1. Chapter 3 Communication at Synapses

2. The Concept of the Synapse
Neurons communicate by transmitting chemicals at junctions, called “synapses”
In 1906, Charles Scott Sherrington coined the term synapse to describe the specialized gap that existed between neurons
Sherrington’s discovery was a major feat of scientific reasoning

3. The Properties of Synapses
Sherrington investigated how neurons communicate with each other by studying reflexes (automatic muscular responses to stimuli)
Example:
Leg flexion reflex: a sensory neuron excites a second neuron, which excites a motor neuron, which excites a muscle

5. The Properties of Synapses (cont’d.)
Sherrington found the same reflexive movements after he made a cut that disconnected the spinal cord from the brain.
Evidently, the spinal cord controlled the flexion and extension reflexes

6. The Properties of Synapses (cont’d.)
Sherrington observed three important points about reflexes:
Reflexes are slower than conduction along an axon
Several weak stimuli presented at slightly different times or slightly different locations produces a stronger reflex than a single stimulus does
As one set of muscles relaxes, another set becomes excited

7. The Properties of Synapses (cont’d.)
Sherrington observed a difference in the speed of conduction in a reflex arc from previously measured action potentials
He believed the difference must be accounted for by the time it took for communication between neurons
Evidence validated the idea of the synapse

8. The Properties of Synapses (cont’d.)

9. The Properties of Synapses (cont’d.)
Repeated stimuli over a short period of time produced a stronger response (Sherrington)
This led to the idea of temporal summation
Repeated stimuli can have a cumulative effect and can produce a nerve impulse when a single stimuli is too weak

10. The Properties of Synapses (cont’d.)
Several small stimuli on a similar location produced a reflex when a single stimuli did not (Sherrington)
Spatial summation: synaptic input from several locations can have a cumulative effect and trigger a nerve impulse

11. The Properties of Synapses (cont’d.)
Presynaptic neuron: neuron that delivers the synaptic transmission
Postsynaptic neuron: neuron that receives the message
Excitatory postsynaptic potential (EPSP): graded potential that decays over time and space
The cumulative effect of EPSPs are the basis for temporal and spatial summation

14. The Properties of Synapses (cont’d.)
Spatial summation is critical to brain functioning
Each neuron receives many incoming axons that frequently produce synchronized responses
Temporal summation and spatial summation ordinarily occur together
The order of a series of axons influences the results

15. The Properties of Synapses (cont’d.)
Sherrington also noticed that during the reflex that occurred, the leg of a dog that was pinched retracted while the other three legs were extended
He suggested that an interneuron in the spinal cord sent an excitatory message to the flexor muscles of one leg and an inhibitory message was sent to the other three legs

16. The Properties of Synapses (cont’d.)

17. The Properties of Synapses (cont’d.)
This led to the idea of inhibitory postsynaptic potential or the temporary hyperpolarization of a membrane
An ISPS occurs when synaptic input selectively opens the gates for positively charged potassium ions to leave the cell or negatively charged chloride ions to enter the cells
Serves as an active “brake” that suppresses excitation

18. Figure 3.7 Sherrington’s Inference of Inhibitory Synapses
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19. Relationship Among EPSP, IPSP, and Action Potentials

20. Relationship Among EPSP, IPSP, and Action Potentials (cont’d.)
Sherrington assumed that synapses produce on and off responses
Synapses vary enormously in their duration of effects
Many inputs interact in ways that are not quite additive. The effect of two synapses at the same time can be more than double the effect of either one, or less than double

21. Relationship Among EPSP, IPSP, and Action Potentials (cont’d.)

22. Relationship Among EPSP, IPSP, and Action Potentials (cont’d.)

23. Relationship Among EPSP, IPSP, and Action Potentials (cont’d.)

24. Relationship Among EPSP, IPSP, and Action Potentials (cont’d.)
The spontaneous firing rate refers to the periodic production of action potentials despite synaptic input
EPSPs increase the number of action potentials above the spontaneous firing rate
IPSPs decrease the number of action potentials below the spontaneous firing rate

