CNS Pharmacology Flashcards
1
Q
Who was the first to demonstrate the usefulness of nitrous oxide as an analgesic in the process of tooth extraction?
A
Horace Wells
2
Q
William Morton was known for his use of ether as a volatile anaesthetic during tooth extraction, T or F?
A
T
3
Q
What was J. Simpson’s contribution to general anaesthesia?
A
He was the first person to demonstrate that chloroform could render patients’ unconscious. Was also deemed the co-discoverer of general anaesthetics
4
Q
What are the two classes of chemical general anaesthetics?
A
Inhalational and intravenous
5
Q
What type of general anaesthetic is NO2?
A
Inhalational chemical general anaesthetic
6
Q
Give an example of some intravenous chemical general anaesthetics?
A
Halogenated hydrocarbons such as isoflurane. Also steroids and barbiturates such as thiopental are also intravenous
7
Q
Give some examples of physical general anaesthesias?
A
Low pressure, hypothermia
8
Q
What is meant by the term surgical anaesthesia?
A
The point at which patients become unresponsive and unable to sense pain
9
Q
What evidence is there to suggest that anaesthetics aren’t agonists acting on a receptor?
A
Steep dose-response curve which isn’t seen in agonist binding. Low pressure can also induce anaesthesia
10
Q
What is significant about the dose-response curve of general anaesthetics?
A
They have very steep dose-response curves
11
Q
What property of general anaesthetics is very closely related to their potency?
A
Lipid solubility
12
Q
Describe what is meant by a MAC value and how this relates to the potency of the general anaesthetic?
A
MAC value – minimum alveolar concentration of anaesthetic to alleviate a response to surgical incision in 50% of patients. The lower the MAC value the higher the potency of the general anaesthetic
13
Q
What is meant by the oil:gas partition coefficient?
A
The ease with which a substance dissolves, or partitions into oil
14
Q
Drugs with a low oil:gas partition coefficient will have a high potency and thus a lower MAC value, T or F?
A
F – drugs with higher oil:gas partition coefficients will have a high potency and lower MAC values
15
Q
What is meant by the Meyer-Overton rule?
A
The effect of an anaesthetic is proportional to the molar concentration of the agent in lipid
16
Q
What is the effect of general anaesthetics on the plasma membrane?
A
General anaesthetics lead to a volume expansion in the plasma membrane
17
Q
What is the impact of general anaesthetics on lipid fluidity?
A
General anaesthetics increase lipid fluidity
18
Q
What aspects of the general anaesthetic mechanism of action are explained by the lipid theory?
A
As antibiotics are thought to lead to a volume expansion of the plasma membrane and an increase in lipid fluidity the lipid theory of antibiotic action accounts for the meyer-overton rule. In addition, the effect of pressure is also explained as we know that a decrease in pressure results in a volume expansion of the lipid membrane and thus will give rise to anaesthesia. Finally this also accounts for the fact that such a diverse range of compound can have anaesthetic effects
19
Q
What aspects of the general anaesthetic mechanism of action aren’t explained by the lipid theory?
A
The fact that decreasing temperature can have anaesthetic effects despite the fact that it leads to a decrease in membrane fluidity. It also doesn’t explain that the binding of anaesthetics is saturable, implying a specific interaction with a protein. Finally there is a loss of actions in some compounds that are extremely lipid soluble and being homologous to known anaesthetics
20
Q
It in fact turned out that the mechanism of action of anaesthetics was a combination of the lipid theory and a protein binding theory, T or F?
A
T
21
Q
What is significant about the binding sites of anaesthetics that have been proven to bind to proteins in the plasma membrane?
A
General anaesthetic binding sites tend to be in hydrophobic domains deep within the membrane
22
Q
What type of proteins do general anaesthetics tend to bind to?
A
Ion channels
23
Q
Which specific receptor is it known that some general anaesthetics bind to and how does this lead to anaesthesia?
