How Do Drugs Affect the Nervous System. … 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. Neuron is the building block of the nervous system A unique type of cell that can communicate with each other Soma or cell body contains the genetic material for the neuron Axon is enclosed in a sheath of white, fatty material called myelin which provides insulation for the axon MS is a disease which results from damage to the myelin sheath; illustrated by uncoordinated, jerky movements Body attacks itself basically Axons primary function is to conduct electrical current (transmit info this way) called an action potential Action potentials are produced by the flow of charged particles (ions) through channels in the myelin When the neuron is at rest, more positively charged particles on the outside than inside, but when action potential begins the channels open and positive ions flow in and produce a charge around 110mV Action potential is all or none meaning it’s either firing with full voltage or at rest; once it’s fired positive ions are pumped back out, channels close and neuron returns to rest (resting potential)

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 Triggers an ACTION Pot. Threshold level of depolarization

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

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?

The Neuron is Like a little battery

Ions are responsible for the charge of a neuron Cations + Anions-

The forces of Diffusion: Concentration Gradients

Diffusion also occurs across electrostatic gradients

The neural membrane is a semi-permeable membrane

The Neurons membrane separates the different ions

The membrane controls diffusion

By opening or closing Ion channels

If ion channels are open; diffusion across concentration and electrostatic gradients will occur

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

Action Potential at the Terminals

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.

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.

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.

Some Basic Functions Associated with Different NT Families: Acetylcholine-(ACH,cholinergic) -Skeletal Muscle control -Parasympathetic Autonomic functions -Thirst -Memory: Alzheimer’s disease Claude Bernard & Curare

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

Norepinephrine- (NE, noradrenergic, a catecholamine) Sympathetic ANS functions hunger mood

Noradrenergic system (Norepinephrine) also called norepinephrine Also found outside the brain Mediates the physical changes that accompany emotional arousal Important in regulating hunger, alertness, and arousal Depletion is linked to depression Resperine (a blood pressure medication) found to cause leaky vesicles thus destroying the nts and depleting the levels and resulting in depression in persons whose moods were normal before treatment Drugs that treat depression successfully generally influence serotonin or NE

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) Found throughout brain and important in sleep regulation Also linked with depression and schizophrenia

Multiple types of synapses Multiple patterns of connectivity Axodendritic Axoaxonic Axosomatic Dendrodendritic 6.1

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 GABA opens ion channels that don’t cause the neuron to fire but rather prevent it If a neuron has a GABA ergic receptor site that’s activated, a larger quantity of the excitatory NT is needed to make the neuron fire Barbituates tranquilizers, valium, librium and alcohol all act on the GABA system Another NT glutamate is one of the most abundant excitatory NTs and hallucinogenics like PCP act on glutamate receptors Adenosine is another inhibitory NT that’s blocked by caffeine and anandamide is a lipid transmitter mimicked by pot

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 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.

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

IONOTROPIC RECEPTORS-

Metabotropic Receptors

NTs Terminology Post synaptic effects 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.

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.

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 exposure The blockade of ACHE leads to too much ACH in ACH synapses, and exaggerated postsynaptic effects. Effects of Nerve gas exposure Neuromuscular Effects Autonomic Nervous System Effects Central Nervous System 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

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

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.

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 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.

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

Drugs may agonize or antagonize neural transmission in many indirect ways.

Acetylcholine Agonists Nicotine Physostigmine Antagonists Muscarinic receptor - Atropine Nicotinic receptor - Curare

Dopamine Cocaine Amphetamine Antipsychotics 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

Chronic Effects Depletion of transmitters Alter transmitter production Alter receptor density Affect neurogenesis

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 Effect can not be overcome by sufficient dose

Drug Interaction Terms Competitive antagonist competes for same receptor site < affinity of NT Noncompetitive same binding site, >> affinity than NT or different binding site or receptor ~

Neurotransmission