1
Q
Describe Luigi Galvani’s observation and his hypothesis/conclusion
A
Observed (in 1790) frog legs handing on a wire would twitch during an electrical storm.
- Hypothesized that sparks from the storm activated muscles
- Applied current to dissected nerve attached to leg and the leg twitched.
- Concluded that the nervous system used electricity to communicate (partially correct)
2
Q
What was early evidence on chemical communication in the nervous system?
A
Otto Loewi did the frog heart experiment:
- 2 containers of fluid (connected through a tube) contained one frog heart each
- Stimulated the vagus nerve which slows the heart
- Other heart shares fluid and exhibits the same response, even though it was not stimulated
- Chemical found to be acetylcholine that was released and transferred through the fluid
3
Q
What are the 5 ions that are most important for neural electrical signals?
A
- Na+
- K+
- Cl-
- Large negatively charged proteins (A-)
- Ca2+
4
Q
There is more sodium (outside/inside) the cell
A
Outside
- 10x more concentrated outside the cell
5
Q
There is more chloride (outside/inside) the cell
A
Outside
6
Q
There is more calcium (outside/inside) the cell
A
Outside
- There’s practically none in the cell
7
Q
There is more potassium (outside/inside) the cell
A
Inside
8
Q
There are more negative proteins (outside/inside) the cell
A
Inside
9
Q
Out of all ions, only __ ions can, to some extent, move freely
- explain what they move through
A
K+
- K+ leakage channels
10
Q
Describe an ion channel
A
A hydrophilic pathway that facilitates ion movement across the plasma membrane
11
Q
True or false: Most channels are closed at rest except for some non-gated Na+ channels
A
False; Most channels are closed at rest except for some non-gated K+ channels
12
Q
What are 3 key features of ion channels?
A
- Permeability
- Selectivity
- Gating
13
Q
What is the cellular membrane potential a function of in general?
A
Concentration differences of mainly metal cations and large organic anions on the inside and outside of the plasma membrane, combined with selective permeability differences for these ions
14
Q
Describe diffusion and what causes it
A
All molecules move and therefore spread from areas of high concentration to low concentration
- No energy required, due to random movements
15
Q
What is it called when ions undergoing diffusion are distributed evenly in solution?
A
Dynamic equilibrium
16
Q
What do semi-permeable membranes selectively restrict?
A
The free diffusion of certain molecules
17
Q
What does movement from areas of high charge to low charge create across the plasma membrane?
A
Separation of charges, which costs energy and creates an electromotive force (EMF, basically electrical attraction/repulsion forces)
18
Q
When is equilibrium reached during diffusion?
A
When the concentration gradient (particularly, of K+) matches the ion’s electrical gradient in the opposite direction
- Charge builds up next to membrane
19
Q
True or false: The outside of the cell membrane is negative relative to the inside
A
False; the inside is negative relative to the outside
20
Q
What is the typical resting membrane potential range for humans? What does this depend on?
A
-65 to -70 mV
Depends on the species and cell type; can range between -40 and -90 mV
21
Q
Resting membrane potential depends mainly on…
A
The concentration of K+ ions
22
Q
True or false: Resting membrane potential is near the voltage at which the concentration gradient pushing K+ out of the cell cancels out the electrostatic forces pulling K+ into the cell
A
True
23
Q
Na+ is 10X more concentrated outside the cell. The membrane is not very permeable to Na+, but some still leaks in. What does this cause, and what reverse it?
A
This would eventually eliminate the charge separation, so the Na+/K+ pump reverses this slow leak (3Na+ in, 2K+ out)
24
Q
True or false: All cells have a resting membrane potential
A
True
25
What are 3 ways the opening state of an ion channel can be changed (change in permeability)?
1. Chemicals (e.g. neurotransmitter reeptors)
2. Mechanical (e.g. stretch receptors)
3. Electrical
- some channels open when the membrane potential reaches a certain threshold (aka voltage-gated)
26
What are the 2 types of electrical signals in neurons?
1. Graded potentials
2. Action potentials
27
Chemical signals cause a/an _____ potential
Graded
28
Mechanical signals cause a/an _____ potential
Graded
29
Electrical signals cause a/an _____ potential
Action
30
What is hyperpolarization also known as?
Polarization
31
Depolarization in a cell means that there is...
Less difference between the inside and outside; thus, the neuron is less negative
32
Hyperpolarization (polarization) in a cell means that there is a...
Larger difference between inside and outside; thus, the neuron is more negative
33
What causes a depolarization?
Increased influx of Na+ (or Ca2+)
34
What causes hyperpolarization?
Either efflux of K+
or
Increased influx of Cl-
35
What two things does a graded change in voltage depend on (hyperpolarization)?
- How is this different for depolarization?
1. Stimulus strength
2. Distance
- stimulator closer to amplifier: greater change in voltage)
These also matter for depolarizing graded potentials, up to a certain threshold (action potential past the threshold)
36
True or false: graded potentials degrade
True
37
True or false: Action potentials change size
False; action potentials are always the same size, no matter how strong the depolarizing stimulus
38
What is the strength of a stimulus coded in?
The patterns and frequency of action potentials
39
What is considered the most important single achievement in cellular neurophysiology?
The Hodkin-Huxley model that described the ionic basis of the action potential
- They derived a relatively simple but detailed mathematical and biophysical model of the action potential; their model is the "textbook" model
40
Describe the timeline for the Hodkin-Huxley model development (3)
1980: Scientists were able to identify and record single ion channels
1990: Cloning of ion channels (to discover their amino acid sequence)
2000: first 3D structure and function of ion channel
41
True or false: since all cells maintain a resting membrane potential, they must all generate action potentials
False; only EXCITABLE cell types (muscle cells and neurons) can generate action potentials
42
True or false: Non-excitable cells can still get graded potentials
True; graded potentials move the membrane potential towards or away from the threshold, but no AP can be generated
43
True or false: action potential amplitude depends on stimulus strength
False
44
Describe graded potentials in 3 points
1. Variable magnitude and duration which depends on strength and duration of triggering event
2. Spread passively (no channel opening outside the point of origin), decrementing with distance from point of initiation
3. Travel over short distances
45
Describe action potentials in 3 points
1. All or nothing event triggered when membrane potential is raised above a certain threshold
2. Spread actively (self-regenerating) in a non-decremented fashion
- due to operating of voltage-gated channels
3. Travel over long distances
46
True or false: Action potentials are unique to each neuron
True; shapes and firing patterns differ widely among different types of neurons
47
True or false: action potentials vary in duration
True; 1 ms to 15 ms
48
Describe the 6 key steps of an action potential
1. Depolarizing input(s) make resting membrane potential less negative
2. If this reaches the threshold potential, this initiates the start of an action potential in the AXON HILLOCK
- does not require further stimulation, it will continue on its own
3. Membrane potential further depolarizes and subsequently the interior becomes positive relative to the outside
4. Membrane potential then repolarizes
5. Overshoots resting potential and becomes hyperpolarized
6. Returns to resting potential
49
What does the axon hillock do?
Integrates potentials from dendrites
50
The membrane potential can reach __ mV during depolarization
+40 mV
51
The total change in membrane potential can be more than __ mV during an action potential
100
52
When a cell depolarizes, the voltage changes causes ___ to open
Voltage-gated Na+ channels
53
What causes the hyperpolarization in an action potential?
The open voltage-gated K+ channels close more slowly
54
What do voltage-gated Na+ channels have that K+ channels lack?
An inactivation gate
55
During the depolarization of an action potential, what happens to voltage-gated Na+/K+ channels?
Voltage-gated Na+ channels open and K+ channels stay closed
56
What happens to the voltage-gated Na+/K+ channels after the peak of an action potential?
The Na+ channels are inactivated, and the K+ channels are open (K+ diffuses out now)
57
What happens to the voltage-gated Na+/K+ channels during the hyperpolarization of an action potential?
The Na+ channels are closed, while the K+ channels are open (and slow to close)
58
Gated channels have which 2 or 3 configurations?
- Closed (resting)
- Closed (inactivated; mainly sodium channels)
- Open
59
True or false: Passive (non-gated) K+ channels (leakage channels) have one configuration
True; open
60
What causes voltage-gated channels to open when the cell depolarizes?
Part of the protein is charged; the protein reshapes when the cell depolarizes
61
What is a refractory period in general?
A period in which triggering another action potential is much more difficult or even impossible
62
What is the absolute refractory period and what causes it?
In the absolute refractory period, no new action potential can be generated.
- Due to the Na+channel inactivation gate
63
What is the relative refractory period and what causes it?
The neuron needs more stronger depolarizing input to reach threshold for an action potential to be generated (b/c cell is more negative than resting membrane potential)
- Due to the K+ channel activation gate
64
The absolute refractory period occurs during which period of the action potential?
Repolarization
65
The relative refractory period occurs during which period of the action potential?
Hyperpolarization
66
Describe how an action potential moves along an axon
When a segment of an axon generates an action potential, it depolarizes the adjacent section
- Action potential brings the adjacent section to threshold, activating its voltage sensitive Na+ channels
- At each segment of the axon, the action potential is regenerated completely (the same size at each stage)
67
You only need about a __ mV change to reach threshold
20
68
Why do action potentials only move in one way?
