neurotransmission in the autonomic nervous system (ans...

Neurotransmission in the

Autonomic Nervous System

(ANS)

Basic principles

Tibor Zelles

Dept. Pharmacology & Pharmacotherapy

Semmelweis University

9-25-2018

Evaluation only.

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Cell communication

Cell Signalling Biology - Michael J. Berridge - http://csb.portlandpresspublishing.com - 2019

Hierarchical neuronal systems:

- pathways of sensori perception & motor control – phasic actions

- synaptic contact

- myelinated axons (50 m/s)

- relay/projection neurons – Glu

- local circuit neurons (interneurons) - GABA/Gly

Nonspecific / Diffuse neuronal systems:

- sleeping-waking, attention, emotional states, appetite – tonic actions

- non-synaptic ‚contact’

- unmyelinated axons (0.5 m/s)

- monoamine transmitters (e.g. NA, DA, 5-HT)

Cellular organization of the brain

Hierarchical neuronal systems in the CNS

BG Katzung, 12th Ed.

Projection /

(interneurons)

BG Katzung, 13th Ed.

Diffuse neurotransmitter pathways in the CNSlargely modulate the function of the hierarchical pathways

Other similar systems (e.g. histamine & orexin)

Implicated in global

functions:

• Sleeping

• Waking

• Attention

• Appetite

• Emotional state

Basic steps in neurochemical transmission

• Synthesis

• Storage

• Release

• Reception/recognition

• Termination

• resides in the presynaptic terminal

• can be released

• synaptic mimicry:

- addition of the substance produces the same

effect as nerve stimulation

- antagonist blocks the response

Criteria for neurotransmitters

Steps involved in excitatory and inhibitory

neurotransmission

Goodman & Gilman’s, 12th Ed.

Types of neurotransmitters & neuromodulators

Rang & Dales’s, 8th Ed.

• Sympathetic

• Parasympathetic

• Enteric

The 3 divisions of the

Autonomic Nervous System (ANS)

ACh & NA as transmitters in the peripheral

nervous system

C, cervical; GI, gastrointestinal; L, lumbar; M, medullary; S, sacral; T, thoracic.

The autonomic nervous system (ANS)

The ANS in more detail

(only for home consumption for gourmets)

Goodman & Gilman’s, 12th Ed.

EPSPs and IPSPs in an autonomic ganglion cell

M2→ G → IK

M1 → Gq → PLC → [Ca2+]i → IK,Ca ↓

BG Katzung, 12th Ed.

The intestinal wall & the enteric nervous system (ENS)

EPAN/IPAN – Extrinsic/Intrinsic Primary Afferent Neuron; EN/IN – Excitatory/Inhibitory Neuron; EC – Entrochromaffin Cell;

SC/AC – Secretory/Absorptive Cell; NP - Neuropeptide BG Katzung, 12th Ed.

BG Katzung, 12th Ed.

BG Katzung, 12th Ed.

→ Aqueous humor secretion (Glaucoma)

β-blockers

BG Katzung, 12th Ed.

-agonists

M-antagonistsmydriasis

(eye

examination)

M-antagonists → cycloplegia (Uveitis; eye examination)

The logic of therapy in ANS pharmacology

(examples)

M-antagonists used for:

• Asthma bronchiale, COPD

The logic of therapy in ANS pharmacology

(examples)

• Urinary incontinence

• (Urinary retention – side effect)

BGKatzung, 9E

The logic of unwanted effects based on ANS

pharmacology - neuromuscular blocking drugs

nAChR inhibition in ganglia

Histamine release

BP

Bronchospasm

Cardiac mAChR inhibition

(increase of NA release, too)

Tachycardia

Cholinergic

junction

BG Katzung, 12th Ed.

LTX

+

-+ /pH

~5

.5

Mechanism of action of BTx

BoNT

motor neuron

ACh release

TeTx

Renshaw cell

Gly release

spastic paralysisflaccid paralysis

-

-+ /pH

~5

.5

MAO

Periferal DOPA

decarboxylase inhibitors[anti-Parkinson]

-MAO-A/BIs

-

COMTIs

COMT

Indirectly acting

sympathomimetics

α-methyl-DOPA

l-DOPA = levodopa[anti-Parkinson]

NA-ergic

junction

[anti-pheochromocytoma]

[antihypertensive]

[anti-Parkinson]

[antidepressant/anti-Parkinson]

[antihypertensive]

[nasal decongestants,

psychostimulants]

[antihypertensive]

[antihypertensive 2 agonists]

BG Katzung, 12th Ed.

Synthesis of DA, NA and A

Periferal DOPA

decarboxylase inhibitors

Metyrosine

α-methyl-DOPA

α-methyl-NA

-

-

Goodman & Gilman’s, 12th Ed.

Metabolism of catecholamines by catechol-O-

methyltransferase (COMT) & monoamine oxidase

(MAO)

BG Katzung, 12th Ed.

Types of ion channels and neurotransmitter

receptors in the nervous system

BG Katzung, 13th Ed.

Structure of nAChRs - ionotropic

mAChRs – metabotropic (mACh1,3,5 stimulatory,

mACh2,4 inhibitory)

Structure of and β adrenergic receptors -

metabotropic

Goodman & Gilman’s, 12th Ed.

Neuromodulation & co-transmission

[A] Postulated homotropic and heterotropic interactions between sympathetic and parasympathetic nerves. [B] Some of the known inhibitory and facilitatory influences on noradrenaline release from

sympathetic nerve endings. 5-HT, 5-hydroxytryptamine; A, adrenaline; ACh, acetylcholine; NA, noradrenaline; NO, nitric oxide; PG, prostaglandin; PGE, prostaglandin E.

Presynaptic regulation of transmitter release from

noradrenergic and cholinergic nerve terminals

Presynaptic inhibition

[A] Inhibitory effect of A on ACh release from postganglionic

parasympathetic nerves in the guinea pig ileum.

[B] NA release from mouse hippocampal slices in response

to trains of electrical stimuli

(α2 KO)

1, Uptake of precursors; 2, synthesis of transmitter; 3, uptake/transport of transmitter into vesicles; 4, degradation of surplus transmitter; 5, depolarisation by propagated action potential; 6, influx of

Ca2+ in response to depolarisation; 7, release of transmitter by exocytosis; 8, diffusion to postsynaptic membrane; 9, interaction with postsynaptic receptors; 10, inactivation of transmitter; 11,

reuptake of transmitter or degradation products by nerve terminals; 12, uptake of transmitter by non-neuronal cells; and 13, interaction with presynaptic receptors. The transporters (11 and 12) can

release transmitter under certain conditions by working in reverse. These processes are well characterised for many transmitters (e.g. acetylcholine, monoamines, amino acids, ATP). Peptide

mediators (see Ch. 19) differ in that they may be synthesised and packaged in the cell body rather than the terminals.

Basic steps in neurochemical transmission

sites of drug action

• Synthesis

• Storage

• Release

• Reception/recognition

• Termination

Goodman & Gilman’s, 12th Ed.

Goodman & Gilman’s, 12th Ed.

Goodman & Gilman’s, 12th Ed.

Thanks for your

attention