A
GABAA receptors – inhibition of regions in the central nervous system leading to anaesthesia
24
Q
Different anaesthetics all interact with the same subunits of the proteins to which they bind, T or F?
A
F – different anaesthetics bind to different subunits
25
Where to intravenous anaesthetics tend to bind on the GABAA receptors?
β subunit
26
Where in the GABAA receptor structure do volatile liquid general anaesthetics tend to bind?
The interface between the α and β subunits
27
What is the function of the two-pore-domain potassium channels?
Regulate the excitability of neurons
28
How do general anaesthetics that bind to the two-pore-domain potassium channels exert their effects?
Increase the excitability of the channels and make the firing of actions potentials less likely
29
Explain ketamine’s anaesthetic effect?
Ketamine is an NMDA receptor antagonist and is known as a dissociative anaesthetic which prevents the action of excitatory glutamate
30
What type of protein is targeted by isoflurane and how does this cause anaesthesia?
Voltage-gated Na+ channels – inhibition of these channels prevent depolarisation and action potential generation
31
What neurotransmitter is secreted at the giant synapse in the brain known as the Calyx of Held?
Glutamate
32
What is the effect of low concentrations of general anaesthetics?
Decreased synaptic transmission in the central nervous system
33
Decrease synaptic transmission at low concentrations of anaesthetics in which area of the brain are responsible for the amnesia experienced?
Hippocampus – new memory formation
34
Decrease synaptic transmission at low concentrations of anaesthetics in which area of the brain are responsible for the loss of consciousness?
Reticular formation
35
Decrease synaptic transmission at low concentrations of anaesthetics in which area of the brain are responsible for the analgesia experienced?
Thalamic sensory relay nuclei
36
What is the effect of high concentrations of general anaesthetics?
Decreased speed of conduction in the central and peripheral nervous system
37
What brain functions are lost at dangerously high anaesthetic concentrations?
Motor control, control of cardiovascular reflexes and respiration as well as autonomic regulation
38
What are the four stages of anaesthesia from lowest to highest drug concentration?
Analgesia, excitement, surgical anaesthesia, medullary paralysis
39
Why is the second stage of anaesthesia dangerous?
In the excitement phase there is an exaggeration of reflexes (i.e. gagging) due to imbalances in excitatory and inhibitory neurons.
40
What are the four ideals for controlling anaesthesia?
Rapid induction and loss of consciousness, analgesia, muscle relaxation and rapid recovery
41
Which types of general anaesthetics are usually used to induce anaesthesia?
Intravenous anaesthetics
42
What are the advantages of intravenous anaesthetics?
Easy administration, less stressful for patients, rapid induction, metabolised well and quickly due to high lipid solubility
43
What are the disadvantages of intravenous anaesthetics?
Pain at site of injection, complex pharmacokinetics, cardiovascular and respiratory depression, control of concentration difficult and little can be done to resolve overdose
44
Ketamine administration leads to complete loss of consciousness, T or F?
F
45
Ketamine is a powerful analgesic, T or F?
T
46
What are some of the side effects of ketamine use?
Cardiovascular excitement, involuntary movements, euphoria, hallucinations and delirium
47
What is the role of inhalation drugs in anaesthesia and why are they more suited to this?
Inhalational anaesthetics are useful in the maintenance of surgical anaesthesia. It is much easier to control the levels of these drugs in the body
48
The reason inhalation anaesthetics are easier to control is because they are metabolised instantly by the body, T or F?
F – there is little to no metabolism of inhalational anaesthetics
49
What four factors are needed to be controlled when maintaining inhalation anaesthetic blood concentration?
Initial drug concentration, pulmonary ventilation, rate of transfer from alveoli to the blood and the rate of loss of the drug from arterial blood
50
What can be done if the state of anaesthesia becomes too deep?
Increase ventilation rate
51
Inhalational drugs are extremely lipid soluble, T or F?