Because K+ channels are still open and harder to reach threshold
69
Stronger stimuli produce ___ action potentials
More frequent
70
What are two solutions to speeding up the speed of the nerve impulse?
1. Make your axons huge (larger diameter means less resistance and better conductivity; squids and other invertebrates)
2. Make it really hard for ions to escape by insulating the axon (myelination; vertebrates)
71
What is multiple sclerosis?
The loss of myelin around axons
72
What is saltatory conduction?
Action potential jumping from node to node, each action potential is regenerated fully at each Node of Ranvier (each note has voltage-gated and K+ channels)
- moves faster (up to 150 m/s) than opening millions of channels over a comparable portion of an unmyelinated neuron
73
True or false: all axons are myelinated
False
74
What is an example of unmyelinated axons?
Group C fibers
- include postganglionic fibers in the ANS and nerve fibers at the dorsal roots (IV fiber)
- carry sensory information
- small diameter, slow conducting
75
True or false: Unmyelinated axons in the PNS are still encased by Schwann cells
False; they are encased by Schwann cell cytoplasm, but there is no wrapped coating of myelin surrounding the axons
76
What 5 things do voltage-gated ion channels shape, in terms of the electrical behaviour of neurons?
1. Excitability
2. Shape of action potential
3. Response characteristics
4. Frequency of action potentials
5. Patterning of action potential trains (neuron "fingerprint")
77
True or false: each neuron has its own characteristic AP shape and activity pattern
True
78
True or false: Action potentials can be considered as binary/digital signals
True; they are all-or-none
79
Action potentials are binary, but sensory input is analog (continuous). Where is the coding of these analog signals?
In the frequency (number of action potentials per second) and pattern of action potentials
80
Graded potentials are also known as...
Post synaptic potentials (PSPs)
81
Excitatory post-synaptic potentials (EPSPs) (depolarize/hyperpolarize) the post-synaptic neuron
Depolarize
- Brings the membrane potential closer to threshold. Thus, increases probability that the cell will fire an action potential
82
Inhibitory post-synaptic potentials (IPSPs) (depolarize/hyperpolarize) the post-synaptic neuron
Hyperpolarize
- Move the potential away from threshold, decrease the probability that the cell will fire an action potential
83
How do EPSPs depolarize the cell?
Opens Na+ channels
- Na+ flows in the cell by its voltage and concentration gradients
84
How do IPSPs hyperpolarize the cell?
Opens K+ channels or Cl- channels
- K+ flows out or Cl- flows into the cell by its concentration gradient
85
True or false: PSPs are all-or-none
False; PSPs are proportional in size to the strength of the stimulus (unlike APs)
86
What determines if the post-synaptic neuron will generate an EPSP or an IPSP?
The neurotransmitter released by the pre-synaptic neuron
87
Neurons receive many simultaneous and consecutive postsynaptic potentials. These signals have what type of effect, and determine what?
These signals have a summative effect and determine whether the electrical message is conveyed or if it stops at that point
88
Describe spatial summation
Spatial = in space
- If PSPs occur simultaneously, they will summate
- This can cause either a larger EPSP, larger IPSP, or cancel each other out
89
Describe temporal summation
Temporal = in time
- If 2 signals occur close enough together in time, the second one has its effect before the first has degraded
90
True or false: spatial and temporal summation act independently
False; reality is a combination of both spatial and temporal summation
91
True or false: the cell body (soma) can fire an action potential
False; the cell body (soma) does not have voltage-gated channels, it cannot fire an action potential
92
Only ____can generate and conduct an action potential
An axon
93
The axon hillock is rich in...
Voltage-gated channels
94
The sum of all the EPSPs and IPSPs at the ____ will determine if the cell with fire an action potential
Axon hillock
95
PSPs spread through the dendrites and cell body. What happens to the PSP as it spreads?
It loses intensity
96
____ potentials are located in the dendrites and soma, while _____ potentials are located in the axons
Graded, action
97
What is the main role of the dendrites?
Enhance the receptive surface of the cell
98
The farther out on a dendrite a synapse occurs...
The weaker the PSP, thus its effect
- The PSP must spread further before it reaches the axon hillock, and therefore it reduces in size (dissipates)
99
What are 2 compensations for synapses that occur farther down a dendrite?
1. Large PSP at distant synapses
2. Signal boosters (voltage-gated calcium channels)
100
In general, how do we receive touch sensory input?
Each hair on our body allows us to detect the slightest displacement
- Dendrite of a touch neuron is wrapped around the base of each hair
- Hair displacement opens stretch-activated channels in the dendrite's membrane
- When channels open, they allow an influx of Na+ ions sufficient to depolarize the dendrite to its threshold level
101
Describe the knee jerk reflex
Hitting the patellar tendon stretches the quadriceps muscle. Stretch receptors in the quadricep detect this and activate motor neurons in the spinal cord, leading to contraction of the quadriceps
- Very fast reflex: only one synapse.
- Sensory neuron contacts motor neuron directly.
- No interneurons.
- Does not go through brain
102
True or false: the sneosry neuron contacts the motor neuron directly during the knee jerk reflex
True
103
True or false: there are large myelinated fibers on both input and output side of the knee jerk reflex
True
104
What is the PSP on the muscle fiber mediated by in the knee jerk reflex?
Mediated by ligand (neurotransmitters) gated ion channels
105
In the visual system, the neural chains exhibit both...
Convergence and divergence
Convergence: multiple photoreceptors (inputs) send signals to a single bipolar or ganglion cell. This means several signals merge into one.
Divergence: one neuron (like a ganglion cell) sends its signal to multiple target neurons in the brain.
106
What is the neural chain for the visual system?
Photoreceptor -> bipolar cell -> ganglion cell -> optic nerve -> brain
107
What allows for greater integration of information in the visual system?
Lateral inhibition by horizontal cells (synapse with photoreceptor cells and inhibit adjacent photoreceptors)
108
How can neurons regulate their own input?
The axon branches, and some of the terminals synapse on the cell from which the axon originates
109
What is a Renshaw loop?
An example where downstream neurons can provide feedback to upstream cells
- Inhibitory cell serves as an interneuron between a neuron's synapse and its dendrites
110
What are the two types of synapses?
1. Electrical
2. Chemical
111
Describe an electrical synapse
- speed, plasticity and prevalence
Direct cytosolic (i.e. electrically conducting) bridges between cells
- Speed: very fast
- Not very plastic
- Not very common in the mammalian brain
112
Describe a chemical synapse
- speed, plasticity and prevalence
Uses extracellular messenger that interacts with transmembrane receptors (neurotransmission)
- Speed: Not as fast as electrical synapses
- Very plastic
- Most common synapse in the brain
113
What is the most common synapse in the brain?
Chemical
114
What is an ionotropic receptor in general?
Ligand-gated channels
- Open in response to binding extracellular messengers
115
What is a metabotropic receptor in general?
G-protein coupled receptors
-G-protein affects other enzymes
116
~__ different chemicals act as a neurotransmiter (small molecule "classical" NTs)
7
117
>___ different chemicals act as neuropeptides (aka neuromodulators)
100
118
Neurotransmitters and neuropeptides are packed in...
Sacks called vesicles
119
What causes neurotransmitters to be released into the synaptic cleft?
The opening of voltage-gated Ca2+ channels
- Calcium concnetration is much higher outside the cell and it flows in through these channels
- This triggers vesicles to fuse with the axon terminal membrane and to release their contents into the synaptic cleft
120
More action potentials results in what (in terms of calcium and NT release)?
More APs= more Ca2+ = more NT release
121
Neurotransmitters binding to receptors on the postsynaptic membrane results in a...
PSP
122
True or false: the neurotransmitter type ultimately determines what effect a neurotransmitter will have on the post-synaptic neuron
False; it's the RECEPTOR TYPE, not the neurotransmitter, than determines this
123
What can neurotransmitters bind to to regulate its own release?
The presynaptic cell
124
To be a neurotransmitter, a substance must have which 4 properties?
1. Must be made, or present in the cell that releases it
2. The released chemical must be capable of producing an effect on its target (receptors must exist on a post synaptic cell)
3. Effect of chemical must be mimicked by exogenous application of same (or similar) substance (i.e. if you inject acetylcholine into a synapse)
- Blocking the release/receptors of the NT must prevent the postsynaptic effect
4. There should be a mechanism to remove or inactivate the neurotransmitter when its work is done
125
Describe the structure of classical neurotransmitters
Small protein molecules
126
Acetylcholine (Ach) action (EPSP or IPSP)
+/-
- depends on the receptor
127
Norepinephrine (NE) action (EPSP or IPSP)
+
128
Dopamine (DA) action (EPSP or IPSP)
+/-
- depends on the receptor
129
Serotonin (5-HT) action (EPSP or IPSP)
+/-
- depends on the receptor
130
Glutamate (Glu) action (EPSP or IPSP)
+
131
GABA action (EPSP or IPSP)
-
- IPSP bc it binds Cl- channels
132
Glycine (Gly) action (EPSP or IPSP)
-
- IPSP bc it binds Cl- channels
133
Define a neuropeptide
Peptides that do not act directly as neurotransmitters but rather increase or decrease the action of neurotransmitters (neuromodulator)
134
True or false: Neurotransmitters can also work as neuropeptides, but neuropeptides cannot act as a neurotransmitter
True
135
Where are neuropeptides synthesized? And what are they packed into?
