along and within the cell membrane.
• Dynamic they can increase in number and avidity
  for their neurotransmitter according to
  circumstances.
• Two Types of Post synaptic Receptors
• Ionotropic receptors NT binding results in
  direct opening of specific ion channels
• Metabotropic receptors binding of NT initiates
  a sequence of internal molecular events which in
  turn open specific ion channels

4
NT binding -gt Membrane Potential Response
5
Ionotropic Receptors

• Work very fast important role in fast
  neurotransmission
• Each is made of several subunits (together form
  the complete receptor)
• At center of receptors is channel or pore to
  allow flow of ions
• At rest - receptor channels are closed
• When neurotransmitter binds -- channel
  immediately opens
• When ligand leaves binding site -- channel
  quickly closes

6
Metabotropic Receptors

• Work by activating other proteins called G
  proteins
• Each is made of several transmembrane regions
• Stimulate or inhibit the opening of ion channels
  in the cell membrane
• Work more slowly than ionotrophic receptors

7
Metabotropic Receptors

• Stimulate or inhibit certain effector enzymes
• Most effector enzymes controlled by G proteins
  are involved in synthesis of second messengers.
• First messenger ligand.
• Second messenger effector enzyme

8
Second messengers Activate Protein Kinases
Can work by affecting NT production, no.
synapses formed, sensitivity of receptors, or
expression of genes (long term effects). Can
result in amplification - interconnections.
9
Other Metabotropic Receptors

• Work more slowly than ionotropic receptors
• Though it takes longer for postsynapic cell to
  respond, response is somewhat longer-lasting
• Comprise a single protein subunit, winding
  back-and-forth through cell membrane seven times
  (transmembrane domains)
• They do not possess a channel or pore

10
Tyrosine Kinase Receptors
TrkA NGF TrkB BDNF and NT-4 TrkC NT-4
11

• Receptors superfamilies
• Ionotropic receptors (ligand-gated channels)
• Metabotropic receptors (G protein-coupled
  receptors)
• Tyrosine Kinase

Almost all neurotransmitters discovered so far
have more than one kind of receptor -- called
receptor subtypes.
12
Receptors are dynamic

• Large and prolonged intake of certain substances
  cause an increase in the number of receptors
  (basis of withdrawal response in addiction).
• Each NT influences its own receptors independent
  of the action of other receptors.
• Excitatory and inhibitory NTs.
• Post-synaptic neuron sums up the influences of
  all NTs.
• All or nothing response (must reach threshold
  to fire).

13
Receptors provide for temporal flexibility (ms to
decades)

• Multiple types of receptors exist for each major
  family of NT receptors.
• Example serotonin at least 14 subtypes exist
  based on potency of binding to different drugs.
• - Imitrix for migraines
• - Prozac for depression
• Affect different serotonin subtypes.
• Can develop drugs to target very specific
  receptors.
• Provides for much variety and subtlety of
  response in the human brain.

14
Richard Restak, MD, PhD

• The brain as a whole can be understood as the
  summation of billions of interacting neurons
  influencing one another via the interplay of
  hundreds of neurotransmitters and their
  receptors, which in turn influence the passage of
  electrically charged particles across the nerve
  cell membrane.

15
Pharmacology of Synaptic Transmission
Drugs affect synaptic transmission in many
different ways. They can act as agonists or
antagonists.
16
Synapses are targets for many recreational drugs
amphetamine cocaine
phencyclidine nicotine
neurotransmitter transporters
neurotransmitter-activated channels
postsynaptic cell
G protein coupled receptors
enzymes
G protein-activated channels
N
C
a
LSD morphine-heroin tetrahydrocannabinol
caffeine
?alcohol?
17
Nicotine

• Nicotine mimics acetylcholine at its receptor
  site.
• Called cholinergic or nicotinic receptor.
• Especially effective within the areas of the
  limbic system involved in the pleasure response.
• Prevents transmission of impulses at NM
  junctions.
• Evolved with plants to protect against insects
  (insecticide).
• Banded krait (Malayan snake) kills its
• prey by attacking the NM junction
• (paralyzes prey).