T
52
Inhalation anaesthetics are redistributed into the fat rapidly, T or F?
F – they are redistributed slowly due to poor fat perfusion
53
What does the high lipid solubility of inhalation anaesthetics allow?
Rapid equilibration between body fluid concentration and alveolar space concentration
54
What is malignant hyperthermia?
Condition associated with the use of general anaesthetics that results in a rapid rise in temperature, huge increases in muscle contraction, hypertension and tachycardia
55
What causes malignant hyperthermia?
Mutations in the ryanodine receptor
56
Where is the mutated protein in malignant hyperthermia found?
Sarcoplasmic reticulum in skeletal (and some smooth) muscle
57
What happens in malignant hyperthermia in the presence of a general anaesthetic?
The ryanodine receptor has an increased sensitivity to anaesthetics and so opens allowing Ca2+ efflux from the sarcoplasmic reticulum. This leads to a oxidative burst by the mitochondria and a massive increase in ATP and intracellular Ca2+
58
How can malignant hyperthermia be treated?
Dantrolene is a ryanodine receptor inhibitor that is given in conjunction with the general anaesthetic to prevent the symptoms
59
What is meant by ataxia?
Irregular, uncontrolled muscle contractions
60
Recall some of the main symptoms of ataxia?
Ataxia/shaking, trunk instability, vertigo, nausea, vomiting, poor balance, nystagmus, tendency to falls
61
What inheritance pattern is seen in Type I episodic ataxia?
Autosomal dominant
62
What is the typical age of onset for type I episodic ataxia?
20-30
63
What can be said about the duration of attacks seen in patients with Type I episodic ataxia?
They are short/brief
64
What causes episodic ataxia type I?
Loss of function mutation in KCNA1
65
What type of protein in affected by the mutation that causes type I ataxia?
Voltage-gated K+ channel
66
What triggers attacks or episodes in type I ataxia?
What triggers attacks or episodes in type I ataxia? Physical or emotional stress, impacts to the vestibular system or sudden changes in position
67
Where is the channel protein that is mutated in Type I ataxia found?
In the cerebellum and neuromuscular junction
68
What can be said about the pattern of possible mutations in the protein that results in type I ataxia?
There is no clear mutation pattern, mutations occur throughout the protein in no specific areas
69
What is the impact on K+ currents as a result of the expression of mutant KCNA1 protein in animal models and what does this tell you about the impact of these mutations on protein function?
Mutant KCNA1 expression results in a decrease in the size of the K+ currents in the neuron thus indicating the mutations are loss of function
70
What part of the action potential is mediated by voltage-gated K+ channels?
Repolarisation
71
How does the mutation in KCNA1 lead to the increase excitability of neurons and thus inappropriate shaking movements?
Loss of function of the voltage-gated K+ channels compromises repolarisation and thus extends depolarisation. This results in the increased excitability of the neurons
72
Explain how the location of the KCNA1 channels accounts for the double impact of their mutation?
As KCNA1 is present both in the cerebellum and neuromuscular junction then mutations will result in problems with muscle contraction at the level of the neuromuscular junction but also problems with the signals coming from the cerebellum in the first place.
73
Why is it thought that acetazolamide is effective in treating ataxia?
Acetazolamide is a carbonic anhydrase inhibitor. By inhibiting carbonic anhydrase there is more HCO3- secretion in the kidney and thus more excretion in the urine. Loss of bicarbonate from the body results in a decrease in body fluid pH which in turn causes a decrease in the excitability of neurons
74
Phenytoin and carbamazepine are also effective medications for the treatment of type I ataxia. What class of compounds are they and how do they work to alleviate symptoms?
Na+ channel blockers that reduce neuronal excitability by preventing depolarisation
75
What is the inheritance pattern of type II episodic ataxia?
Autosomal dominant
76
How does the onset of type II episodic ataxia differ from that of type I?
