Chapter 3. Communication at Synapses
Essay Questions:
1.	Describe the spatial and temporal summations
2.	List the major functions of 7 neurotransmitters and 3 peptides
3. 	List eight steps in chemical synaptic transmission
4.	Define agonists and antagonists and list the receptors of major neurotransmitters
5.	Describe how amphetamine, nicotine, cocaine and physostigmine affect events on synaptic transmission

Chapter 3. Communication at Synapses
1. 	The concept of synapse
1.1. 	Terminology 
	Presynaptic neuron
	Synaptic cleft (20 nanometers)
	Postsynaptic neuron
	Polarization: -70 mv (inside) to 0 mv (outside)
	Hyperpolarization: from -70 mv to -90 mv (inside) and 0 mv (outside). 
	This is also called Inhibitory postsynaptic potential (IPSP)
	Depolarization: from -70 mv to -55 mv (inside) and 0 mv (outside)
	This is also called Excitatory postsynaptic potential (EPSP)

1.2. 	Neural integration: 
	The following events occurs in the membrane of the presynaptic neuron
(1). 	Spatial summation  
	EPSP + EPSP = a greater EPSP
	Two simultaneous EPSP's sum to produce a greater EPSP
	IPSP + IPSP = a greater IPSP
	Two simultaneous IPSP's sum to produce a greater IPSP	
	IPSP + EPSP = 0 (no potential)
	A simultaneous IPSP and EPSP cancel each other out
(2). 	Temporal summation   
	Two EPSPs elicited in rapid succession produce a larger EPSP
	Two IPSPs elicited in rapid succession produce a larger IPSP

1.3. 	Relationship among EPSP, IPSP, and Action potential
(1). 	The number of synapses on neuron's surface
	The greater the number of EPSPs, the greater the probability of action potential
(2). 	The location of synapse
	A synapse located close to the axon hillock has greater influence in inducing action potential

2. 	Chemical events at the synapse
2.1. 	Synaptic transmission is chemical
	History:
	In 1921, the principle of synaptic transmission was build up by the simple experiment by Loewi.  
	The chemical released at the vagus nerve to the heart (vagus-heart synapse) was acetylcholine.
	Later, scientist found that the chemical released at the sympathetic nerve to the heart (sympathetic-heart synapse) was norepinephrine (noradrenaline)	
		 
2.2. 	Neurotransmitters and peptides
(1). 	Major functions of seven neurotransmitters
 1). 	Norepinephrine (NE): 
	excitatory effects in the sympathetic nervous system
 		increases arousal in CNS: high NE causes mania, 
					low NE causes depression
2). 	Epinephrine (EP): same as NE but produced mainly in PNS
3). 	Dopamine (DA): 	low DA causes Parkinson's disease 
	high DA causes schizophrenia, euphoria, and orgasm 
4). 	Serotonin (5-HT): mood regulation, visual hullucination
	Low 5-HT causes depression (prozac treats depression) 		
	High 5-HT induces hullucination (LSD-hullucination)
5). 	Acetylcholine (ACh): 
	excitation of skeletal muscle and inhibition of heart muscle in PNS
 		learning and memory in CNS (Alzeimer's disease)
6). 	Glutamate: excitatory effects in CNS
	ex: Chinese food contains glutamic acid in the form of monosodium glutamate (MSG) makes some people crazy
7). 	GABA: inhibitory effects in CNS
	Low GABA causes pileptic seizure. 
	As a result, all brain neurons are over excited (Epilepsy), no brake system.
	Treatment: benzodiazepine stimulates GABA receptors.
	Barbiturates and alcohol also stimulate GABA receptors

(2). 	Major functions of peptides
	Structure: short chains of two or more amino acids, smaller than protein, usually larger than amino acids neurotransmitters
1). 	Endorphins: inhibits pain 
2).	Substance P: causes pain
3).  	Angiotensin: increases blood pressure
4).	Vasopressin: constricts blood vessels
5).  	Oxytocin: uterus contraction and milk release
 