18
Nicotine experiment Keller and Schwartz

• Gave radioactively labeled nicotine to rats.
• Found gt number of nicotinic
• receptors vs. controls.
• Unusual receptors usually ? in numbers when
  there is a shortage of stimulation.
• Solution nicotine initially exerts a stimulatory
  effect (agonist), and then desensitizes receptors
  to render them nonfunctional for long periods.
• This stimulates the neurons to produce more
  receptors.

19
Nicotines Appeal

• Nicotine in the brain causes release
• of a wide variety of NTs, including endorphins,
  and dopamine (pleasure).
• Anxiety-reducing effects.
• Lessening of irritation and aggression,
  suppression of appetite (loss of weight).
• With repeated smoking, these effects diminish
  the brain becomes tolerant to nicotine.
• Smoker smokes more ? dependence.

20
Nicotine Addiction

• Brain has modified its functioning in
• response to regular nicotine hits.
• Smoker attempts to cut down craving
• due to events at nicotinic-acetylcholine
• receptors.
• Withdrawal irritability, frustration, anger,
  anxiety, difficulty concentrating, restlessness,
  decreased heart rate, increased appetite and/or
  weight gain.
• 70-80 of people who try to quit smoking relapse
  within one year.

21
Is nicotine a bad drug or a good drug?

• Alzheimers disease dramatically reduced number
  of cerebral nicotinic receptors.
• Could prescribe nicotine to increase receptors.
• Problems ethical considerations, possible
  unknown side effects, much testing to be done.
• At the level of the neuron there are no good or
  bad drugs, only drugs that alter the brain.
• Social and economic factors play a role.

22
Caffeine good or bad?

• Caffeine ingestion is almost universal.
• Leads to activation of cerebral cortex (EEG).
• Most helpful when a person is already tired.
• Caffeine blocks the brains receptors for
  adenosine, an inhibitory NT (inhibits release of
  excitatory NTs)
• Leads to stimulation, alertness, and an elevation
  of mood.

23
Caffeine the bad

• Too much restlessness, difficulty composing
  thoughts, vertigo, headaches, agitation, and an
  irregular heartbeat.
• Withdrawal headache, irritability,
  restlessness, and drowsiness.
• Headache due to caffeines ability to constrict
  BVs that feed the brain and scalp.
• Withdraw caffeine vasodilation ? headache.
• Addicting

24
Caffeine the good?

• Many over-the-counter headache remedies contain
  caffeine.
• Caffeines actions resemble those of amphetamines
  fatigue disappears, mood improves, and
  sociability is enhanced.
• It is very likely that new substances will be
  synthesized in the future that have similar
  desirable effects.
• Would these developments alter our tendency to
  put judgmental labels on commonly used substances
  that act on the brain?

25
Angel Dust, a.k.a. PCP

• Phencyclidine was first developed as an
  anesthetic no apparent side effects in animals.
• Humans 15 showed marked confusion, violence,
  and psychotic behavior as in schizophrenia.
• Became a popular street drug in the 1960s.
• At the same time, researchers were carrying out
  non-FDA approved experiments using PCP as a
  facilitator for psychotherapy.
• Also used as a model for schizophrenia.

26
PCP Side Effects

• Low dose induced a state resembling
  drunkenness.
• Larger doses person felt no pain (analgesic
  effect).
• High doses patient acted schizophrenic
  effects lasted about 4 hours.
• Afterwards depression, paranoia, and sometimes
  suicidal or homicidal behavior.
• Highest doses epileptic convulsions,
  respiratory depression, and death.
• Users found that bad effects could be reduced by
  smoking rather than ingesting the drug.

27
PCP the good

• In 1981, neuroscientists discovered a PCP
  receptor in the brain.
• Hypothesis PCP might be acting at the same sites
  in the brain responsible for schizophrenia.
• Couldnt confirm or disprove this hypothesis.
• However, this lead to many other discoveries that
  revolutionized treatment for stroke and other
  destructive brain injuries (excitotoxic theory
  glutamate).

28
Synapses are the targets of therapeutic drugs

• Antidepressant drugs
• serotonin uptake inhibitors
• Analgesics (morphine)
• opiate receptor agonists
• Antipsychotic drugs
• DA receptor antagonists
• Anticonvulsant drugs
• GABAA modulators
• Antianxiety agents
• GABAA modulators