Type II ataxia has an earlier onset typically in childhood to teenage years
77
How do the attacks in type II ataxia differ from that in type I?
The duration of the attacks are much longer from 30mins to 24hours
78
How do they symptoms of type II ataxia differ from type I?
Type II episodic ataxia is more likely to lead to trunk instability, vertigo, nausea, vomiting and headaches
79
What triggers the onset of symptoms in type II ataxia?
Physical or emotional stress, impacts to the vestibular system and sudden changes in position
80
Episodic ataxia type II is caused by mutations in which protein?
CACNA1A
81
What type of protein is mutation in type II ataxia?
Voltage-gated Ca2+ channel
82
Where is the mutant protein found in type II ataxia?
In the cerebellum
83
Describe the structure of the CACNA1A protein?
Membrane protein with 24 transmembrane domains in 4 blocks of 6. Each block of 6 contains a pore region and the 4th TMD is the voltage sensor
84
CACNA1A is regulated by cGMP, T or F?
F – it is highly regulated by β accessory proteins
85
What are the two types of mutations seen in CACNA1A that result in episodic ataxia type II?
Substitution mutations and truncation mutations
86
Which type of type II ataxia mutation elicits the most severe symptoms in patients?
Truncation mutations
87
What can be said about the mutation patterns seen in CACNA1A?
There is no clear mutation pattern however there is some indications of clustering of mutations
88
A mutation in CACNA1A will cause episodic ataxia type II, T or F?
F – mutations in CACNA1A can cause one of three different allelic disorders. Missense mutations tend to cause familiar hemiplegic migraine whereas a repeat expansion of the c-terminus will result in spinocerebellar ataxia type VI
89
Episodic ataxia is a progressive neurodegenerative disease, T or F?
T
90
In which cells of the cerebellum is CACNA1A found?
Purkinje and granule cells
91
CACNA1A is found in the axons of the cells in the cerebellum, T or F?
F – it is more commonly found on the somas
92
What is the endogenous role of CACNA1A?
What is the endogenous role of CACNA1A? Mediates exocytotic neurotransmitter release
93
What is seen in CACNA1A knockout model mice?
They develop normally up until 10 days however after that they begin to show problems with balance, ataxia and twisting motions, mimicking the symptoms in human patients. They usually die after 3-4 weeks, relatively earlier than equivalent in humans
94
The G239R mutation is a common type II episodic ataxia mutation. What does this nomenclature represent?
What does this nomenclature represent? This means that it is a glycine (G) to arginine (R) transition mutation that occurs at position 239 in the protein
95
When measuring Ca2+ in cells, why are barium ions used instead of Ca2+?
Barium is in the same group as calcium and thus also forms a 2+ ion. Calcium currents are difficult to measure because during Ca2+ influx there is a feedback mechanism whereby Ca2+ influx results in the closure of the channels through which they move through. By using Ba2+ this effect is prevented
96
What are the results of the G239R mutation on Ca2+ currents and the downstream effects on action potential generation?
There is a decrease in the size of the Ca2+ currents and thus there is less Ca2+ coming into the cell. This means that there is a decrease in the amount of neurotransmitter released into the synaptic cleft and therefore less likely action potential generation in the postsynaptic cells
97
In contrast to type I episodic ataxia, where there is an increase in neuronal excitability, the mutation that causes type II ataxia leads to a decrease in excitability of cells in the cerebellum, T or F?
T
98
Explain the double effect of CACNA1A mutations?
As a result of a CACNA1A mutation there is a loss of function of the voltage-gated Ca2+ channels. This causes a decrease in the Ca2+ currents generated in the neurons in the cerebellum and thus less neurotransmitter release and less neuronal excitability. In addition to the smaller Ca2+ currents there is a change in the voltage dependency of the CACNA1A channel so that its highest activity is seen at a more positive membrane potential. This increases the time taken until the voltage-gated Ca2+ channels are activated thus decreasing the overall effectiveness of the channel
99
Explain the overall summary of effects of CACNA1A mutations in episodic ataxia type II?