The cell body of a neuron, packed in larger "dense-core vesicles"
- dense-core vesicles are transported from the cell body to the presynaptic terminal
136
What is Dale's exclusion principle?
Although different neurotransmitters can be produced at different synapses within the brain, individual neurons are capable of releasing only one classical neurotransmitter from its axonal terminal
137
True or false: Dale's exclusion principle applies to neuropeptides
False; there is common co-release of classical neurotransmitters and (multiple) neuropeptides
138
What is the exception to Dale's exclusion principle?
Co-release of classical neurotransmitters (GABA-glycine, ACh-glutamate, Dopamine-glutamate)
- although rare
139
Describe how dopamine acts as both a neurotransmitter and a neuromodulator in rat striatal neurons
- Acts as classical neurotransmitter by activation of dopamine D1 receptors in postsynaptic cell
- Acts as neuromodulator through activating dopamine D2 receptors on the presynaptic terminal. Activation of this GPCR activates the serine/threonine protein kinase C, which downregulates DA exocytosis in the terminal ("autoregulation")
140
Describe Ionotropic receptors in 4 points
1. Receptor and ion channel are one-in-the-same structure
2. Fast (milliseconds)
3. Excitatory or inhibitory
4. K+, Na+, Ca2+, Cl- channels
141
Describe Metabotropic receptors in 3 points
1. Receptor protein and effector (ion channel or enzyme) are separate structures
2. Slower (seconds)
3. K+, Ca2+ channels (maybe Na+ channels)
142
Describe the metabotropic receptor activation pathway when it is coupled to an ion channel (3 steps)
1. Transmitter binds to receptor
2. The binding of the transmitter triggers the activation of a G protein
3. The alpha subunit of the G protein binds to a channel, causing a structural change in the channel that allows ions to pass through it
143
Describe the metabotropic receptor activation pathway when it is coupled to an enzyme (4 steps)
1. Transmitter binds to receptor
2. The binding of the transmitter triggers the activation of a G protein
3. The alpha subunit binds to an enzyme, which activates a second messenger
4. The second messenger can activate other cell processes (i.e. activating DNA or forming a new ion channel)
144
What is the main purpose of a 2nd messenger system?
Amplification of a signal
- one messenger binds to one receptor, several G proteins are activated, each G protein activates an adenylate cyclase, each adenylate cyclase generates hundreds of cAMP molecules, each cAMP activates a protein kinase A, each protein kinase A phosphorylates hundreds of proteins
145
2nd messenger systems result in what short term changes? (2)
1. Turn proteins on or off
2. Change their kinetics
146
2nd messenger systems result in what long term change?
Gene expression
147
How does Ca2+ influx impact 2nd messenger pathways?
Many intracellular enzymes are calcium sensitive.
- Calcium influx through ligand-gated calcium channels can lead to activation of these second messenger pathways
148
What 4 things can calcium influx result in?
1. Change in electrical properties of cell
2. Muscle contraction
3. Secretion
4. Bind Calmodulin
- Ca-calmodulin activated enzymes activate protein kinases, which then phosphorylate proteins and responses in cells (muscle contraction, altered metabolism, altered transport)
149
What can happen if neurotransmitters aren't cleared from the synapse?
Receptor desensitization
150
What are the 3 ways in which active neurotransmitter is eliminated from the synaptic cleft?
1. Diffusion of neurotransmitter away from the synapse
2. Inactivation of the neurotransmitter by enzymatic breakdown (degradation)
3. Removal of the neurotransmitter by glia uptake (microglia are very close to the synapses) or reuptake by the pre-synaptic neuron
151
Describe desensitization in ionotropic receptors, using the nicotinic ACh receptor as an example
Once ACh molecules have bound the receptor, the channel opens and remains open for about 1 ms. It subsequently closes, even if ACh is still bound to the receptor (the desensitized state). After a short time, ACh molecules will detach from the desensitized channel and the channel will switch back to its resting state.
- during the desensitized state, the channel is blocked from being bound by other neurotransmitters
- Alternatively, channels switch directly between activated and rested states.
152
Describe desensitization in metabotropic receptors
Involves phosphorylation of the activated receptor by a specific kinase (GPCR kinase, GRK).
1. Agonist binds to receptor
2. Phosphorylation of receptor with GRK
3. The phosphorylated receptor then binds to arrestin, causing it to lose its ability to associate with a G-protein, and to undergo endocytosis, which removes the receptor from the membrane.
153
Describe the enzymatic degradation of Acetylcholine (ACh)
Acetylcholine (ACh) in the synaptic cleft is deactivated by acetylcholine-esterase, an enzyme splitting ACh in its components, acetate and choline. - Choline is taken up in the presynaptic terminal and recycled.
- Acetate is taken up in the general circulation and metabolized.
154
Describe the re-uptake and deactivation of norepinephrine (NE)
Norepinephrine (NE) actions in the synaptic cleft are terminated by (active) reuptake in the presynaptic terminal or by methylation
155
Reuptake transporters have been discovered thus far for which 6 neurotransmitters?
1. Glutamate
2. GABA
3. Glycine
4. Catecholamines (epinephrine, norepinephrine, and dopamine)
5. Serotonin
6. Histamine
156
True or false: Re-uptake transporters are targets of some drugs
True; e.g. SSRIs
157
Other than classical neurotransmitters and neuropeptides, what other chemicals are involved in neurotransmission? (2)
1. Gases
2. Lipids
158
True or false: each chemical has only one receptor
False; each chemical can have numerous receptors with very distinct distributions and different effects
159
What was the first identified neurotransmitter?
Acetylcholine
160
Acetylcholine is degraded by...
Acetylcholinesterase (AChE)
161
What are the 2 classes of ACh receptors?
1. Ligand-gated ion channel
- Nicotinic receptor (bc nicotine also activates this receptor)
2. G-protein coupled receptor
- Muscarinic receptor (5 types)
162
What is known as "THE" neurotransmitter in the neuromuscular junction?
Acetylcholine
163
True or false: Acetylcholine is a major NT of the autonomic nervous system
True
164
Describe acetylcholine production and projection in the brain
Produced in the basal forebrain and brainstem
Projects to the Hippocampus, Amygdala, and Cerebral Cortex
165
Other than muscle movement, what is acetylcholine involved in?
Learning and memory
- Decline associated with Alxheimer's disease
166
What are the 3 different groups of monoamines?
1. Catecholamines
2. Indolamines
3. Imidazoleamines
167
What are the 3 types of Catecholamines?
1. Dopamine
2. Norepinephrine (noradrenaline_
3. Epinephrine (adrenaline)
168
What are the 2 types of Indolamines?
1. Serotonin
2. Melatonin (hormone)
169
What is a type of imidazoleamine?
Histamine
170
Dopamine is made from which amino acid?
Tyrosine
171
Dopamine is produced in which 3 main systems?
1. Mesolimbic
2. Mesocortical
3. Mesostriatal
172
Describe where the Dopamine is produced and where it projects to in the mesolimbic and mesocortical pathways
Produced from the ventral tegmental area.
Projects to nucleus accumbens, amygdala, hippocampus and cortex
173
Dopamine release from the mesolimbic and mesocortical pathways are associated with the ___ pathway, and excessive release is associated with ____
Reward, schizophrenia
174
Describe where the Dopamine is produced and where it projects to in the mesostriatal pathway
Produced from the substantia nigra.
Projects to the striatum (caudate and putamen)
175
Loss of Dopamine production in the mesostriatal pathway is associated with...
Parkinson's disease
176
Dopamine binds __ receptors, all of which are ____
5, GPCR
177
Norepinephrine is made from...
Dopamine
178
What pathway is norepinephrine used in?
The autonomic NS (it is specifically the postganglionic NT in the sympathetic NS)
179
Norepinephrine is produced by which 3 brain areas?
3 brain areas in the BRAIN STEM:
1. Locus Coeruleus
2. Lateral Tegmental Area
3. Dorsal Medullary Group
180
True or false: Noreprinephrine projects narrowly
False; it projects widely
181
Norepinephrine modules many physiological states, including... (7)
1. Mood (many antidepressants work on NE pathways)
2. ADHD/attention
3. Sleep/wake
4. Sexual behaviour
5. Arousal
6. Stress reactions
7. Cognitive functions
182
Norepinephrine acts on how many receptors (and which type?)
4 GPCRs
183
Serotonin is also known as... (2)
5-hydroxytryptamine (5-HT)
184
Serotonin is made from...
Amino acid Tryptophan
185
Serotonin is produced by...
the Raphe nuclei
186
True or false: Serotonin projects widely in the brain
True
187
What 3 things does Serotonin regulate?
