Advanced Pharmacology -1

1. NEUROHUMORAL
TRANSMISSION IN CNS
Presented by AYUSH ROY
M.Pharm 1st year
Guided by – Mr. Rajana James
School of Pharmaceutical Science
GCU Guwhati

2. CONTENT
i. Introduction
ii. Neurohumoral Transmission in CNS
iii.Histamine
iv.Serotonin
v. Dopamine

3. ❑ Central Nervous System
The central nervous system is made up of the brain and spinal cord.
• Brain – Most complex organ of the human body and responsible
for wide range of functions from normal survival functions to high
level of cognitive process.
• Spinal Cord – Long tube structure that extends from base of brain
to vertebral column.
❑ Neuron
INTRODUCTION

4. NEUROHUMORAL TRANSMISSION IN CNS
• Neuro refers to Neurons.
• Humoral refers to chemical messengers in our body.
• Neurohumoral transmission refers to how neurons communicate each other and other cells using chemical
messengers (neurotransmitters).
❑ Steps Involved in Neurohumoral
Transmission
1. Impulse Conduction
2. Neurotransmitter Release
3. Neurotransmitter Action on Post Junction Membrane
4. Termination of Neurotransmitter Action

5. 1. Impulse Conduction
➢Refer to Passage of an Impulse along nerve fibre.
➢After receiving an information from a Peripheral Organ through Sensory Nerve.
➢CNS sends message or Impulse through efferent autonomic nerve.
➢Impulse Conduct by generating Action Potential.
➢Action Potential is self-propagating & is conducted along Axonal Fibre.
➢Note: Resting Potential is - 70mv ( negative Inside Neuron) Depolarization – Influx
of Na+ Repolarization – Efflux of K+.
2. Neurotransmitter Release
➢Depolarisation leads to stimulation and opening of voltage sensitive Ca+ Channel.
➢Ca+ helps in fusion between Axoplasmic Membrane and Synaptic Vesicle (Store
house of Neurotransmitter)
➢Neurotransmitter release by Exocytosis.

6. 3. Neurotransmitter Action on Post - Junctional Membrane
The Released Transmitter combines with specific receptors on the post junctional membrane
Depending on its Nature induces an :- 1. Excitatory Post Synaptic Potential(EPSP).
2. Inhibitory Post Synaptic Potential(IPSP).
• For EPSP
Influx of Na+ and Ca+ and efflux of K+
causing depolarization of the effector
organ.
• For IPSP
Influx of Cl- takes place causing
hyperpolarization of the effector organ.

7. 4. Termination of Neurotransmitter Action
It is either Locally Degraded or Partly taken back into Pre junctional Neuron by active
Reuptake

8. NEUROTRANSMITTERS IN CNS
1. Monoamine Neurotransmitters
a. Histamine
b. Serotonin
c. Dopamine
2. Amino acid Neurotransmitters
a. GABA (Gamma –Aminobutyric Acid)
b. Glutamate
c. Glycine

9. HISTAMINE
• Histamine is a monoamine neurotransmitter in the CNS in addition to its well-known physiological
function in immune and allergic responses
• It is an autacoid—that is, a molecule secreted locally to increase or decrease the activity of nearby cells.
❑ Synthesis of Histamine

10. ❑ Storage: Histamine are stored in
• Mast Cells: Mast cells are a type of white blood cell found in connective tissues throughout the body,
especially in areas like the skin, respiratory tract, and gastrointestinal tract. They contain granules filled
with histamine.
• Basophils: Basophils are another type of white blood cell, found in the bloodstream. Similar to mast cells,
basophils also contain histamine-filled granules.
❑ Release: Histamine can be released from mast cells and basophils in response to different stimuli,
including:
• Allergens: When a person is exposed to an allergen (such as pollen, insect venom, or certain foods) and they
have allergies, it can trigger an allergic response. This response includes the activation of mast cells and the
release of histamine.
• Tissue Injury: Physical injury or trauma to a tissue can cause mast cells to release histamine. This is part of
the body's natural response to injury and inflammation.
• Immunologic Responses: Immune reactions can also lead to histamine release. For example, in response to
certain infections or immune challenges, mast cells and basophils may release histamine as part of the
immune response.

11. ❑ Histamine Receptors
There are four known types of histamine receptors, creatively named H1, H2, H3, and H4.
1. H1 Receptors (Histamine H1 Receptor):
• Mechanism of Action: Coupled to Gq proteins. Activation leads to the activation of phospholipase C and
the subsequent formation of inositol trisphosphate (IP3) and diacylglycerol (DAG)causing increase level of
Ca+.
• Location: smooth muscle cells, endothelial cells, and nerve cells.
• Functions: Smooth muscle contraction (e.g., bronchoconstriction in the lungs and contraction of intestinal
muscles).Increased vascular permeability. Stimulation of sensory nerve endings, leading to itching.
Promotion of wakefulness and alertness when activated in the central nervous system
2. H2 Receptors (Histamine H2 Receptor):
• Mechanism of Action: Coupled to Gs proteins. Activation stimulates adenylate cyclase, leading to increased
levels of cyclic AMP (cAMP) in the cell.
• Location: Parietal cells in the stomach lining.
• Functions: Regulation of stomach acid production. This is why H2 receptor antagonists (H2 blockers) are
used to reduce stomach acid production in conditions like heartburn and ulcers.