25. The Discovery of Chemical Transmission at Synapses
German physiologist Otto Loewi was the first to convincingly demonstrate that communication across the synapse occurs via chemical means
Neurotransmitters are chemicals that travel across the synapse and allow communication between neurons
Chemical transmission predominates throughout the nervous system

27. The Sequence of Chemical Events at the Synapse
The major sequence of events allowing communication between neurons across the synapse:
The neuron synthesizes chemicals that serve as neurotransmitters
Action potentials travel down the axon
Released molecules diffuse across the cleft, attach to receptors, and alter the activity of the postsynaptic neuron

28. The Sequence of Chemical Events at the Synapse (cont’d.)
Sequence of events (cont’d.)
The neurotransmitter molecules separate from their receptors
The neurotransmitters are taken back into the presynaptic neuron for recycling or diffuse away
The postsynaptic cell may send reverse messages to slow the release of further neurotransmitters by presynaptic cells

31. The Sequence of Chemical Events at the Synapse (cont’d.)
Major categories of neurotransmitters include the following:
Amino acids
Monoamines
Acetylcholine
Neuropeptides
Purines
Gases

32. The Sequence of Chemical Events at the Synapse (cont’d.)

33. The Sequence of Chemical Events at the Synapse (cont’d.)
Neurons synthesize neurotransmitters and other chemicals from substances provided by the diet
Acetylcholine synthesized from choline found in milk, eggs, and nuts
The amino acid tryptophan serves as a precursor for serotonin
Catecholimines contain a catechol group and an amine group (epinephrine, norepinephrine, and dopamine)

35. The Sequence of Chemical Events at the Synapse (cont’d.)
Vesicles: tiny spherical packets located in the presynaptic terminal where neurotransmitters are held for release
MAO (monoamine oxidase): a chemical that breaks down excess levels of some neurotransmitters
Exocytosis: refers to the excretion (release) of the neurotransmitter from the presynaptic terminal into the synaptic cleft
Triggered by an action potential arriving from the axon

36. The Sequence of Chemical Events at the Synapse (cont’d.)
Transmission across the synaptic cleft which is only 20 to 30 nanometers wide by a neurotransmitter takes fewer than .01 microseconds
Most individual neurons release at least two or more different kinds of neurotransmitters
The combination makes the neuron’s message more complex, such as brief excitation followed by prolonged inhibition
Neurons may also respond to more types of neurotransmitters than they release

38. The Sequence of Chemical Events at the Synapse (cont’d.)
The effect of a neurotransmitter depends on its receptor on the postsynaptic cell
An ionotropic effect refers to when a neurotransmitter attaches to receptors and immediately opens ion channels
Transmitter-gated or ligand-gated channels are channels controlled by a neurotransmitter

39. The Sequence of Chemical Events at the Synapse (cont’d.)
Most effects occur very quickly (sometimes less than a millisecond after attaching) and are very short lasting (e.g., half-life 5 ms)
Most ionotropic effects rely on glutamate or GABA (gamma-amino-butyric acid)
Most of the brain’s excitatory ionotropic synapses use the neurotransmitter glutamate.
Most of the inhibitory ionotropic synapses use GABA, which opens chloride gates, enabling chloride ions, with negative charge

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41. The Sequence of Chemical Events at the Synapse (cont’d.)
Metabotropic effects occur when neurotransmitters attach to a receptor and initiates a sequence of slower (after about 30 ms) and longer lasting metabolic reactions (about a few seconds)
Metabotropic synapses use many neurotransmitters such as dopamine, norepinephrine, serotonin, and sometimes glutamate and GABA

42. The Sequence of Chemical Events at the Synapse (cont’d.)
When neurotransmitters attach to a metabotropic receptor, it bends the receptor protein that goes through the membrane of the cell
Bending allows a portion of the protein inside the neuron to react with other molecules
Metabotropic events include behaviors as taste, smell, and pain (exact timing not important)
For vision and hearing, the brain needs rapid, information (ionotropic events)

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44. The Sequence of Chemical Events at the Synapse (cont’d.)
The portion inside the neuron activates a G-protein: one that is coupled to guanosine triphosphate (GTP), an energy storing molecule
G-protein increases the concentration of a “second-messenger”
The second messenger communicates to areas within the cell
May open or close ion channels, alter production of activating proteins, or activate chromosomes

