How Do Drugs Affect the Nervous System?

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How Do Drugs Affect the Nervous System? .
Understanding Neural Transmission
Drugs act on Neurons and their communication with
other cells
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Beauty in the nervous system?
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The Basis of the Nervous System

• Neurons Single cell unit of the nervous system
• 10 billion in the brain alone
• Receives, processes and transmits information
• Each neuron in the brain received signals from
  thousands of other neurons.

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In most respects the neuron is like other cells
of our body
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But is different in that it can produce
electrical impulses near its cell body region
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A Classical Study showing the RESTING MEMBRANE
POTENTIAL (RMP) of the Neuron
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The RMP

• The RMP for a typical neuron is about -70mv

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Threshold voltage change (depolarization)
triggers the Action Potential
Hyperpolarization- in the case of neurons means
to make the RMP more negative. Depolarization
means to make the RMP more positive
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Once triggered, the AP is all or none, and
one-way.
The AP will travel to the terminal and there
initiate a chemical event
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The Neuronal communication process can be thought
of as an electro-chemical event.

• Most Psychoactive drugs directly affect the
  chemical portion of the process

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The Neuronal communication process can be thought
of as an electro-chemical event

• How is the electric signal produced?
• How is the Chemical event produced?

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The Neuron is Like a little battery
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Ions are responsible for the charge of a neuron
Cations Anions-
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The forces of Diffusion Concentration Gradients
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Diffusion also occurs across electrostatic
gradients
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The neural membrane is a semi-permeable membrane
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The Neurons membrane separates the different ions
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The membrane controls diffusion
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By opening or closingIon channels
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If ion channels are open diffusion across
concentration and electrostatic gradients will
occur
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Triggering the release of RMP energy

• How does threshold depolarization trigger a
  dynamic response?
• Changes membrane permeability
• Activating/opening ion channels
• -Voltage-gated Na ion channels
• Open only when a critical level of depol occurs
• Other ion channels then become involved

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Action Potential at the Terminals
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Terminal Boutons end adjacent to other cells
The Synapse- a very small space between the
boutons of one neuron and typically the dendrites
of another.
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The Synapse PRESYNAPTIC and POSTSYNAPTIC
processes
Any process associated with the terminal bouton
of Neuron A are considered to be presynaptic
processes. Any process associated with effects
of NT release on neuron B are considered
postsynaptic processes.
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PRESYNAPTIC Exocytosis
The Action Potential leads to release of
Neurotransmitter substance (exocytosis) into the
synapse.
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Synaptic release of Neurotransmitter substances
may in turn affect postsynaptic neurons
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Neurotransmitters
There are many different Neurotransmitter
Families.
Different NTs are found in different pathways and
are involved in different functions/ or different
components of functions.
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Some Classical NTs, terminology and postsynaptic
effects

• NTs Terminology
  Post synaptic effects
• Acetylcholine/ACH Cholinergic /-
• Serotonin/5-HT serotonergic /-
• GABA (gamma-amino-butyric acid) GABA-ergic -
• Glutamate/Glu Glutamatergic
• Norpinephrine /NE Adrenergic /-
• Dopamine /DA Dopaminergic /-
• Enkephalin/Endorphin /-
• Many other neurotransmitters are derived from
  precursor proteins, the so-called peptide
  neurotransmitters. As many as 50 different
  peptides have been shown to exert their effects
  on neural cell function.

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Some Basic Functions Associated with Different NT
Families

• Acetylcholine-(ACH,cholinergic)

-Skeletal Muscle control -Parasympathetic
Autonomic functions -Thirst -Memory Alzheimers
disease
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Pattern of projection pathways associated with
acetylcholine brain nuclei ( cholinergic systems
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Norepinephrine- (NE, noradrenergic, a
catecholamine)

• Sympathetic ANS functions
• hunger
• mood

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Noradrenergic system (Norepinephrine)
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Dopamine- ( DA, dopaminergic, a catecholamine)

• movement (Parkinsons disease)
• wanting
• mood
• attention, and learning.
• Dopamine excess may be involved in Schizophrenia.

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Dopamine
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Parkinsons Disease

• Parkinsons disease, dopamine and the substantia
  nigra

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Parkinsons disease and MPTP

• 1980s designer drugs MPPP/MPTPP and the case
  of the frozen addicts

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Serotonin ( 5-HT, serotonergic, an indolamine)

• -sleep, dreaming, mood

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Serotonergic System (Serotonin)
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Multiple types of synapses

• Multiple patterns of connectivity
• Axodendritic
• Axoaxonic
• Axosomatic
• Dendrodendritic

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Endorphins

• Modulate the experience of pain
• Involved in breathing and heart rate, cough
  reflex, nausea and vomiting
• Involved in feelings of euphoria and reward

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GABA

• Most prevalent inhibitory neurotransmitter in the
  brain
• GABA secreted by local interneurons all over
  the brain.
• Implicated in relaxation/anti-anxiety

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Glutamate

• Most prevalent excitatory NT.
• Involved in many brain circuits, but especially
  important in the formation of memories.
• Brain injury is associated with release of Glut.
  In high concentration, which in turn may be toxic
  to neurons.

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Neurotransmitters bind to receptor sites to
produce postsynaptic effects
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NT-Receptor Specificity
A given NT substance will only activate specific
receptor proteins, and can not activate receptors
for other NTs

• Lock Key Model
• NT key
• Receptor lock

Activation of a receptor will lead to either
Excitation or Inhibition.
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Two General Types of Receptor

• Ionotropic receptors the receptor is an ion
  channel
• Metabotropic receptors Activation of the
  receptor will in turn activate a second
  messenger chemical that may open or close ion
  channels

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IONOTROPIC RECEPTORS-
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Metabotropic Receptors
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How can one NT sometimes produce excitatory
postsynaptic effects and in other cases produce
inhibitory postsynaptic effects?