1. Sleep
2. Mood
3. Anxiety
188
Serotonin binds to _ classes of receptors (__ in total)
7
13-15
189
What type of receptors does Serotonin bind to?
One ligand-gated ion channel, others GPCR
190
Histamine is made from...
Amino acid histidine
191
Where is histamine made?
Tuberomammillary nucleus of hypothalamus
192
True or false: histamine is narrowly spread
False; it is widely spread
193
Histamine plays a key role in...
Arousal
- anti-histamines can make you drowsy
194
Outside the brain, histamine plays a key role in...
Immune response (allergies)
195
Why did old anti-histamines make you drowsy?
They were originally able to cross the blood-brain barrier
196
Histamine binds __ receptors; __ of these are in the brain
5, 4
197
What types of receptors do histamine molecules bind to in the brain?
3 GPCR and 1 Cl- channel
198
Some sleeping aids make use of...
1st generation antihistamine main adverse effects: inducing drowsiness
199
What is the most common class of neurotransmitters in the CNS?
Amino acid transmitters
200
Glutamate and aspartate are...
Excitatory amino acid transmitters
201
How many types of glutamate receptors are there?
4, 1 GPCR
202
What processes are glutamate and aspartate involved in? (2)
Learning and memory
203
Massive release of glutamate can lead to ____ following stroke
Cell death
204
GABA and glycine are...
Inhibitory amino acid transmitters
205
How many types of GABA receptors are there? What are their sub-types?
3 types
1 ligand-gated channel, 2 GPCR (involves Cl- channels)
206
What are the 3 main classes of peptides?
1. Opioid peptides
2. Neuropeptides
3. Pituitary peptides
207
In general, opioid peptides are responsible for...
Regulating pain
208
What are two types of opioid peptides?
Enkephalines and endorphines
209
True or false: there are many neuropeptides, with a wide array of functions
True
210
What are two types of posterior pituitary peptides?
1. Oxytocin
2. Vasopressin
211
True or false: peptides are often co-localized with a small classical neurotransmitter
True
212
What is an example of a type of lipid transmitter molecule?
Endocannabinoids
213
What are two types of endocannabinoids?
1. Anandamide
2. 2-arachidonoyl glycerol (2-AG)
214
How often are lipid transmitter molecules (e.g. Endocannabinoids) synthesized?
As needed
215
What is the role of lipid transmitter molecules (e.g. endocannabinoids)?
They serve as a retrograde messenger (released by post-synaptic neuron and work on the pre-synaptic neuron)
216
What 4 things do lipid transmitter molecules (e.g. endocannabinoids) play a role in?
1. Memory
2. Appetite
3. Pain
4. Anxiety
217
__ receptor is the most abundant GPCR receptor in the brain. ___, the psychoactive component of cannabis, directly binds to and activates the ___ receptor.
CB1, THC, CB1
218
What 6 brain regions are CB1 and CB2 receptors found in?
1. Hypothalamus
2. Ventral striatum
3. Amygdala
4. Neocortex
5. Hippocampus
6. Cerebellum
219
What is the effect is cannabis binds CB1/CB2 in the hypothalamus?
Increased appetite
220
What is the effect is cannabis binds CB1/CB2 in the ventral striatum?
Euphoria and relaxation
221
What is the effect is cannabis binds CB1/CB2 in the amygdala?
Increased anxiety and paranoia
222
What is the effect is cannabis binds CB1/CB2 in the neocortex?
Altered senses and disordered thinking
223
What is the effect is cannabis binds CB1/CB2 in the Hippocampus?
Impaired learning
224
What is the effect of cannabis binding CB1/CB2 in the Cerebellum?
Decreased motor control
225
What is an example of purine transmitter molecules?
Adenosine
226
Adenosine is involved in...
Sleep regulation
227
How does caffeine relate to adenosine?
When adenosine binds to its receptors, neural activity slows down and you feel sleepy. Caffeine acts as an adenosine-receptor antagonist (prevents binding of adenosine to receptor)
228
What is an example of a gas transmitter molecule?
Nitric oxide (NO)
229
Nitric oxide acts as a...
Retrograde messenger
230
What is Nitric oxide involved in? (2 proccesses)
Memory (causes enhanced Glu release)
- Also important for smooth muscle relaxation (e.g. dilation of blood vessels)
231
What is an example of an ion that acts as a transmitter molecule?
Zn2+
232
True or false: A change in behaviour needs a change in the brain (plasticity)
True
233
The nobel prize in physiology/medicine 2000 was awarded to Arvid Carlsson, Paul Greengard and Eric R. Kandel for their discoveries concerning...
Signal transduction in the nervous system
- figured out how memory formation occurred at a molecular level
234
What is habitutation?
Over time, decreased response to steady or repeated stimuli.
- Nervous system is interested in change, so unchanging and irrelevant stimuli are ignored by brains.
235
Describe habituation in humans and in sea slugs
You don't hear the air conditioner after it's been running for a while.
For the slug: ignores waves
- If you spray a water jet on a slug (simulates waves), the gill initially withdraws from the water jet. However, after repeated stimulation, the gill no longer withdraws from the water jet, demonstrating habituation
236
In general, what underlies habituation?
Synaptic plasticity in the sensory neurons from the skin of siphon, and motor neurons to retract gill
- Habituation alters the COMMUNICATION between the sensory and motor neurons
237
Describe how synaptic plasticity in the motor neurons underlies habituation in the sea slug
With repeated stimuli, the motor neurons have smaller responses. But, you can apply a stimulatory drug to show a normal response, so motor neurons are not dysfunctional.
With repeated stimulation:
- Ca2+ channel desensitizes in response to AP, causing decreased Ca2+ influx and less NT release
- Causes a smaller response in post-synaptic motor neuron
- Can last ~30 mins
238
What is sensitization in general? What's an example?
Exhibiting greater responses based on experience (think of building tension in a scary movie)
- A single shock to the tail enhances the gill withdrawal response
239
Describe how synaptic plasticity underlies sensitization in the sea slug
The tail shock sends a message to the skin of the siphon to motor neuron circuit (interneuron from tail synapses onto sensory neuron).
This message enhances NT release from the gill/siphon sensory neuron
- Ca2+ has a larger effect, more NT release causes larger response in motor neuron
- Lasts for minutes or longer
240
Overall, what are habituation and sensitization caused by?
Changes in NT release between pre- and post-synaptic neurons
241
What are 4 potential causes of changes in neurotransmission?
What do all of these mechanisms do?
1. More (or less) NT release (pre-synaptic modulation)
2. More (or less) sensitive receptors (post-synaptic modulation)
3. Larger (or smaller) synapses (pre- and post-synaptic changes)
4. Change in inactivation/removal of NT
All of these mechanisms change amplitude of response (PSP) in post-synaptic cells)
242
What are 3 types of structural changes in synapses? What do all of these types of changes involve/underlie?
1. Formation of new synapses (synaptogenesis)
2. Existing synapses can be eliminated (synaptic pruning, use it or lose it) in favour of more effective and stronger synapses
3. Existing synapses can be strengthened
All these types of changes involve protein synthesis and underlie long-term changes in the brain
243
Other than the number of connections, what are 8 ways in which the nature of synaptic connections can change (leading to plasticity)?
1. Increased axonal transport
2. Increase in number of synaptic vesicles
3. Change in size of synaptic cleft
4. Change in dendrite stem length and width
5. Increase in terminal size or area
6. Increase in density of contact zones
7. Increase in spine size or area
8. Increase in protein transport for spine construction
244
True or false: dendrites change over time
True
245
In mice, what has enriched housing/environment been shown to do to the dendrites?
Increases dendritic branching
246
What two things can happen to dendritic spines?
1. Added
- Filopodia (projections from the cell membrane) may form, and are constantly looking for new connections.
- Will become spines if connections are useful.
2. Eliminated (pruning)
247
What do long-term changes in the synapses involve?
Changes in gene expression and physical re-wiring
- Lasts for days
- Involves changes in protein synthesis
248
Which synapses are involved in memory formation?
Glutamatergic synapses
249
What are the two classes of glutamatergic receptors (and specific types)
1. Ionotropic receptors or ligrand-gated ion channels
- NMDA receptors
- AMPA receptors
2. Metabotropic or GPCRs
- mGluR
250
What are 4 glutamate receptor agonists?
1.Glutamate
2. Kainate
3. AMPA
4. NMDA
251
Which glutamatergic receptors are involved in synaptic plasticity?
1. NMDA
2. AMPA
252
Describe NMDA receptors
- Glutamate/NMDA bind
- high Na/high Ca2+ flow in
- K+ flows out
- BUT Mg2+ blocks channel
253
Describe AMPA receptors
- Glutamate/AMPA bind
- high Na+/ low Ca2+ glow in
- K+ flows out
- Cell depolarizes
- NO Mg2+ block
254
What are the 2 main differences between NMDAR and AMPAR?