45. The Sequence of Chemical Events at the Synapse (cont’d.)
Metabotropic effects utilize a number of different neurotransmitters
Neuropeptides are often called neuromodulators
Release requires repeated stimulation
Released peptides trigger other neurons to release same neuropeptide
Diffuse widely and affect many neurons via metabotropic receptors

46. The Sequence of Chemical Events at the Synapse (cont’d.)

47. The Sequence of Chemical Events at the Synapse (cont’d.)
General rule: a neuron delivers neuropeptides that diffuse to receptors throughout a wide area, but delivers other transmitters in small amounts directly adjacent to their receptors
Neuropeptides are important for hunger, thirst, intense pain, and other long-term changes in behavior and experience
Video:

48. The Sequence of Chemical Events at the Synapse (cont’d.)
A hormone is a chemical secreted by a gland or other cells that is transported to other organs by the blood where it alters activity
Endocrine glands are responsible for the production of hormones
Hormones are important for triggering long-lasting changes in multiple parts of the body
For example, birds that are preparing for migration secrete hormones that change their eating and digestion to store extra energy for a long journey.

49. The Sequence of Chemical Events at the Synapse (cont’d.)
Protein hormones and peptide hormones are composed of chains of amino acids and attach to membrane receptors where they activate second messenger systems
Hormones secreted by the brain can control the release of other hormones

51. The Sequence of Chemical Events at the Synapse (cont’d.)
The pituitary gland is attached to the hypothalamus and consists of two distinct glands that each release a different set of hormones:
Anterior pituitary: composed of glandular tissue and synthesizes six hormones
Posterior pituitary: composed of neural tissue and can be considered an extension of the hypothalamus

53. The Sequence of Chemical Events at the Synapse (cont’d.)
Neurons in the hypothalamus synthesize the hormones oxytocin and vasopressin, which migrate down axons to the posterior pituitary
Also known as antidiuretic hormones
The hypothalamus secretes releasing hormones
Flow through the blood and stimulate the anterior pituitary to release a number of other hormones

55. The Sequence of Chemical Events at the Synapse (cont’d.)
The hypothalamus maintains a fairly constant circulating level of hormones through a negative-feedback system
Example: TSH-releasing hormone

57. The Sequence of Chemical Events at the Synapse (cont’d.)
Neurotransmitters released into the synapse do not remain and are subject to either inactivation or reuptake
Reuptake refers to when the presynaptic neuron takes up most of the neurotransmitter molecules intact and reuses them
Transporters are special membrane proteins that facilitate reuptake
Example: serotonin is taken back up into the presynaptic terminal

58. The Sequence of Chemical Events at the Synapse (cont’d.)
Examples of inactivation and reuptake include:
Acetylcholine is broken down by acetylcholinesterase into acetate and choline
Excess dopamine is converted into inactive chemicals:
COMT: enzymes that convert the excess into inactive chemicals

59. The Sequence of Chemical Events at the Synapse (cont’d.)
Negative feedback (for inhibiting further release of neurotransmitters) in the brain is accomplished in two ways:
Autoreceptors: receptors that detect the amount of transmitter released and inhibit further synthesis and release
Postsynaptic neurons: respond to stimulation by releasing chemicals that travel back to the presynaptic terminal where they inhibit further release

60. The Sequence of Chemical Events at the Synapse (cont’d.)
A few special-purpose synapses operate electrically
Faster than all chemical transmissions
Needed when exact synchrony (e.g., rhythmic breathing) between two cells is important
Gap junction: the direct contact of the membrane of one neuron with the membrane of another
Depolarization occurs in both cells, resulting in the two neurons acting as if they were one

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62. Synapses, Drugs, and Addiction
Drugs work by mimicking our own neurochemistry
Example: receptors in the brain respond to LSD and cocaine
Drugs alter various stages of synaptic processing
Antagonist: a drug that blocks a neurotransmitter
Agonist: a drug that increases a neurotransmitter’s effects