12. 3. H3 Receptors (Histamine H3 Receptor):
• Mechanism of Action: Coupled to Gi/o proteins. Activation inhibits adenylate cyclase, leading to decreased
levels of cAMP and reduced release of neurotransmitters.
• Location: Central nervous system
• Functions: H3 receptors play a role in regulating neurotransmitter release. Activation of H3 receptors can
lead to a reduction in the release of histamine and other neurotransmitters, modulating various neural
functions.
4. H4 Receptors (Histamine H4 Receptor):
• Mechanism of Action: Also coupled to Gi/o proteins, similar to H3 receptors. Activation of H4 receptors
modulates immune responses and chemotaxis.
• Location: H4 receptors are mainly expressed on immune cells, such as mast cells, eosinophils, and T cells.
• Functions: H4 receptors are involved in immune responses, chemotaxis (movement of immune cells
towards sites of inflammation), and modulation of cytokine release. Their activation plays a role in allergic
and inflammatory responses.

13. ❑Histamine agonist and antagonist
1st Gen
Diphenhydramine
Chlorpheniramine
Mepyramine
2ndGen
Cetrizine
Loratidine
Cyclizine

14. SEROTONIN
• The scientific name for serotonin is 5-hydroxytryptamine, or 5-HT
• It is a monoamine neurotransmitter.
• About 90% of is found/localized in the intestines: the rest in brain and platelets.
• The level of 5-HT in whole blood is in the range of 65–250 mg/ml.
• It is popularly thought to be a contributor to feelings of well-being and happiness it is a key mediator in the
physiology of mood, vascular function and gastrointestinal motility.
❑ Synthesis ,Storage and Release
Serotonin is stored and released in a manner similar to other neurotransmitters. Here's how it works:
• Synthesis and Storage :
Serotonin is synthesized in nerve cells (neurons) from the amino acid tryptophan.
Vesicles: Once synthesized, serotonin is packaged into storage vesicles within the neuron. These vesicles
are specialized compartments that hold neurotransmitters until they are needed for release.

15. • Release of Serotonin:
The release of serotonin occurs when a nerve signal or action potential arrives at the neuron's
presynaptic terminal.
❖ Reuptake: After serotonin has exerted its effects, it is typically taken back up into the presynaptic
neuron in a process called reuptake. A specific protein called the serotonin transporter (SERT) is
responsible for reuptaking serotonin from the synaptic cleft back into the neuron.
❖ Metabolism and Recycling: Inside the neuron, serotonin can be metabolized by enzymes like
monoamine oxidase (MAO). Some of the metabolites can be recycled to produce more serotonin.

16. ❑ 5-HT Receptors
Are categorized into seven major classes (5-HT1 to 5-HT7)
5-HT1 Receptors:
• Location:5-HT1 receptors are widely distributed throughout the central nervous system.
• Mechanism of Action: These receptors are generally associated with inhibitory effects. When activated, they typically inhibit
adenylate cyclase activity, leading to a decrease in cyclic AMP (cAMP) levels.
There are several subtypes within the 5-HT1 receptor family, including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F
1. 5-HT1A Receptors:
Functions: 5-HT1A receptors play a role in mood regulation and anxiety. Medications that target 5-HT1A receptors are used
in the treatment of anxiety disorders and depression.
2. 5-HT1B Receptors:
Functions: 5-HT1B receptors are involved in the regulation of mood, anxiety, and pain perception. Medications that target 5-
HT1B receptors may be used in the management of migraine headaches.
3. 5-HT1D Receptors:
Functions: 5-HT1D receptors are implicated in the regulation of pain, mood, and vascular tone. Activation of these receptors
can lead to vasoconstriction and may be involved in migraine pathophysiology. Medications targeting 5-HT1D receptors are
used in the treatment of migraines.
4. 5-HT1E Receptors:
Functions: The specific functions of 5-HT1E receptors are still being studied, and their roles in neurotransmission and
physiology are not fully understood.
5. 5-HT1F Receptors:
Functions: The functions of 5-HT1F receptors are still being investigated

