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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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How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Jan 04, 2016

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Berenice Hardy
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Page 1: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission

Drugs act on Neurons and their communication with other cells

Page 2: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Beauty in the nervous system?

Page 3: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.
Page 4: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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.

Page 5: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

In most respects the neuron is like other cells of our body

Page 6: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

But is different in that it can produce electrical impulses near its cell body region

Page 7: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

A Classical Study showing the RESTING MEMBRANE POTENTIAL

(RMP) of the Neuron

Page 8: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

The RMP

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

Page 9: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

“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

Threshold level of depolarization

Triggers anACTION Pot.

Page 10: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Once triggered, the AP is all or none, and “one-way.”

The AP will travel to the terminal and there initiate a chemical event

Page 11: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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

Most Psychoactive drugs directly affect the chemical portion of the process

Page 12: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Action Potential at the Terminals

Page 13: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

The Synapse- a very small space between the boutons of one neuron and typically the dendrites of another.

Terminal Boutons end adjacent to other cells…

Page 14: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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.

Page 15: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

PRESYNAPTIC Exocytosis

The Action Potential leads to release of Neurotransmitter substance (exocytosis) into the synapse.

Page 16: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Synaptic release of Neurotransmitter substances may in turn affect “postsynaptic” neurons

Page 17: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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.

Page 18: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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.

Some Classical NTs, terminology and postsynaptic effects

Page 19: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Some Basic Functions Associated with Different NT Families:

• Acetylcholine-(ACH,cholinergic)

-Skeletal Muscle control-Parasympathetic Autonomic functions-Thirst-Memory: Alzheimer’s disease

Page 20: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Pattern of projection pathways associated with acetylcholine brain nuclei ( cholinergic systems

Page 21: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Norepinephrine- (NE, noradrenergic, a catecholamine)

–Sympathetic ANS functions–hunger –mood

Page 22: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Noradrenergic system (Norepinephrine)

Page 23: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Dopamine- ( DA, dopaminergic, a catecholamine)

– movement (Parkinson’s disease)– “wanting” – mood– attention, and learning.– Dopamine excess may be involved in

Schizophrenia.

Page 24: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Dopamine

Page 25: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Parkinson’s Disease

• Parkinson’s disease, dopamine and the substantia nigra

Page 26: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.
Page 27: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Parkinson’s disease and MPTP

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

Page 28: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Serotonin ( 5-HT, serotonergic, an indolamine)

• -sleep, dreaming, mood

Page 29: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Serotonergic System (Serotonin)

Page 30: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Endorphins

• Modulate the experience of pain• Involved in breathing and heart rate, cough

reflex, nausea and vomiting • Involved in feelings of euphoria and reward

Page 31: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

GABA

• Most prevalent inhibitory neurotransmitter in the brain

• GABA secreted by “local” interneurons all over the brain.

• Implicated in relaxation/anti-anxiety

Page 32: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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.

Page 33: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Neurotransmitters bind to receptor sites to produce postsynaptic effects

Page 34: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

NT-Receptor Specificity

Activation of a receptor will lead to either Excitation or Inhibition.

Lock & Key Model NT = key Receptor = lock

A given NT substance will only activate specific receptor proteins, and can not activate receptors for other NTs

Page 35: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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.

How can one NT sometimes produce excitatory postsynaptic effects and in other cases produce inhibitory postsynaptic effects?

Page 36: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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.

ACH release in the somatic branch of the PNS activates the “Nicotinic” ACH receptor (nACHr). An ionotropic receptor type.

Activation of the mACHr leads to an inhibitory response.

Activation of the nACHr leads to an excitatory response.

Page 37: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Effects depend on receptor subtype

Page 38: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Deactivation of NT’s

• Enzyme Breakdown• Reuptake

Page 39: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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…..

Page 40: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

“Nerve Gases” – and their typical mechanism of action…

Page 41: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Most nerve gases produce their effects by blocking the breakdown of ACH ( by binding to

and blocking the action of ACHE).

Page 42: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Effects of Nerve gas exposureNeuromuscular

Effects

Autonomic Nervous

System 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

The blockade of ACHE leads to too much ACH in ACH synapses, and exaggerated postsynaptic effects.

Page 43: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Monoamine Oxidase: MAO• MAO acts to break down NE and 5-HT

Page 44: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Reuptake

The serotonin transporter enzyme is responsible for terminating the effects of 5-HT in serotonergic synapses

Page 45: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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.

Of Interest???

Selective serotonin reuptake inhibitors- Bind to and reduce the effectiveness of the 5-HT transporter

Page 46: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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

Page 47: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

How Do Drugs affect the nervous system?

Ligand – a fancy term for substances that bind to receptors

-neurotransmitters-drugs

Page 48: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

In general we classify drug effects into 2 basic types:

• Drugs may act as Antagonists: • The ligand may block the receptor, or in indirect ways

decrease the effect of the NT at its receptor.

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

Page 49: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Drug Action

• Direct Agonist: Ligand Activates receptor

• Direct Antagonist: Ligand Blocks receptor

• Indirect agonism or antagonism• Alters enzyme activity• Blocks reuptake

• Etc…

Page 50: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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

Page 51: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Acetylcholine

Muscarinic receptor -Atropine

Nicotinic receptor -Curare

Antagonists

Agonists

NicotinePhysostigmine

Page 52: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Dopamine• Cocaine

– dopamine reuptake inhibitor

• Amphetamine– increases DA release

• Antipsychotics– block post-synaptic

dopamine receptor

Page 53: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

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

Page 54: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

Serotonin

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

Page 55: How Do Drugs Affect the Nervous System? …. Understanding Neural Transmission Drugs act on Neurons and their communication with other cells.

GABA

•Valium, Xanax, Ativan •Act as GABA agonists

•GHB, Rohypnol•GABA agonist