Decreased Ca2+ influx, less neurotransmitter release leading to problems with the control of skeletal muscle
100
Name an effective treatment for type II episodic ataxia?
Acetazolamide
101
What are seizures?
Episodic neuronal discharge
102
What are the four main causes of epilepsy?
Tumour, trauma, genetics/inherited, infection
103
What are the two main types of epilepsy and how can they be further subdivided?
Partial epilepsy – where only one area of the brain is affected. Generalised epilepsy – where the whole brain is affected and symptoms are more severe. These can be subdivided into simple epilepsy where the patient doesn’t lose consciousness and complex epilepsy where they do
104
Complex generalised epilepsy is the most severe type, T or F?
T
105
Epilepsy can be acquired, T or F?
T – can be acquired as a result of neuronal damage or in autoimmune disease
106
What causes seizures at the neuronal level?
Increase excitability of neurons
107
Epilepsy is usually only caused by mutations in ion channels of excitatory neurons that leads to an increase in excitability, T or F?
T or F? F – mutations in ion channels that cause epilepsy have been found in excitatory and inhibitory neurons
108
Inhibitory neurons modulate the levels of excitation in the excitatory neurons, T or F?
T
109
Increased excitability of the neurons can happen via two mechanisms, what are these?
Mutations that lead to a direct increase in excitation of the excitatory neurons or that lead to a decrease inhibition of the excitatory neurons by the inhibitory neurons
110
Which phase of the action potential is mediated by the voltage-gated Na+ channels?
Depolarisation
111
Which phase of the action potential is mediated by the voltage-gated K+ channels?
Repolarisation
112
What aspect of electrical excitation in the nervous system is mediated by the voltage-gated Ca2+ channels?
Release of neurotransmitters from the presynaptic neurons in synaptic transmission
113
On the membrane of which type of neurons are AchRs found?
Postsynaptic excitatory neurons
114
What type of receptor is the AchR?
Ligand-gated ion channel
115
Activation of AchRs causes what in the neuron?
Opening of the channel and Na+ influx
116
On the membrane of which type of neurons would you find GABAA receptor?
Postsynaptic membrane of inhibitory neurons
117
What type of receptor is the GABAA receptor?
Ligands gated ion channel
118
Activation of the GABAA receptor causes what?
Opening of the channel and Cl- influx shifting the membrane potential more negative towards hyperpolarisation
119
What is the role of the HCN or hyperpolarisation-activated cyclic nucleotide gated channel?
The HCN channels is a voltage-gated channel that becomes activated when the membrane is hyperpolarised. As the membrane potential shifts more negative the open probability of the channel increases and its action is increased, shifting the membrane potential back towards depolarisation. This channel is regulated by cyclic nucleotides such as cAMP and cGMP and is important in determining the timing of action potential firing.
120
Explain how mutations in ion channels present in inhibitory neurons can lead to epilepsy?
Loss of function mutations in ion channels in the inhibitory neurons can lead to less GABA release at the synapse and thus a decrease inhibition of the excitatory neurons effectively increasing its excitability
121
What two channels can be affected by mutations that lead to loss of inhibition by inhibitory neurons?
Voltage-gated Ca2+ channels at the presynaptic terminal when mutated can have a loss of function results in less GABA release in the cleft and thus less inhibition of the excitatory neurons. Voltage-gated Na+ such as Nav1.1 present in axon can also have loss of function mutations. These channels mediate depolarisation and a loss in function will lead to decreased depolarisation and less action potential generation. This in turn will decrease the frequency of GABA release into the synapse thus resulting in a decrease in inhibition of the excitatory neuron
122
As well as mutations on the postsynaptic membrane and axon of excitatory neurons, mutation in ion channels in the dendrites can also lead to an increase in excitation, T or F?