2.3. 	Eight steps in chemical synaptic transmission
(1). 	Synthesis of neurotransmitters  
	Ex. of acetylcholine
	Steps: 
1).	Food (milk contains choline)
2).	Choline in blood circulation
3).	Neurons receive these choline molecules
4).	Cell body combine choline with acetate to synthesize the acetylcholine
5).	Acetylcholine are stored in vesicles of the presynaptic neurons
	These chemical molecules are called precursors. If the diet has a high concentration of precursors, the brain may produce a slightly higher neurotransmitters. Ex: drink more milk, more choline, more Ach, and better memory
(2). 	Transport of transmitters
	Steps: 
1).	Neurotransmitters are in vesicles
2).	Transport from cell body to axon terminal buttons
	Is very slow, it takes hours, days for millimeters
	Exception: terminal buttons can synthesize certain neurotransmitters, such as acetylcholine and catecholamine, so they can be released repeatedly within a short time.
(3).	Release and diffusion of transmitters
	Steps: 
1). 	Action potentials reach the end of axon. Then the depolarization changes the voltage across the membrane and opens the calcium gates followed an increased calcium concentration inside the presynaptic cell.
2). 	Axon terminal releases a certain amounts of its meurotransmitters in the next 1 or 2 milliseconds
3). 	The chemicals diffuse across the synaptic cleft to the postsynaptic membrane, where it attaches to a receptor
(4). 	Activation of receptors of the postsynaptic neuron 
	In order to open the door of a room, you need a key and a lock. Here the key is a neurotransmitter, the lock is a 	receptor. The lock only can be open by a right key; the receptor only can be activated by a right neurotransmitter
Steps: 
1). 	The neurotransmitter attaches to a receptor on the membrane of the postsynaptic neuron
2). 	The neurotransmitter opens the gates for some types of ions, such as, sodium gates: excitatory effects, chloride gates: inhibitory effects 
(5). 	Separation of neurotransmitter molecules from receptors and then they stay in synaptic cleft
(6). 	Inactivation of neurotransmitters: specific enzyme inactivates the neurotransmitter
	Acetylcholine (after activates receptor) is broken down by acetylcholinesterase into two fragments: acetate and choline
	Choline diffuse back to the presynaptic neuron, which takes it up and reconnects it with acetate already in the cell to form acetylcholine again
(7). 	Reuptake of neurotransmitters: presynaptic neuron takes up the most of the neurotransmitter molecules in the cleft intact and reuses them
	Serotonin and catecholamine are detached from membrane-receptors and stay in synaptic cleft
	Some serotonin and catecholamine molecules are converted by enzymes (monoamine oxidase, MAO) into inactive chemicals that can not stimulate the receptor.
(8). 	Empty vesicles return to cell body

3.	How drugs affect synapses?
3.1. 	Concept of agonists and antagonists  see Ove. 7 and Fig. 5.8
(1). 	Agonists: drugs that facilitate the activity of the synapses of a particular neurotransmitter (ex: Ach, 5-HT, DA, NE). 
(2). 	Antagonists: drugs that inhibit the activity of the synapses of a particular neurotransmitter

