October 24, 2001.
Guest professor:
Robert R. Ross, Ph.D.
x3654 

neurotransmitters, neuromodulators

Hormones:  any substance released by a cell which acts on another cell to regulate its function

Paracrines:  a class of hormones which act on cells adjacent to the source of the hormone

Neurotransmitters/neuromodulators:  paracrines secreted by neurons at synapses, mainly involved in neuron-to-neuron, neuron-to-secretory cell, and neuron-to-muscle communication
-  Classic, small molecular weight neurotransmitters
1.  Acetylcholine
2.  Biogenic amines (dopamine, norepinephrine, epinephrine, serotonin, histamine
3.  Amino acids (-aminobutyric acid, glycine, glutamate)

-  Neuropeptides
-  Gaseous transmitters (nitric oxide, carbon monoxide)

The evolution of the neurotransmitter concept:

Dale’s principle:  a neuron is limited to one transmitter

Restatement of Dale’s principle by Eccles:  a neuron releases the same neurotransmitter at all its processes

Current view:  neurons can colocalize two or more transmitters;  a transmitter can be specifically localized to different parts of a neuron.
________________

Up till the late 1950s:  	only Ach and biogenic amines were known
in mid- to late 1960s:  	amino acids were described with neurotransmitter function
mid-1970:  	the first neuropeptides (opioids) were discovered
late 1980s:  	the first gaseous neurotransmitter were described (1998 Nobel prize in physiology)

synaptic transmission

Synapse:  functional connection between neuron and neuron, neuron and muscle fiber, or neuron and secretory cells.  It can be excitatory or inhibitory.

Parts of the chemical synapse

1.  Presynaptic neuron
- synaptic terminal
- synaptic vesicles (neurotransmitters/neuromodulators)
- calcium channels

2.  Synaptic cleft

3. 	Postsynaptic neuron
- postsynaptic membrane
- receptors
- ion channels

The events of the synaptic transmission

1. 	Action potential arrives at the synaptic terminal 
2. 	Voltage-gated calcium channels open
3. 	Calcium influx
4. 	Fusion of the synaptic vesicles with the presynaptic membrane
5. 	Exocytosis (neurotransmitter release)
6. 	Neurotransmitter/neuromodulator binds to the receptor
7. 	Direct effect on ion channels or G protein-mediated effects on ion channels
8. 	Excitatory postsynaptic potential (EPSP):  Na+/K+ channels open, postsynaptic cell becomes less negative
      Inhibitory postsynaptic potential (IPSP):  K+ or chloride channels open, postsynaptic cell becomes more negative
9. 	Removal of the NT from the synaptic cleft (presynaptic re-uptake, enzymatic breakdown, diffusion)

Neurotransmitters:  -  elicit the changes in membrane potential  
-  can be small MW classic neurotransmitters or neuropeptides or gaseous nt.
-  rapid, brief action

Neuromodulators:  	-  typically, they do not affect membrane potential themselves, but modulate (enhance or     suppress) the effects of neurotransmitters at the synapse 
-  typically neuropeptides; one particular peptide may serve a neurotransmitter role at one synapse and a neuromodulator role at another synapse
-  slow, prolonged action
-  small MW neurotransmitters and peptide neuromodulators often coexist and corelease 

neurotransmitters/neuromodulators

I. 	Classic, small-molecule transmitters

1.  Acetylcholine (ACh):  the first neurotransmitter discovered (Loewi and Navratil, 1921)

2.  Biogenic amines:   
Dopamine (DA)
NE
Epinephrine
Serotonin (5-HT)
Histamine

3.  Amino acids:
-aminobutyric acid (GABA):  the principal inhibitory neurotransmitter in the brain
Glycine
Glutamate:  the most abundant neurotransmitter in the brain
Aspartate

4.  ATP (purinergic transmission)

II. 	Neuropeptides

1.  Hypothalamic hormones:
TRH
CRH, etc.

2.  Neurohypophysis hormones:
ADH
Oxytocin

3.  Adenohypophysis hormones:
-endorphin
MSH
PRL
ACTH
LH
GH
TSH

4.  Gastrointestinal peptides:
CCK:  the most abundant neuropeptide in the brain
Vasoactive intestinal peptide (VIP)
Substance P (SP)
Insulin
Glucagon
SST
Gastrin
Neurotensin
Motilin