T
123
Explain how mutations in ion channels on the postsynaptic membrane of excitatory cells leads to an increase in excitation of the excitatory neurons seen in epilepsy?
Loss of function mutations in the GABAA receptors will lead to a decrease in Cl- influx and as a result less inhibition of the excitatory neurons causing overexcitation.
124
How can mutations in ion channels present in the axons of excitable neurons lead to epilepsy?
The Nav1.2 ion channel mediates depolarisation in the excitatory neurons. A gain of function mutation in this ion channel would cause overexcitation and thus epilepsy. This is due to increased depolarisation in the excitatory neurons.
125
Explain how mutations in the AchRs can cause overexcitation which may lead to epilepsy?
he AchRs are found on the postsynaptic membrane of excitatory neurons. Gain of function mutations in these receptors will lead to increased Na+ influx and thus increased depolarisation in excitatory neurons which as a result will show increased excitability
126
Describe the classic voltage-gated Na+ channel structure, as shown by Nav1.1?
24 transmembrane domain protein in 4 blocks of 6. Each block contains a pore region and a voltage sensor which is the 4th transmembrane domain in each.
127
What two types of mutation are known to cause epilepsy?
Missense and truncation mutations
128
Both types of mutations cause the same types of epilepsy, T or F?
F – missense and truncation mutations cause different types of epilepsy with different symptoms
129
There is a clear pattern of mutations in the Nav1.1 protein that result in epilepsy, T or F?
F – there is no clear pattern
130
Depending on where in the protein each type of mutation is determines the severity and the types of symptoms shown in the patients, T or F?
T
131
Why are knockout models for epilepsy often heterozygotes?
This mimics what is seen in the patients where the epilepsy is caused by a dominant mutation and thus patients only have one faulty copy
132
What is seen in the inhibitory neurons of the Nav1.1 knockout mice in comparison to wild type?
Knockouts still showed some action potential generation but in a much less regular pattern. Sometimes the neurons fired, sometimes they did not and on occasions where they did not, there was a loss of inhibition of the excitatory neurons
133
How can the knockout data be used to explain the fact that patients with epilepsy don’t show symptoms all of the time?
Nav1.1 knockouts still retained some ability of the inhibitory neurons to fire action potentials, thus inhibition did still occur some of the time. Where action potentials weren’t generated is where there was overexcitation and explains what is seen in humans where seizures come on almost spontaneously
134
Missense mutations in Nav1.1 can have varying degrees of severity from mild symptoms to severe, T or F?
F
135
What type of mutation leads to the most severe types of epilepsy?
Loss of function mutations as a result of truncation
136
What is meant by pain?
Unpleasant sensory and emotional experience associated with actual or potential tissue damage
137
Why is pain useful?
Important protective mechanism to tell you something is wrong
138
A loss of function in what channel is responsible for a diminished or lack of pain perception?
Nav1.7
139
What is erythromalgia and what causes it?
Erythromalgia is a heightened sense of pain that can be triggered by non-noxious stimuli. It is caused by a gain of function mutation in Nav1.7
140
What is the purpose of anxiety?
A fear response that acts as a perception of danger
141
Why can small levels of anxiety be good?
Anxiety acts as a motivational response to a negative emotion
142
What are the two different types of anxiety and how to they differ?
Generalised anxiety is where there is a negative feeling all of the time with no actual trigger. Fear-induced anxiety is an irrational response to a potential fearful stimulus.
143
Give some examples of fear-induced anxiety?
Phobias, PTSD, OCD and panic disorders
144
What two means are there for treating clinical anxiety?
Psychiatric, pharmacological
145
What are the two types of drugs used to treat anxiety?
Antidepressants, antiepileptics and antipsychotics. Otherwise drugs that interact with the GABA receptors
146
What type of receptor are the GABAA receptors?
Ligand-gated ion channels – ionotropic
147
What type of neurotransmission are the GABAA receptors involved in?