3.2.	Receptors of major neurotransmitters
(1).	Acetylcholine (ACh)		
1). 	Nicotinic receptors: activated by nicotine and blocked by curare. 
2). 	Muscarinic receptors: activated by muscarine and blocked by scopolamine. 
(2). 	Noradrenergic receptors:
1). 	alpha 1 receptor: excitatory
	Phenylephrine is selective agonist, and prazosin is selective antagonist
2). 	alpha 2 receptor: inhibitory 
	Yohimbine is selective antagonist.
3). 	beta 1 receptor: produces cardiac stimulation. 
	Dobutamine is selective agonist and metoprolol is selective antagonist
4). 	beta 2 receptor: produces excitatory effects. 
	Albuterol is selective agonist and IPS339 is selective antagonist.
(3).	Dopaminergic receptors:
1). 	D1 receptor: located presynaptically on nigroneostriatal neurons and postsynaptically in the striatum. 	
	Dihydroxidine is selective agonist. SCH23390 is an antagonist.  
2). 	D2 receptor: located presynaptically on the corticostriatal neurons and postsynaptically in the striatum and substantia nigra. Apomorphine is a full agonist. Sulpiride is an antagonist.
(4).	Serotonergic receptors
1). 	5-HT1A: inhibitory effects 
2). 	5-HT1B
3). 	5-HT1C 
4). 	5-HT1D 
5). 	5-HT2
6). 	5-HT3 
7). 	5-HT4 
(5). 	GABA receptors
1). 	GABAA 
2). 	GABAB 		

3.3. 	Effects of drugs on the presynaptic neuron
	By altering the synthesis of the neurotransmitter or the amount of transmitter that is released.	see overhead 12
	ex: the synthesis of NE
	Steps: Food - tyrosine - dopa - dopamine - NE
     		AMPT (Alpha-methyl-paratyrosine): 
	It is similar to tyrosine. It blocks the enzyme from attaching to tyrosine, as a result, very little tyrosine is converted to dopa. (Antagonist) 
	Amphetamine: increases the release of NE,EP, and DA from presynaptic terminal (agonist).
	Reserpine: causes the leakage from the vesicles that store NE (Antagonist)

3.4. 	Effects of drugs on the postsynaptic receptors
(1). 	Some drugs first attach directly to the receptors and then activate the receptors. They have a similar physical shape to the neurotransmitter to fit the same receptor site
	If the neurotransmitter is acetylcholine
 	Nicotine: binds to nicotinic receptors of the acetylcholine neurotransmitter junction. 
	Results: increase of skeletal muscle activity
	question: is nicotine an agonist or antagonist of acetylcholine? agonist
(2). 	Some drugs attach to the receptors but fail to activate the receptors
	Something like a wrong key which can fits into a lock but can not turn the lock.
	d-tubocurarine: is a false transmitter at nicotinic receptor of acetylcholine neurotransmitter junction, produces paralysis and death from asphyxiation

3.5. 	Effects of drugs on the events following transmission
(1). 	Some drugs prevent the reuptake of neurotransmitter by presynaptic neurons. 
	As a result, the neurotransmitter stays longer in the synapse where they may excite their receptors repeatedly.
	Cocaine: blocks the reuptake of NE, 5-HT, and DA
	See Overhead T14
(2). 	Some drugs interfere with an enzyme that inactivates a neurotransmitter after it stimulates postsynaptic receptors
	physostigmine: blocks acetylcholinesterase and then prolongs the effects of acetylcholine at its synapse. It can increase rat's memory
 
3.6. 	Synaptic effects of abused drugs
(1). 	Methylphenidate (Ritalin) is used to treate ADD: blocking the reuptake of dopamine by presynaptic terminals
(2). 	Morphine and other opiate drugs: increasing dopamine activity indirectly. Opiates stimulate the relaes of endorphins which inhibit GABA release. GABA reduction thenincreases dopamine release
(3). 	Marijuana: not fully understood. 
	It combines with receptors of cannabinoids in the brain. Brain produces its own chemical, anandamide, which combines with cannabinoid receptors, then inhibits the serotonin receptor 3 (5-HT3) synapses. The consequence is the the relieve of nausea
(4). 	Amphetamine: increasing the release of norepinepherine, epinephrine, and dopamine from presynaptic terminal
(5). 	Cocaine: blocking the reuptake of dopamine and norepinephrine
(6). 	Nicotine: increases acetylecholine which in turn increases dopamine activity
(7). 	Alcohol: inhibits the flow of sodium across the membrane, facilitates GABA receptor sensitivity, and increases dopamine activity