1. 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

2. Beauty in the nervous system?

4. 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)

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

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

7. A Classical Study showing the RESTING MEMBRANE POTENTIAL (RMP) of the Neuron

8. The RMP
The RMP for a typical neuron is about -70mv

9. “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

10. Once triggered, the AP is all or none, and “one-way.”
The AP will travel to the terminal and there initiate a chemical event

11. The Neuronal communication process can be thought of as an “electro-chemical” event.
Most Psychoactive drugs directly affect the chemical portion of the process

12. 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?

13. The Neuron is Like a little battery

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

15. The forces of Diffusion: Concentration Gradients

16. Diffusion also occurs across electrostatic gradients

17. The neural membrane is a semi-permeable membrane

18. The Neurons membrane separates the different ions

19. The membrane controls diffusion

20. By opening or closing Ion channels

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

23. 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

25. Action Potential at the Terminals

26. 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.

27. 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.

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

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

30. 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.

31. 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.

32. 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

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

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

35. 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

36. Dopamine- ( DA, dopaminergic, a catecholamine)
movement (Parkinson’s disease)
“wanting”
mood
attention, and learning.
Dopamine excess may be involved in Schizophrenia.

37. Dopamine

38. Parkinson’s Disease
Parkinson’s disease, dopamine and the substantia nigra

40. Parkinson’s disease and MPTP
1980’s “designer drugs” MPPP/MPTPP and the case of the frozen addicts

41. Serotonin ( 5-HT, serotonergic, an indolamine)
-sleep, dreaming, mood

42. Serotonergic System (Serotonin)
Found throughout brain and important in sleep regulation
Also linked with depression and schizophrenia

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

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

45. 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

46. 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.

47. Neurotransmitters bind to receptor sites to produce postsynaptic effects

48. 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.

49. 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

50. IONOTROPIC RECEPTORS-

51. Metabotropic Receptors

52. 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.

53. 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.

54. Effects depend on receptor subtype

55. Deactivation of NT’s
Enzyme Breakdown
Reuptake

56. 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…..

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

58. Most nerve gases produce their effects by blocking the breakdown of ACH ( by binding to and blocking the action of ACHE).

59. 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

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

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

62. 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.

63. 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

64. How Do Drugs affect the nervous system?
Ligand – a fancy term for substances that bind to receptors
-neurotransmitters
-drugs

65. 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.

66. Drug Action Direct Agonist: Ligand Activates receptor
Direct Antagonist: Ligand Blocks receptor
Indirect agonism or antagonism
Alters enzyme activity
Blocks reuptake
Etc…

67. 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

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

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

70. Dopamine Cocaine Amphetamine Antipsychotics
dopamine reuptake inhibitor
Amphetamine
increases DA release
Antipsychotics
block post-synaptic dopamine receptor

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

72. Serotonin
Selective-serotonin reuptake inhibitors (SSRIs) – used to treat depression

73. GABA Valium, Xanax, Ativan Act as GABA agonists GHB, Rohypnol

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

75. 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

76. 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 ~

77. Neurotransmission