NMDAR has high Ca2+ permebability, while AMPAR has low Ca2+ permeability
- Mg2+ block exists
255
What are the 6 steps for synaptic plasticity in the glutamatergic system for memory and learning
1. Glutamate binds to both NMDA and AMPA receptors
2. Initially, only AMPAR is activated since NMDAR is blocked by Mg2+
3. Activation of AMPAR causes influx of Na+ and depolarizes the post-synaptic area
4. If neuron is sufficiently depolarized (to ~-35 mV), Mg2+ is expelled from NMDAR (voltage-dependent part of NMDAR activation)
5. Influx of Na+ and Ca2+ through NMDAR
6. Influx of Ca2+ through the NMDAR leads to a number of intracellular events
- Further depolarization
- Activation of Ca2+ sensitive enzymes (2nd messengers) like Calmodulin (CaM) and Calcium-calmodulin dependent protein kinase (CaMK)
256
What are the 2 ways that CaMK enhances excitability?
1. It mobilizes new AMPA receptors (more post-synaptic receptors)
2. It makes existing AMPA receptors more responsive (increases their conductance for Na+)
- positive feedback system
257
Other than activation of 2nd messengers, Ca2+ can also activate what 2 other retrograde signals?
1. Nitric Oxide (NO) synthase
- Produces NO, which diffuses out of the cell to influence the presynaptic terminal
- Enhances glutamate release (more positive feedback)
2. Production of molecules that also alter the release of glutamate
- Arachidonic acid
- Endocannabinoids
258
What is a way that Ca2+ can also trigger changes in gene expression?
Activates cyclic-AMP responsive element binding protein (CREB). CREB binds to DNA and promotes gene expression.
- This leads to new proteins: new receptors, rewiring, LONGER TERM PLASTICITY
259
What happens if cAMP synthesis/regulation is dysfunctional?
Learning and long-term memory formation are affected.
260
True or false: Short term memory requires changes in gene expression and protein synthesis
False; it does not
261
How is a drug defined?
A chemical substances of known structure, other than a nutrient or an essential dietary ingredient, that, when administered to a living organism, produces a biological effect.
262
True or false: drug=medicine
False; many drugs are not used in medicines but are nevertheless useful research tools
263
How is medicine defined?
A chemical preparation, which usually but not necessarily contains one or more drugs, administered with the intention of producing a therapeutic effect
264
True or false: medicines usually contain other substances (vehicles, stabilizers, solvents, etc) besides the active drug, to make them more convenient to use
True
265
Pharmacology is divided into which two domains?
1. Pharmacokinetics
2. Pharmacodynamics/signal transduction
266
Define pharmacodynamics
Mechanisms of drug action (what the drug does to the body)
Quantitative relationship between:
1. Drug concentration and receptor interaction
AND
2. Specific cellular response(s)
267
What 3 things does pharmacodynamics look at?
1. Receptor binding
2. Mechanism of action
3. Side/adverse effects
268
Define pharmacokinetics
What the body does to drugs (i.e. how the body responds to the drug)
269
Pharmacokinetics deals with the mechanisms and quantitative characteristics of which 4 processes?
ADME
1. Absorption
2. Distribution
3. Metabolism
4. Elimination
270
Pharmacokinetics looks at the relationship between...
- What predictions does it make?
Dose and effect
Predictions of the time course of drug action
271
Define absorption
Passage of drug from side of administration or tissue, into blood (plasma)
272
Absorption is important for all routes of administration except... (2)
1. i.v. (directly into blood)
2. Inhaled (directly into lungs e.g. bronchodilators)
273
What are the 6 main routes of administration?
1. Oral or rectal (into gut_
2. Percutaneous (skin)
3. Intravenous
4. Intramuscular
5. Intrathecal (into the spine -> CSF -> brain)
6. Inhalation
274
What is an advantage of injecting a drug directly into the brain?
Allows it to act quickly in low doses because it encounters fewer barriers (like the blood-brain barrier)
275
Taking drugs ____ is the safest, easiest, and most convenient way to administer them
Orally
276
Drugs that are weak acids...
Pass from the stomach into the bloodstream
277
Drugs that are weak bases...
Pass from the intestines to the bloodstream
278
Drugs injected into muscle encounter...
More barriers than do drugs inhalaed
279
Drugs inhaled into the lungs encounter...
Few barriers en route to the brain
280
Drugs ______ encounter the fewest barriers to the brain
Injected into the bloodstream
281
Drugs must be (hydrophilic/hydrophobic)
Hydrophobic (lipophilic)
282
Drugs contained in adhesive patches are....
Absorbed through the skin and into the bloodstream
283
Upon oral administration, the drug is absorbed through the gut. The drug can then go through where?
The liver (portal system) which contains enzymes that destroy drugs
Or to the plasma
284
Define oral bioavailability
Percentage of the ingested drug that gains unaltered access to the systemic circulation (compared to IV administration)
- i.e. was not destroyed or altered by any enzymes
285
How to calculate bioavailability?
(Area under the curve of oral)/(area under the curve of injected) x 100
Curve: Plasma concentration of drug on y-axis, time on x-axis
286
True or false: Oral bioavailability is easy to quantify
False; oral bioavailability is VERY VARIABLE! It is dependent on many factors; even those within the same drug group can have drastically different bioavailabilities
287
Low oral bioavailability can be overcome by simply...
Increasing the dose of the orally-administered drug (relative to an injected dose)
- therefore, this is not usually an important therapeutic issue
288
What is the exception to the "increased dose" rule for low oral bioavailabilities?
With extensive hepatic (liver) first-pass metabolism, increasing an oral dose could produce unacceptable levels of active or toxic metabolites
289
True or false: poor oral absorption can be intentional
- Explain why or why not, using examples
True; to enhance actions in the gut
Ex:
- antidiarrheals (so it stays in rectum rather than being absorbed)
- vancomycin for C difficile infections
- 5-aminosalicylic acid for inflammatory bowel disease
290
Explain how gastro-intestinal motility affects drug absorption/distribution of oral drugs
Some disorders (e.g. migraine) cause gastric stasis which slows down absorption.
- Also, taking drug after food may be more slowly absorbed as progress to small intestine can be impaired
291
Explain how splanchnic blood flow affects drug absorption/distribution of oral drugs
Splanchnic circulation is the blood flow to and from the organs of the abdomen, including the stomach, small intestine, colon, pancreas, and spleen.
Food increases splanchnic blood flow so drugs which require biotransformation in liver (pro-drugs) reach effective concentrations if taken with a meal
292
Explain how the digestive tract affects drug absorption/distribution of oral drugs
Contents (enzymes/pH)
293
Explain how the liver affects drug absorption/distribution of oral drugs
- What is 1st pass metabolism?
1st pass metabolism: Drugs administered orally are first exposed to the liver and may be metabolized before reaching the rest of the body
294
Explain how drug formulation affects the drug absorption/distribution of oral drugs (3)
1. Tablet vs. suspension
2. Slow or quick release capsules
3. Particle size
295
Describe the digoxin example with the drug formulation
Different hospitals showed variation in oral absorption among different formulations of digoxin (they had different pharmaceutical sources)
- The large variation has caused the formulation of digoxin tablets to be standardized since the study was published (to ensure all patients get the same effect)
296
Explain how the blood-brain barrier serves as a barrier to drug absorption
Tight junctions in brain capillaries mean that drugs can mainly gain access to the brain by lipid solubility and/or carrier-mediated transport
297
What is the two compartment model of pharmacokinetics?
A drug is ingested and travels to the liver. The drug is then absorbed in the plasma (central component) or excreted through 1st pass metabolism.
The drug travels from the central compartment (plasma) to the peripheral compartment (tissues) or directly to the site of action (receptor) to have a therapeutic (or toxic) effect
298
Drug metabolism is a form of...
Biotransformation
299
What are 3 potential effects of metabolism of drugs?
1. Drug inactivation
2. Formation of active metabolites from active drug
3. Formation of active metabolites from inactive drug (pro-drug)
300
Describe drug inactivation through drug metabolism
Production of inactive metabolites that can be excreted thus the drug is conversed into a more water-soluble compound that facilitates elimination by the kidney
301
Describe the formation of active metabolites from active drug through drug metabolism
- Provide an example
The drug is converted into similar active metabolites (sometimes toxic)
- conversion of codeine to morphine
302
Describe the formation of active metabolites from inactive drug (pro-drug)
- Provide an example
Some drugs are given as an inactive pro-drug; metabolism will render them active
- cortisone to hydrocortisone
303
What organ is the principle site of drug metabolism?
The liver
304
Other than the liver, what other 4 organs contribute to drug metabolism?
1. Kidney
2. Intestine
3. Lung (anaesthetics)
4. Plasma
All contain enzymes that can metabolize drugs
305
Define excretion in terms of drugs
Clearing the drug (or its metabolites) out of the body
306
What are 4 ways of drug excretion?
1. urine
2. Feces
3. Breast milk
4. Exhaled through air
307
Some chemicals are hard to excrete. What happens to these chemicals and what are some examples of chemicals that do this? What does this lead to?
Build up in the body
- e.g. heavy metals, like Mercury: accumulation in CNS leads to severe neurological conditions
- Ca2+ also builds up in bones and teeth
308
Drug metabolism is separated into __ phases, which both ___ lipid solubility, thereby...
