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?

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.

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

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

A Classical Study showing the RESTING MEMBRANE POTENTIAL

(RMP) of the Neuron

The RMP

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

“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.

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

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

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

Most Psychoactive drugs directly affect the chemical portion of the process

Action Potential at the Terminals

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…

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.

PRESYNAPTIC Exocytosis

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

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

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.

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

Some Basic Functions Associated with Different NT Families:

• Acetylcholine-(ACH,cholinergic)

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

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

Norepinephrine- (NE, noradrenergic, a catecholamine)

–Sympathetic ANS functions–hunger –mood

Noradrenergic system (Norepinephrine)

Dopamine- ( DA, dopaminergic, a catecholamine)

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

Schizophrenia.

Dopamine

Parkinson’s Disease

• Parkinson’s disease, dopamine and the substantia nigra

Parkinson’s disease and MPTP

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

•

Serotonin ( 5-HT, serotonergic, an indolamine)

• -sleep, dreaming, mood

Serotonergic System (Serotonin)

Endorphins

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

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

GABA

• Most prevalent inhibitory neurotransmitter in the brain

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

• Implicated in relaxation/anti-anxiety

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.

Neurotransmitters bind to receptor sites to produce postsynaptic effects

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

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?

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.

Effects depend on receptor subtype

Deactivation of NT’s

• Enzyme Breakdown• Reuptake

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…..

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

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

and blocking the action of ACHE).

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.

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

Reuptake

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

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

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

How Do Drugs affect the nervous system?

Ligand – a fancy term for substances that bind to receptors

-neurotransmitters-drugs

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

Drug Action

• Direct Agonist: Ligand Activates receptor

• Direct Antagonist: Ligand Blocks receptor

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

• Etc…

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

Acetylcholine

Muscarinic receptor -Atropine

Nicotinic receptor -Curare

Antagonists

Agonists

NicotinePhysostigmine

Dopamine• Cocaine

– dopamine reuptake inhibitor

• Amphetamine– increases DA release

• Antipsychotics– block post-synaptic

dopamine receptor

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

Serotonin

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

GABA

•Valium, Xanax, Ativan •Act as GABA agonists

•GHB, Rohypnol•GABA agonist