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64. A Survey of Abused Drugs
Addictive substances affect dopamine and norepinephrine synapses
Olds and Milner (1954) placed rats in a Skinner box that allowed self-stimulation of the brain by the pressing of a lever
Rats sometimes pressed the lever 2,000 times per hour to stimulate the release of dopamine in the nucleus accumbens (having role in processing of reward, motivation, reinforcement learning)

65. Photo credit: Omikron/Photo Researchers, Inc.

66. A Survey of Abused Drugs
Other behaviors that release dopamine include sexual excitement, gambling, and video games
People with major depression show less than normal response in the nucleus accumbens. They show little motivation and report getting little joy out of life
Like sex and food, addictive drugs strongly activate the nucleus accumbens by releasing dopamine or norepinephrine

67. A Survey of Abused Drugs (cont’d.)
Berridge and Robinson (1998) suggest an important distinction be made between “liking” and “wanting” behaviors
Small parts of the nucleus accumbens respond to pleasure (liking)
Larger parts respond to motivation (wanting)
People addicted to drugs are highly motivated to get them even if they no longer provide pleasure

69. A Survey of Abused Drugs (cont’d.)
Drugs are categorized according to their predominant action or effect upon behavior
Stimulant drugs increase excitement, alertness, motor activity, and elevate mood
Examples: amphetamines, cocaine, methylphenidate (Ritalin), MDMA (Ecstasy), and nicotine
Amphetamine and cocaine inhibit the dopamine transporter, thus decrease reuptake and enable prolonged effects

70. A Survey of Abused Drugs (cont’d.)
Amphetamine and cocaine stimulate dopamine synapses by increasing the release of dopamine from the presynaptic terminal
Methylphenidate (Ritalin) also blocks the reuptake of dopamine but in a more gradual and more controlled rate
Often prescribed for people with ADD
Research has found inconclusive results on whether Ritalin use in childhood makes one more likely to abuse drugs as an adult

71. A Survey of Abused Drugs (cont’d.)
Nicotine is the active ingredient in tobacco. It enhances reward.
Stimulates one type of acetylcholine receptor known as the nicotinic receptor
Nicotinic receptors are abundant in the nucleus accumbens and facilitate dopamine release
Repeated exposure to nicotine makes it more rewarding, but it makes every other stimulus less rewarding

72. A Survey of Abused Drugs (cont’d.)
Opiate drugs are those that are derived from (or similar to those derived from) the opium poppy
Opiates decrease sensitivity to pain and increase relaxation by attaching to endorphin receptors in the brain
Examples: morphine, heroin, methadone.
People used opiates for centuries without knowing how the drugs affected the brain.

73. A Survey of Abused Drugs (cont’d.)
The brain produces peptides called endorphins (for inhibiting pain signals)
Endorphin synapses may contribute to certain kinds of reinforcement by inhibiting the release of GABA indirectly
Inhibiting GABA indirectly increases dopamine (GABA inhibits dopamine)
Endorphins also have reinforcing effects independent of dopamine

74. A Survey of Abused Drugs (cont’d.)
Tetrahydocannabinol (THC) is the active ingredient in marijuana
Psychological effects of marijuana include an intensification of sensory experience and an illusion that time has slowed down
THC attaches to cannabinoid receptors throughout the brain
When certain neurons are depolarized, they release anandamide or 2-AG as retrograde transmitters that travel back to the incoming axons and inhibit further release

75. A Survey of Abused Drugs (cont’d.)
Anandamide and 2-AG tell the presynaptic cell, “The postsynaptic cell got your message. You don’t need to send it again.”
The cannabinoids in marijuana attach to these same presynaptic receptors, again telling them, “The cell got your message. Stop sending it.”
The presynaptic cell, unaware that it hadn’t sent any message at all, stops sending.
The chemicals in marijuana decrease both excitatory and inhibitory messages from many neurons

76. A Survey of Abused Drugs (cont’d.)
Hallucinogenic drugs cause distorted perception
Many hallucinogenic drugs resemble serotonin in their molecular shape
Hallucinogenic drugs stimulate serotonin type 2A receptors (5-HT2A) at inappropriate times or for longer duration than usual thus causing their subjective effect