2, reduce, increasing renal elimination
309
Phase 1 of drug metabolism involves which 3 types of reactions?
Hydroxylation reactions
1. Oxidation
2. Reduction
3. Hydrolysis
310
Phase 2 of drug metabolism involves what type of reaction?
Conjugation (adding large polar molecules to the drug)
311
True or false: Phase 1 is always followed by phase 2 in drug metabolism
False; phase 1 followed by phase 2 is common but not universal
- A phase 2 reaction can occur without a phase 1 reaction
- A phase 2 reaction may precede the phase 1 (hydroxylation) reaction
312
What model is used to describe drug-receptor interactions?
The lock-and-key model
The drug, hormone, neurotransmitter or neuropeptide fits the lock's shape (allows for selectivity)
313
True or false: drug molecules must bind to receptors to produce a pharmacological response, and receptors always only have one binding site
False; drug molecules must bind to receptors to produce a pharmacological response, but receptors can have multiple binding sites
314
What 3 things does pharmacodynamics (where, how and how well do drugs do what they need to do) depend on?
1. Concentration and distribution of drug
2. Binding affinity of drug to receptor (higher affinity drugs can displace lower affinity drugs when competing for same receptor site)
3. Selectivity of the drug (how well does the drug bind only to the receptor it is intended for?)
315
True or false: no drugs are 100% specific
True
316
What are the 4 primary drug receptors?
1. Receptors
2. Ion channels
3. Enzymes
4. Transporters
317
>90% of clinical useful drugs act on...
Membrane receptors, including ion channels
318
What are the 4 main drug targets in terms of signal transduction?
1. Ligand-gated ion channels (ionotropic)
2. G-protein coupled receptor (GPCR, metabotropic)
3. Kinase-linked
4. Nuclear receptor
319
Define drug affinity
Tendency of drug to bind to receptor
- Receptor occupation is governed by affinity
320
Define drug efficacy
Tendency of drug once bound to activate receptor, resulting in a response
- Receptor activation is governed by efficacy
321
What is the efficacy of an antagonist?
0 (since no response)
322
Receptors have which two major properties?
1. Recognition/selectivity
2. Response
323
Describe the recognition/selectivity of drug-receptor interactions
(Ideally) drugs interact (bind) a receptor with high affinity (i.e. at low concentrations) and with a high degree of chemical specificity
- However, no drug is completely specific!
324
Describe the response aspect of drug-receptor interactions
As a consequence of drug binding, something happens: a series of events are initiated that ultimately produces the desires (therapeutic) cellular response (process of signal transduction)
325
What do bioassays provide information on?
The pharmacological activity of new or chemically undefined substances
326
Define an agonist
Ligand/drug that binds to target and elicits a cellular response (i.e. receptor stimulation)
- Related to potency/efficacy
327
Define an antagonist
Ligand/drug that binds to target without causing a response (i.e. receptor blockade)
328
Define an inverse agonist
Ligand/drug that binds to target and elicits a cellular response (i.e. receptor inhibition). Directly inhibit "spontaneous" activity of a receptor (negative efficacy)
- Important for receptors that are constitutively active
- Related to potency/efficacy
329
What's a partial agonist?
Will never be able to have a full 100% drug effect, like a full agonist
330
How do antagonists look on opioid effect x log dose graphs?
No effect at all
331
What is a dose-response curve?
y-axis: percentage of individuals responding
x-axis: concentration
332
What can quantal dose-response curves be used to determine?
Quantal: "all or none" (e.g. sleep-induction, death, patient responding)
- proportion of subjects will vary with dose, so we can figure out the [] at which the majority of the population will respond
333
The shape and slope of the curve on a quantal dose-response curve is determined by...
Individual variation
334
A more uniform population will give a _____ curve on a quantal dose-response curve
Steeper
335
What is the minimal effective dose (MED) on a quantal dose-response curve?
Lowest dose that will produce the desired (therapeutic) response
336
What is the maximum tolerated dose (MTD) on a quantal dose-response curve?
Highest dose that can be administered without adverse (toxic) events
337
What is the ED50 on a quantal dose-response curve
Effective dose in 50% of population
338
What is TD50 on a quantal dose-response curve?
Toxic effect in 50% of population
339
What is the therapeutic window on a quantal dose-response curve?
Concentration range between the MED and MTD
- range at which you can get a response without killing anyone
340
What is the therapeutic index on a quantal dose-response curve?
Safety margin; refers to range between ED50 and TD50
341
If the therapeutic index on a quantal dose-response curve is small, then...
Drug likely isn't optimal
342
Define drug potency
A COMPARATIVE expression of drug activity (rather than absolute) expression of drug activity
343
True or false: potency is very relevant to therapeutic effectiveness
False; potency is very useful to characterize receptor systems but is not relevant to therapeutic effectiveness
- e.g. Drug A will not be better therapeutically than a less potent drug B: both can produce the same maximal effect; drug A will simply produce the therapeutic effect at a lower dose
344
How are potency and EC50 related?
The higher the potency, the lower the EC50 (i.e. the lower the dose required to get drug activity)
345
Dose-response curves are visualized on a ____ scale
Semilog
- just makes the visualization of the curve better
346
Agonists elicit a _____-dependent response
concentration
347
What is a competitive antagonist?
Binds the sample binding site of another compound that normally binds the site
348
In the presence of a competitive antagonist, increasing the concentration of the agonist drug (or natural ligand)...
Can still produce a maximal response (Emax), because of mass action competition
349
True or false: competitive antagonism is surmountable
True
350
How does a competitive antagonist affect the concentration-effect curve?
It shifts to the right (higher EC50)
351
What is a non-competitive antagonist?
Chemical forms a strong chemical bond with the receptor (in a different site from the binding site), resulting in receptor inactivation because the antagonist dissociates very slowly (or not at all) from the receptors
352
True or false: non-competitive antagonism is surmountable
False; the receptor is irreversibly inactivated, therefore the antagonism is non-surmountable
353
How does a non-competitive antagonist affect the concentration-effect curve?
Decreases Emax (maximum response)
354
How is non-competitive antagonism related to time?
The longer a non-competitive antagonist has access to the receptor, the more Emax decreases
355
Inverse agonist synonym
Negative agonist
356
What are constitutively active receptors?
Receptors that show an appreciable level of activation when no ligand is present
357
Drugs that activate receptors and directly enhance communication at a synapse are known as...
Agonists
358
Drugs that activate receptors and directly decrease communication at a synapse are known as...
Inverse agonists
359
Drugs that block receptor and indirectly decrease communication at a synapse are known as...
Antagonists
360
Hormones/neurotransmitters, agonists, inverse agonists and antagonists are all ___-dependent
Dose
361
Which of the following shows no receptor response?
- Hormone/neurotransmitter
- Agonist
- Inverse agonist
- Antagonist
Antagonist
362
Define psychoactive drug
Drug that affects the CNS and alters behaviour, including mood and cognition (therapeutic and recreational)
363
Most psychoactive drugs affect
- list 5 examples of processes that are affected
Neurotransmission in some manner
- Synthesis
- Packaging
- Release
- Degradation or clearance
- Change receptor activity or number
364
Define drug tolerance
Repeated exposure to drugs reduces the effectiveness of the drugs (reduced response to a given dose, and need a higher dose to get the same effect)
365
Define metabolic tolerance
Body is more efficient and elimination of the drug
366
Define cellular tolerance
Target tissue has decreased sensitivity (can happen b/c there's less receptors present, as the body's way of returning to homeostasis when taking drugs)
367
Define learned tolerance
Adapt behaviour based on experience to compensate for the effects of the drug
- "Learned tolerance is when a person has carried out a task enough times while under the influence, that they can still perform the task with similar effectiveness to when they are sober."
368
Define cross tolerance
Tolerance for one drug is carried over to a different member of the same drug group
- e.g. morphine use can lead to tolerance for other opiates
369
Define DRUG sensitization
Intermittent exposure to a drug can lead to enhanced responses to subsequent exposure to the same dose
- can last for a long time
- can occur even after a single dose
370
Describe amphetamines, and how they are related to drug sensitization
Amphetamine use results in enhanced release of dopamine, and blocks reuptake transporters of NE, dopamine and serotonin (stuck in synaptic cleft)
- rearing (animal stands on hind legs to explore environment), sniffing, walking: more of each behaviour to the same dose on subsequent tests
371
What is the most used psychoactive drug in the world?
Caffeine
372
What is the main arousing feature of caffeine?
Blocking adenosine receptors
373
Caffeine withdrawal can lead to...(3)
- Irritability
- Headache
- Sleepiness
374
Caffeine is a _____ to adenosine
Competitive antagonist
- they have very similar structures
375
Nicotine affects which neurotransmitter and how?
Affects acetylcholine
- Activates nicotinic acetylcholine receptor (ionotropic receptor)
376
What effect does nicotine have at low and high doses?