• NTs Terminology
  Post synaptic effects
• Acetylcholine/ACH Cholinergic /-
• Serotonin/5-HT serotonergic /-
• GABA (gamma-amino-butyric acid) GABA-ergic -
• Glutamate/Glu Glutamatergic
• Norpinephrine /NE Adrenergic /-
• Dopamine /DA Dopaminergic /-
• Enkephalin/Endorphin /-
• Many other neurotransmitters are derived from
  precursor proteins, the so-called peptide
  neurotransmitters. As many as 50 different
  peptides have been shown to exert their effects
  on neural cell function.

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One Neurotransmitter may activate any of a
family of receptor subtypes
ACH in the ANS can activate the Muscarinic ACH
receptor (mACH), a metabotropic receptor type.
Activation of the mACHr leads to an inhibitory
response.
ACH release in the somatic branch of the PNS
activates the Nicotinic ACH receptor (nACHr).
An ionotropic receptor type.
Activation of the nACHr leads to an excitatory
response.
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Effects depend on receptor subtype
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Deactivation of NTs

• Enzyme Breakdown
• Reuptake

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NT-receptor interactions must stop!Enzymatic
degradation
ACH is broken apart in the synapse by the enzyme
acetylcholine-esterase (ACHE).
The importance of the termination of NT-receptor
interactions is critical for normal function..
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Nerve Gases and their typical mechanism of
action
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Most nerve gases produce their effects by
blocking the breakdown of ACH ( by binding to and
blocking the action of ACHE).
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Effects of Nerve gas exposure
The blockade of ACHE leads to too much ACH in ACH
synapses, and exaggerated postsynaptic effects.
Neuromuscular Effects Autonomic NervousSystem Effects Central NervousSystem Effects
Twitching Weakness Paralysis Respiratory failure Reduced Vision Small pupil size Drooling Sweating Diarrhea Nausea Abdominal pain Vomiting Headache Convulsions Coma Respiratory arrest Confusion Slurred speech Depression Respiratory depression
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Monoamine Oxidase MAO

• MAO acts to break down NE and 5-HT

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Reuptake
The serotonin transporter enzyme is responsible
for terminating the effects of 5-HT in
serotonergic synapses
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Of Interest??? Selective serotonin reuptake
inhibitors- Bind to and reduce the effectiveness
of the 5-HT transporter
SSRIs approved to treat depression, with their
generic, or chemical, names followed by available
brand names in parentheses Citalopram (Celexa)
Escitalopram (Lexapro) Fluoxetine (Prozac,
Prozac Weekly) Paroxetine (Paxil, Paxil CR,
Pexeva) Sertraline (Zoloft) These medications
may also be used to treat conditions other than
depression. Side effects of SSRIs All SSRIs
have the same general mechanism of action and
side effects. However, individual SSRIs have some
different pharmacological characteristics. That
means you may respond differently to certain
SSRIs or have different side effects with
different SSRIs.
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Of interest??SSRI possible side-effects
Side effects of SSRIs include Nausea Sexual
dysfunction, including reduced desire or orgasm
difficulties Dry mouth Headache Diarrhea
Nervousness Rash Agitation Restlessness
Increased sweating Weight gain Drowsiness
Insomnia
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How Do Drugs affect the nervous system?
Ligand a fancy term for substances that bind to
receptors -neurotransmitters -drugs
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In general we classify drug effects into 2 basic
types
Drugs may act as Agonists- the Ligand may mimic
the NT and activate the receptor, or facilitate
the natural effects of the NT in indirect ways

• Drugs may act as Antagonists
• The ligand may block the receptor, or in indirect
  ways decrease the effect of the NT at its
  receptor.

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Drug Action

• Direct Agonist Ligand Activates receptor
• Direct Antagonist Ligand Blocks receptor
• Indirect agonism or antagonism
• Alters enzyme activity
• Blocks reuptake
• Etc

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Forms of Drug Action at the Synapse

• Ways to agonize
• Stimulate release
• Receptor binding
• Inhibition of reuptake
• Inhibition of deactivation
• Promote synthesis
• Ways antagonize
• Block release
• Receptor blocker
• Prevent synthesis

8. Autoreceptors
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Drugs may agonize or antagonize neural
transmission in many indirect ways.
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Acetylcholine
Agonists
Nicotine Physostigmine
Antagonists
Muscarinic receptor - Atropine Nicotinic
receptor - Curare
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Dopamine

• Cocaine
• dopamine reuptake inhibitor
• Amphetamine
• increases DA release
• Antipsychotics
• block post-synaptic dopamine receptor

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Cocaine acts as a monoamine agonist by blocking
the reuptake transporter enzyme
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Serotonin

• Selective-serotonin reuptake inhibitors (SSRIs)
  used to treat depression

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GABA

• Valium, Xanax, Ativan
• Act as GABA agonists
• GHB, Rohypnol
• GABA agonist

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Chronic Effects

• Depletion of transmitters
• Alter transmitter production
• Alter receptor density
• Affect neurogenesis

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Agonist/Antagonist

• Agonist
• Drug binds and induces full pharmacological
  effect
• Partial Agonist
• Drug binds and exerts only a partial effect
• Competitive Antagonist
• Binds to same receptor as agonist
• Reduces the effect
• Effect can be overcome by sufficient dose
• Noncompetitive Antagonist
• Binds in other ways, but disrupts agonist binding
  
• Reduces the effect
• Effect can not be overcome by sufficient dose

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Drug Interaction Terms

• Competitive antagonist
• competes for same receptor site
• lt affinity of NT
• Noncompetitive
• same binding site, gtgt affinity than NT
• or different binding site or receptor

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Neurotransmission