5. 	Atrial natriuretic peptide

6. 	
Cytokines:
Interleukin 1
Tumor necrosis factors
Interferons
Fibroblast growth factors

7.   Miscellaneous:  
Angiotensin
Calcitonin gene-related peptide
Neuropeptide Y
Bradykinin

III. 	Gaseous neurotransmitters:

1.  Nitric oxide
•	Produced by nitric oxide synthase (NOS) from L-arginine; 3 isoforms of NOS

•	Neurons (constitutive enzyme, nNOS)  neurotransmitter
•	Macrophages (inducible enzyme, iNOS, activated by cytokines IL-1, TNF)  nonspecific defense system
•	Endothelia (constitutive, eNOS;  old name:  endothelium-derived relaxing factor, EDRF)  vasodilation

•	Highly diffusible
•	Both anterograde and retrograde neurotransmitter
•	Reaches every cell (wherever O2 can reach NO can reach, too)
•	Activates a wide variety of second messenger systems;  the major target is guanylyl cyclase ( cGMP) 

2.  Carbon monoxide:  -  produced by heme oxygenase (the enzyme’s primary function is to degrade heme in aging RBC; heme oxygenase-2 is the neuronal isoform of the enzyme localized in discrete neuron populations throughout the brain)
 -  activates guanylyl cyclase

the role of peptides in the regulation of complex neural functions

Complex neural functions are regulated by complex neural networks.

Complex neural networks consist of thousands of neurons and the neurons can use dozens of various neurotransmitters.

Yet:  the injection of a single peptide may significantly affect complex neural functions, e.g.,
“satiety peptides”, e.g., CCK, interleukins
“analgesic peptides”, e.g., opioids
“memory peptides”, e.g., oxytocin
“sleep peptides”, e.g., delta sleep-inducing peptide, interleukins

How can one single peptide (neurotransmitter) affect the function of a complex network (i.e., modulate a complex neural function)?

1.  As a neurotransmitter at a strategic point in a neural network.

Inhibition of the peptide action suppresses the activity of the network.
Stimulation of the peptide action increases the activity of the network.

2.  As an endocrine agent present in the blood.

The peptide triggers the action of the neuronal network    complex response

3.  As both an endocrine agent triggering and a neurotransmitter sustaining the function of a network.

-  opioid peptides in pain suppression
-  cholecystokinin in the regulation of feeding

ENDOGENOUS opioids

Endogenous opioids:  (neuro)peptides with morphine-like activities.

Opioid prohormones and hormones:

1.  Proopiomelanocortin derivatives

ACTH
- MSH
- Corticotropin-like intermediate lobe peptide (CLIP)

-lipotropin
- -LPH  MSH
- -endorphin

2.  Proenkephalin derivatives

Met-enkephalin
Leu-enkephalin

3.  Prodynorphin derivatives

-neoendorphin
-neoendorphin
Dynorphin

Opioid receptors

:  morphine, endorphin, enkephalins
supraspinal (periaqueductal gray matter, hypothalamus)

:  enkephalins
spinal cord, basal ganglia, limbic system

:  dynorphin
spinal cord

Receptor activation  inhibition of adenylyl cyclase via a G protein system

Localization and function of endogenous opioids

Spinal cord 	 	pain modulation
Brain stem 		emetic effects, respiration
Hypothalamus		GH, PRL
		TSH, FSH, LH
Limbic system		euphoria
Pituitary		systemic effects
Adrenal medulla		systemic effects
GI tract		gut motility

Mechanism of pain-suppressive actions

1.  Presynaptic inhibition in the spinal cord suppressing SP release from peripheral sensory neurons.

2.  Inhibition of the projection neurons in the spinal cord.

3.  Supraspinal site of action.

Pathophysiology

1. Opioid tolerance
2. Physical dependence (withdrawal syndrome)