Low initial doses: stimulant
Higher repeated doses: relaxation
- Leads to the release of other NTs (dopamine)
- Highly addictive (strong withdrawal - anxiety and irritability)
- Rapid tolerance
377
Other than nicotine, what's a class of drugs that affects acetylcholine?
AChE inhibitors
378
What is the main type of drug that affects GABA, and what effects does it have?
Benzodiazepines (e.g. valium)
- Anxiety
- Sleep
379
How do benzodiazepines impact GABA?
Enhance transmission at the GABA receptor, opening Cl- channels
- Reduces the responsiveness of a cell (b/c the cell is further away from the threshold)
- Rapid tolerance
380
Other than benzodiazepenes, what other drug acts on the GABA channel? What properties does it have?
Alcohol
- depressant-like properties
- moderate use may be beneficial
381
How does alcohol impact the use of benzodiazepenes?
The effects of alcohol and benzodiazepenes summate
382
What are 5 potential effects of excessive alcohol use?
- Nerve damage
- Poor diet (thiamine deficiency = Korsakoff's syndrome)
- Fetal alcohol syndrome
- Cortical loss
- Decreased neurogenesis
383
Describe the anterior cortical grey matter in recovering alcoholics
Starts lower than control. Increases slightly up to controls, but never perfect
- i.e. SOME recovery is possible
384
Describe the lateral ventricles of recovering alcoholics
Starts higher than control. Decreases slightly down to controls, but never perfect
- i.e. SOME recovery is possible
385
What is the main excitatory neurotransmitter in the forebrain and cerebellum?
Glutamate
386
What are two drugs that affect glutamate?
Phencycladine (PCP; angel dust) and Ketamine
387
What are the effects of Phencycladine (PCP; angel dust)?
- Hallucinogenic
- Cognitive impairment
388
What are the effects of Ketamine?
It is a dissociative anaesthetic
- Low IV doses show benefits for depression
389
How do Phencycladine and Ketamine affect glutamate?
Act by blocking NMDA receptors
- Remember that these receptors are essential for synaptic plasticity (important for learning and memory)
390
In general, antidepressants are used to treat...
Mood and affective disorders (one of the most common psychiatric disorders)
391
Prevalence of mood and affective disorders in males?
5.8%
392
Prevalence of mood and affective disorders in females?
9.5%
393
What are 3 classes of antidepressants? Briefly describe each
1. MAOIs: Inhibits the breakdown of serotonin
2. Tricyclics: Prevents the reuptake of serotonin and NE from the synaptic cleft
3. SSRIs: Prevents the reuptake of serotonin from the synaptic cleft
394
What is known as the therapeutic lag of antidepressants?
Can take weeks before you see any improvements in mental health
395
What are 3 5-HT receptor agonists? What effect do they all have?
LSD, mescaline, ecstasy (all halucinogenic)
396
Antipsychotics are used to treat...
- what is this disorder associated with?
Schizophrenia (which is associated with excessive mesolimbic dopaminergic activity)
397
How do antipsychotics act?
They reduce dopaminergic-related activity (particularly in the frontal lobe)
398
Describe 1st generation neuroleptics
Chlorpromazine and Halperidol
- Act as D2 (dopamine receptor) antagonists
- Lots of movement-related side effects
399
Describe atypical neuroleptics
Clozapine
- Less movement-related side effects
400
Describe the drugs that treat ADHD
Drug ("stimulants") prevent the reuptake of DA (and/or NE)
- Enhance activity at the synapse, particularly in brain areas that play a part in controlling attention and behaviour
401
How do amphetamines and cocaine affect dopamine?
They block the reuptake of dopamine, enhancing activity at the synapse
402
How is Parkinson's disease treated?
Treatment with L-DOPA
- L-DOPA crosses the blood-brain barrier, and is converted into dopamine with DOPA decarboxylase enzyme
- Remaining cells now make and release more dopamine
403
A problem with treating Parkinson's with L-DOPA is that there are lots of dopamine receptors outside of the brain, resulting in a variety of adverse effects like constipation. How is this mitigated?
Prevent synthesis of dopamine outside the brain by using Benserazide
- does not cross the blood-brain barrier and inhibits DOPA decarboxylase
404
What are opiates used for?
Pain relief
405
Opium is derived from what? What can they be converted into? What do these all bind?
Derived from the poppy Papaver somniferum
Opium can be converted into various alkaloids including morphine, codeine and heroine, which all bind and activate opioid receptor (GPCR)
406
What are two endogenous opioid receptor ligands?
Enkephalins and endorphins
407
Describe the effects of opioid use and the brain on opioids
Major drug of abuse
- Tolerance, sensitization
- Potency and overdose risk
- Excessive stimulation of the Dopamine reward system
408
What receptors do cannabinoids activate?
Endocannabinoid receptors
409
What is THC in cannabinoids?
The plant's primary component for causing psychoactive effects
410
What are 7 effects of cannabinoid use?
- Relaxation
- Decrease nausea
- Increase appetite
- Hallucinations
- Paranoia
- Does exhibit tolerance and dependance
- Respiratory problems when smoked
411
What 2 things are cannabinoids used in treating?
Glaucoma and chronic pain
412
Describe cannabidiol (CBD) (2)
- May not produce the same effects that drive recreational use of cannabis
- May help with a variety of ailments (e.g. epilepsy)
413
What is Ecstasy derived from?
Amphetamine
414
What are 4 effects of Ecstasy use?
1. Long-term reduction in serotonin levels
2. Change in transporter activity
3. Loss of 5-HT axons
4. Persistent psychiatric and cognitive problems
Can persist for 18 months
415
Define substance abuse
Drug use where someone relies on a drug, and its use becomes a major component of their life
416
Define addiction/substance dependence (4)
- Escalating substance abuse, compulsive and relapsing
- Disproportionate amount of time seeking, preparing and consuming the drug (repetitive and persistent)
- Interferes with everyday activities and responsibilities
- They may want to stop, understand the negative consequences, and may not even derive pleasure from the drug anymore
417
Describe escalation in terms of drug use
Increase dose and or frequency
- Not just response to tolerance (i.e. not just physiological): pathological increase in MOTIVATION to consume
- Important component of transitions from sporadic user to addiction
418
What is the mechanism of addiction formation?
Activation of the dopaminergic system: ventral tegmentum -> nucleus accumbens
- Some drugs of abuse activate the NAcc directly (e.g. cocaine) while others activate it indirectly (e.g. nicotine)
419
Drugs that block what can help with addiction?
Drugs that block dopaminergic pathway
420
What is wanting and liking theory (3 steps)?
1. Initial use produces pleasure (liking)
2. Repeated use causes less pleasure and tolerance (liking goes down)
3. Drug taking behaviour classically conditions various setting/situation cues (wanting)
421
Why don't all drug users become addicted?
Genetics (predisposition), and interactions between nature & nurture (genetics + environment)
422
What have twin studies and adoption studies shown regarding addiction rates?
Twin studies have shown that addiction has higher concordance in identical than in fraternal twins.
Adoption studies show that addiction rates better match biological parents.
423
True or false: most animals don't enjoy alcohol but can be selectively bred to consume it
True
424
What are the body's 2 main control systems?
1. Endocrine system
2. Nervous system
425
Compare the endocrine and nervous systems (2 each)
Endocrine:
1. "PA system", uses circulation of body fluids to broadcast messages throughout body.
2. Acts slow, over extended periods of time.
Nervous:
1. "Cellular"; uses dedicated structures to send messages to individual target cells (electrical + chemical signals).
2. Acts fast, over limited periods of time.
426
True or false: small changes in hormone levels can result in big changes in behaviour, physiology and development
True
427
Define hormone
Chemicals secreted by one group of cells (endocrine glands) that are carried through bloodstream to other parts of the body
- Acts on specific target tissues to produce specific physiological effects
428
What are exocrine glands?
Release hormones outside of body (tears, saliva, sweat)
429
What are endocrine glands?
A specialized organ that produces and releases hormones directly into the bloodstream to regulate bodily functions
430
True or false: hormones can only be released by endocrine and exocrine glands
False; hormones can also be released by non-endocrine tissues like the stomach (gastrin) and heart (natriuretic peptide, reduces blood pressure)
431
How was the role of testes inferred?
Castration led to changes in birds and eunuchs
- Upon testes being removed, bird underwent significant changes (became smaller, did not mount hens, was not aggressive and had weak crowing).
- If one of the testes was re-implanted immediately after its removal, rooster developed normal wattles and normal behaviour
432
What is the main hormone secreted by the testes?
Testosterone
433
What are the main functions regulated by secretion by the pineal gland?
Reproductive maturation; body rhythms
434
The pituitary gland is split into which 2 parts?
1. Anterior pituitary
2. Posterior pituitary
435
What are the main functions of the hormones secreted by the anterior pituitary?
Hormone secretion by thyroid, adrenal cortex, and gonads; growth
436
What are the main functions of the hormones secreted by the posterior pituitary?
Water balance; salt balance
437
What are the main functions of the hormones secreted by the thyroid?
Growth and development; metabolic rate
438
What are the main functions of the hormones secreted by the adrenal cortex?