17. 5-HT2 Receptors:
Location: 5-HT2 receptors are found in various regions of the central nervous system and on vascular smooth muscle
cells.
Mechanism of Action: These receptors are associated with excitatory effects. Activation of 5-HT2 receptors typically
leads to the activation of phospholipase C (PLC) and the subsequent production of inositol trisphosphate (IP3) and
diacylglycerol (DAG).
Functions: 5-HT2 receptors are involved in mood regulation, perception, and vascular smooth muscle contraction.
Activation of 5-HT2A receptors is implicated in hallucinogenic effects, while activation of 5-HT2B receptors is
associated with heart valve disease.
5-HT3 Receptors:
Location: 5-HT3 receptors are primarily located in the central and peripheral nervous systems, especially in areas
associated with nausea and vomiting.
Mechanism of Action: These receptors are ion channels, specifically ligand-gated ion channels. Activation of 5-HT3
receptors leads to the influx of sodium ions, causing neuronal depolarization and excitation.
Functions: 5-HT3 receptors play a role in regulating nausea and vomiting. Antagonists of these receptors are
commonly used as antiemetic drugs to treat chemotherapy-induced nausea and vomiting.
5-HT4 Receptors:
Location: 5-HT4 receptors are found in the gastrointestinal tract and in the central nervous system.
Mechanism of Action: Activation of 5-HT4 receptors leads to the stimulation of adenylate cyclase, resulting in
increased They play a role in promoting peristalsis in the gut and have been targeted for the treatment of
gastrointestinal disorders.

18. 5-HT5 Receptors:
• Location: 5-HT5 receptors are found in the central nervous system.
• Functions: The functions of 5-HT5 receptors are still being studied, and their roles in
neurotransmission and physiology are not fully understood.
5-HT6 Receptors:
• Location: 5-HT6 receptors are primarily found in the central nervous system
• Mechanism of Action: 5-HT6 receptors are associated with excitatory effects. Activation of these
receptors typically leads to the activation of adenylate cyclase and an increase in cyclic AMP (cAMP)
levels.
• Functions: 5-HT6 receptors are believed to play a role in cognition and memory processes. They have
been studied as potential targets for medications aimed at improving cognitive function, particularly in
diseases like Alzheimer's disease.
5-HT7 Receptors:
• Location: 5-HT7 receptors are widely distributed in the central nervous system and are also found in
various peripheral tissues.
• Mechanism of Action: 5-HT7 receptors are associated with excitatory effects. They activate adenylate
cyclase, leading to increased cAMP levels.
• Functions: 5-HT7 receptors are involved in various physiological processes, including mood
regulation, sleep-wake cycles, and thermoregulation.

19. ❑ Some Drugs Acting on 5-HT receptors

20. DOPAMINE
• Dopamine belongs to the family of catecholamines
• Hormones Epinephrine and Norepinephrine (other catecholamines) are derived from Dopamine.
• Significant role in learning, goal-directed behavior, regulation of hormones, motor control.
❑ Dopamine synthesis and Metabolism
(Dihydroxyphenylacetic acid + Homovanillic acid)

21. ❑ Storage and Release

22. • These are Metabotropic receptors
• The major dopamine receptor subtypes are categorized into two families: D1-like receptors and D2-like receptors. :
I. D1-Like Receptors (Excitatory):
1.D1 Receptor (DRD1):
• Location: Found in various brain regions, including the cortex and striatum.
• Mechanism: D1 receptors are coupled to G-proteins that activate adenylate cyclase, leading to an increase in
cyclic AMP (cAMP) levels.
• Function: Activation of D1 receptors is generally associated with excitatory effects and is involved in cognitive
functions, motor control, and reward processing.
2.D5 Receptor (DRD5):
• Location: Predominantly found in the hippocampus and other brain regions.
• Mechanism: D5 receptors are also coupled to G-proteins that activate adenylate cyclase and increase cAMP
levels.
• Function: The exact function of D5 receptors is still being studied, but they are believed to be involved in
learning and memory.
II. D2-Like Receptors (Inhibitory):
1.D2 Receptor (DRD2):
• Location: Widely distributed in the brain, including the striatum.
• Mechanism: D2 receptors are coupled to G-proteins that inhibit adenylate cyclase activity, leading to a
decrease in cAMP levels.
• Function: Activation of D2 receptors is generally associated with inhibitory effects. These receptors are
involved in motor control, mood regulation, and the treatment of psychiatric disorders.
❑ Dopamine receptors

23. 2.D3 Receptor (DRD3):
• Location: Found in regions of the brain, including the limbic system
• Mechanism: D3 receptors are also coupled to G-proteins that inhibit adenylate cyclase.
• Function: D3 receptors play a role in regulating mood, emotion, and drug addiction.
3.D4 Receptor (DRD4):
• Location: Predominantly found in the midbrain or medulla oblongota.
• Mechanism: D4 receptors are coupled to G-proteins that inhibit adenylate cyclase.
• Function: D4 receptors are involved in cognition, emotion, and attention.