77. A Survey of Abused Drugs (cont’d.)
Types of hallucinogens:
Lysergic acid diethylamide (LSD)
Methylenedioxymethamphetamine (MDMA or “ecstasy”): a stimulant at small dosages but a hallucinogen at larger dosages
Indication that long-term use of hallucinogenic drugs is associated with impaired memory and learning, and loss of serotonin receptors

78. A Survey of Abused Drugs (cont’d.)

79. Alcohol and Alcoholism
Alcohol is a drug that has a long historical use and is used widely throughout the world
In moderate amounts, alcohol is associated with relaxation
In greater amounts it impairs judgment and damages the liver and other organs, and ultimately can ruin lives
Alcoholism/alcohol dependence is the habitual use of alcohol despite medical or social harm

80. Alcohol and Alcoholism (cont’d.)
Alcohol has a number of diverse physiological effects, including:
Enhanced response by the GABAA receptor (the brain’s main inhibitory site)
Blockage of glutamate receptors (the brain’s main excitatory site)
Both the GABA and the glutamate effect lead to a decrease in brain activity.
Increased dopamine activity

81. Alcohol and Alcoholism (cont’d.)
Strong influence of genetics on alcoholism
The genetic basis for early-onset alcoholism is stronger than for later-onset, especially in men
Researchers distinguish between two types of alcoholism
Type I/Type A
Type II/Type B

82. Alcohol and Alcoholism (cont’d.)
Type I/Type A characteristics include:
Later onset (usually after 25)
Gradual onset
Fewer genetic relatives with alcoholism
Equal quantity between men and women

83. Alcohol and Alcoholism (cont’d.)
Type II/Type B characteristics include:
Earlier onset (usually before 25)
More rapid onset
More genetic relatives with alcoholism
Men outnumber women

84. Alcohol and Alcoholism (cont’d.)
Genes influence the likelihood of alcoholism in many ways, such as:
Long form type 4 receptor are more sensitive and need more alcohol to provide reinforcement
More active COMT (an enzyme that breaks down dopamine ) decreases reinforcement and is linked to impulsivity (no forethought, reflection, or consideration of the consequences). They tend to choose immediate rewards instead of bigger rewards later.

85. Alcohol and Alcoholism (cont’d.)
Prenatal environment also contributes to the risk for alcoholism.
A mother who drinks alcohol during pregnancy increases the probability that her child will develop alcoholism later,
Research on sons of alcoholic fathers shows:
Less average intoxication after one drink
Stress decreases more than for the average person
Smaller than normal amygdala

86. Alcohol and Alcoholism (cont’d.)

87. Addiction
As the addiction progresses, the pleasures become weaker while the costs and risks increase. Users raise the amount to greater levels.
Body reacts strongly when the drug is absent. The effects of drug cessation are called withdrawal.
Various factors contribute to continued substance abuse:
Tolerance (decrease enjoyable effects) develops
Cravings (abnormal desire) in response to cues
Brain reorganization (in nucleus accumbens and prefrontal cortex, change in response to rewards)

88. Medications to Combat Substance Abuse
Medications used to combat alcoholism include:
Antabuse (Disulfiram plus alcohol produce vomiting, chest pain, sweating, etc.)
Revia (blocks opiate receptors and thereby decreases the pleasure from alcohol)
Many do not respond to other treatments so medications have been used to reduce cravings

89. Medications to Combat Substance Abuse (cont’d.)
After alcohol consumption, enzymes in the liver metabolize it into a poisonous substance called acetaldehyde
Acetaldehyde is converted into acetic acid, a chemical that the body can use as a source of energy. Antabuse (disulfiram) inhibits the enzyme responsible for this process.
Accumulation of acetaldehyde results in sickness

90. Medications to Combat Substance Abuse (cont’d.)
Most studies suggest that Antabuse has been only moderately effective
When effective, it supplements the alcoholic’s own commitment to quit
Daily routine of pill ingestion may reaffirm commitment not to drink
Many quit taking the pill and continue to drink

91. Medications to Combat Substance Abuse (cont’d.)
Methadone is an opiate similar to heroin and morphine but is absorbed and metabolized slowly
Perceived to be less harmful than other drugs
Assumed to satisfy cravings associated with previous drug use
Levomethadyl acetate (LAAM) is similar to morphine but can be taken three times a week rather than daily