Salt and carbohydrate metabolism; inflammatory reactions
439
What is the main function of the hormones secreted by the adrenal medulla?
Emotional arousal
440
What is the main function of the hormones secreted by the pancreas?
Sugar metabolism
441
What are the main functions of the hormones secreted by the gonads?
Body development; maintenance of reproductive organs in adults
442
Describe the neurocrine function of hormones
Neurotransmitter communication between neurons
443
Describe the autocrine function of hormones
Hormones act on the same cell that released it
444
Describe the paracrine function of hormones
Hormones act on nearby cells (neighbours)
445
Describe the endocrine function of hormones
Hormones travel through the blood to reach target
446
Describe the pheromone function of hormones
Hormones that target another member OF THE SAME SPECIES
447
Describe the allomone function of hormones
Hormones that target members of ANOTHER SPECIES
448
Neural signals are (directed/global), while hormonal signals are (directed/global)
Directed, global (affects all cells with appropriate receptors)
449
Neural signals are (slow/fast), while hormonal signals are (slow/fast)
Fast, slow
450
Neural signals are (analogue/digital), while hormonal signals are (analogue/digital)
Digital, analogue
451
Neural signals can regulate _____ behaviours, while hormonal signals usually only regulate _____
Voluntary behaviours; events that are not under conscious control
452
What are two similarities between neural and hormonal signals?
1. Both use chemical messengers
- Released to influence other cells
- Stored for triggered release
2. Can activate 2nd messenger systems
- Often the same systems
453
What are neurosecretory cells
Neurons that release hormones
- i.e. are neurotransmitters or hormones released?
454
True or false: some chemicals can act as both a neurotransmitter and a hormone
True; e.g. norepinephrine and epinephrine
455
What are the 9 general principles of hormone action?
1. Act in a gradual fashion (slow onset, long duration)
2. Change the intensity or probability of a behaviour (but usually don't initiate it)
3. Environmental factors influence which hormone is released, and how much (e.g. aggression + testosterone, behaviour can act as an "environmental factor")
4. One hormone can affect many targets, one target can be affected by many hormones
5. Pulsatile release
6. Rhythmic levels (i.e. time of day)
7. Hormones can interact (effect of one can be very different depending on the presence or absence of another)
8. Similar structure between animal species
- Can have a very different function though: e.g. prolactin in mammals is associated with milk production, but is related to the control of water and salt balance in fish)
9. Can only affect cells that contain appropriate receptors
- Cell and tissue location of receptors quite similar between species.
456
Describe protein hormones (2)
- What are they also known as?
Aka peptide hormones
- Made of a string of amino acids
- Water soluble
457
Describe amine hormones (2)
Based on a single amino acid (Tyrosine or Tryptophan with modified group(s))
- Water-soluble
458
Describe steroid hormones (2)
Based on a cholesterol molecule
- Lipid-soluble
459
What are the 2 general effects of hormone action?
1. Regulate development (organizational)
- Proliferation, growth, differentiation
- Early events (e.g. cell division)
- Later events (e.g. puberty + secondary sex traits)
2. Modulate cellular activity (activational)
- Regulate rate of cellular function
- e.g. insulin and thyroid hormones affect metabolism in almost every cell in the body
- Other hormones are very specific (e.g. luteinizing hormone works only in the gonads)
460
Describe how protein and amine hormones (water-soluble) act
Most bind to a specific receptor on the membrane of cells (often kinase-linked receptors). This activates second messengers (e.g. cAMP)
- Same 2nd messenger can have a different effect in different cells
- Same 2nd messenger can even have a different effect in the same cell
461
Describe kinase-linked receptors (4)
- Located in cellular membrane
- Receptor is an enzyme
- Direct coupling between hormone and receptor
- Mediate effects on growth and differentiation such as gene transcription and protein synthesis
462
Describe how steroid hormones (lipid-soluble)
- 4 steps
1. Pass right through the cell membrane
2. Bind to receptors (nuclear receptors) located in the cytosol or nucleus
3. The activated receptor binds to DNA and regulates gene transcription and therefore protein production
4. Slow in onset and act more slowly (hours to days)
- Can have long lasting effects on development or adult function of cells
463
The location of nuclear receptors is ____, and the effector is _____
Intracellular (cytosol or nucleus), gene transcription
464
Nuclear receptor family can be considered as...
Ligand-activated transcription factors (they transduce signals by modifying gene transcription)
465
True or false: some steroids may act at cell surface receptors to produce rapid effects
True; this may change 2nd messenger activity or membrane potentials
466
What are the 4 mechanisms of feedback?
1. Autocrine
2. Target cell feedback
3. Brain regulation
4. Brain and pituitary regulation
467
Describe autocrine feedback
Releasing hormone affects cell releasing it through negative feedback
468
Describe target cell feedback and provide an example
Releasing cell detects effect of target
- If initial effect is too small, more hormone is released
- If the effect is sufficient, no more is released
Ex: as glucose increases, so does insulin. As glucose drops, so does insulin
469
Describe brain regulation (feedback) and provide an example
Detection upstream of the endocrine cell
Ex: epinephrine
- Hypothalamus regulates adrenal medulla release of epinephrine
- This affects many targets, and the brain detects these effects (racing heart) and regulates further release
470
Describe brain and pituitary regulation (feedback) (3)
- Hypothalamus regulates pituitary function with "releasing hormones"
- Pituitary regulates target gland with "tropic hormones"
- Released hormone feeds back to turn off both hypothalamus and pituitary
471
The anterior pituitary is also known as...
Adenohypophysis
472
Describe the anterior pituitary and its tissue origin
Produces and releases many hormones (most of these target other glands)
- Glandular tissue in origin
- Actively regulated by releasing hormones produced by cells in the hypothalamus
473
Describe the posterior pituitary and its tissue origin
Site of hormone release (oxytocin and vasopressin), but not production
- Neural tissue in origin
- Released from neuroendocrine cells that originate in the hypothalamus (supra-optic nucleus and paraventricular nucleus)
- Axons from these areas descend through pituitary stalk and synapse on blood vessels in posterior pituitary
474
What is vasopressin also known as, and what does it regulate?
AKA antidiuretic hormone (ADH)
- Regulates fluid balance and blood pressure
475
The neurons that pass through the posterior pituitary originate in which nuclei in the hypothalamus?
Supraoptic and paraventricular nuclei
476
What are 4 functions of oxytocin?
1. Regulates reproductive and parental behaviour
2. Causes uterine contractions, can be used to induce labour.
3. Regulates milk letdown response (30-60 s time lag, can be classically conditioned)
4. Important for social bonding
477
What is the pituitary portal system?
Neuroendocrine cells in the hypothalamus release their chemicals onto blood vessels that make up the pituitary portal system
- Blood flows a short distance to anterior pituitary
478
Where are the adrenal glands located? What are they split into?
On top of the kidneys
Outer shell: cortex
Inner core: Medulla
479
Describe the adrenal cortex
Different layers of cells which each produce a different steroid hormone
480
Describe the adrenal medulla (3)
- Considered part of the sympathetic nervous system
- Receive lots of neural input
- Secrete amine hormones (Epinephrine and norepinephrine)
481
What 3 hormone classes are released by the adrenal cortex?
1. Glucocorticoids (cortisol)
2. Mineralocorticoids (aldosterone)
3. Sex steroids
482
Describe glucocorticoids (cortisol) released by the adrenal cortex (4)
- Increase blood pressure
- Increases protein breakdown
- Anti-inflammatory (decreases body's response to tissue injury)
- Can be neurotoxic in high levels (kills neurons in the hypothalamus)
483
Describe mineralocorticoids released by the adrenal cortex (aldosterone) (2)
- Regulate mineral balance (Na+, K+)
- Regulate fluid balance (thirst, kidney function)
484
Describe sex steroids released by the adrenal cortex
- Androstenedione
- Regulates adult pattern of body hair
485
What 3 things do the gonads (ovaries and testes) regulate?
Courtship, mating, and parental behaviour
486
True or false: sex steroids are male/female exclusive
False; they are not male or female exclusive, just more prevalent in specific sexes
487
Sex steroids are based on ____ molecules, and (can/cannot) be interconverted
Cholesterol
Can (e.g. progestogens -> androgens -> estrogens)
488
What do the Sertoli cells make in the testes?
Sperm
489
What do the Leydig cells make in the testes? How are they regulated?
Testosterone
- Regulated by LH from the anterior pituitary (which is regulated by GnRH from the hypothalamus)
490
What 2 things does testosterone regulate?
1. Puberty changes
2. Seasonal breeding and characteristics (e.g. rutting and antlers)
491
What 2 molecule conversions occur in the ovaries?
1. Estrogens -> estradiol
2. Progestins -> Progesterone
492
What 2 things may estrogens regulate?
1. May improve cognition
2. May protect brain from stress and stroke
493
Describe how oral contraceptives regulate ovulation
Oral contraceptives (mix of progesterone and estrogen) mimic feedback to the hypothalamus and pituitary to prevent GnRH release
- No GnRH = no LH or FSH surge = no ovulation
NEUR 321
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