Fast inhibitory neurotransmission
148
Where abouts at the synapse are GABAA receptors found?
Postsynaptically on the dendrites and cell bodies
149
As GABA is an inhibitory neurotransmitter, binding to GABAA receptors causes influx of which ions?
Cl-
150
How many different subunits make up the GABAA receptor?
5
151
How does subunit composition vary?
Subunit vary depending on the location, function and intended pharmacology of the receptor
152
GABAA receptors have a single binding site, T or F?
F – they have several
153
What is the name given to the GABA binding site on the GABA receptor?
Orthosteric site
154
Name a compound that is an agonist of the GABA binding site on the GABAA receptor?
Muscimol
155
Name an antagonist of the GABA binding site on the GABAA receptors?
Picrotoxin, bicuculline
156
What is the result of antagonism of the GABA binding site?
Seizures
157
What is the name of the site on the GABAA receptors where benzodiazepines bind?
Allosteric site
158
What is the role of the site which benzodiazepines bind to?
? The allosteric site is responsible for the regulation of channel activity
159
Name an agonist of the site in which benzodiazepines bind?
Diazepam
160
Name an antagonist of the site in which benzodiazepines bind?
Flumazenil
161
What other compounds also bind to the site on the GABAA receptor that benzodiazepines bind to?
Barbiturates, neurosteroids and general anaesthetics
162
What class of receptors are the GABAB receptors?
GPCRs
163
What are the proteins coupled to the GABAB receptors?
Gi or Go
164
What type of neurotransmission is mediated by the GABAB receptors?
Slow transmission – they modulate neurotransmission
165
GABAB receptors are only found postsynaptically, T or F?
F – they are found both presynaptically and postsynaptically
166
Activation of the GABAB receptors at the axon terminals causes what?
Inhibition of voltage-gated Ca2+channels and neurotransmitter release
167
Activation of postsynaptic GABAB receptors on the soma and dendrites causes what?
Activation of GIRK K+ channels and the inhibition of depolarisation, action potential generation and excitability
168
Name a classic agonists and selective antagonist of the GABAB receptor?
Agonist – baclophen. Antagonist – phaclophen
169
What is the standard subunit composition of a GABAA receptor?
2 α subunits, 2 β subunits and 1 γ subunit
170
Where is the orthosteric site found in the GABA receptor?
β subunits
171
Where is the allosteric site found in the GABA receptor?
At the interface between the α and γ subunits
172
Different genes code for the different GABA receptor subunits, T or F?
T
173
Which GABA receptor subunit is responsible for the sedative effect caused by benzodiazepines?
α1 subunit
174
Which effect of benzodiazepines are the α2, α3 and α5 subunits responsible for?
Anxiolytic effect
175
GABAA receptors are part of the nicotinic receptor superfamily, T or F?
T
176
How can anxiety be studied in animals?
Small rodents tend to dislike being in bright light for fear of predation. If you shine a bright light on a mouse its blood cortisol levels will increase as it is stressed and the mouse will begin to look for shade. Administration of diazepam removes the bright light avoidance behaviour as the mouse is less anxious
177
Describe how a conflict test can be useful in studying the effects of anxiolytics on anxiety?
If you train an animal to press a lever in order to receive a reward it will continue to elicit this behaviour. If you occasionally provide an electric shock after pulling the lever the animal will reduce the amount of lever pulling as it is anticipating an electric shock. Applying analgesics doesn’t reduce this behaviour despite the animal no longer being able to sense pain. However, administration of anxiolytics does result in no decrease in lever pulling after occasional electric shocking as the anticipation has been removed.
178
What is the overall effect of benzodiazepine at the level of neurotransmission in the brain?
Benzodiazepines increase the level of inhibitory neurotransmission in the brain
179
What are the five main physiological effects of benzodiazepines?
Sedation and reduced anxiety, hypnosis, anterograde amnesia, anticonvulsant, reduced muscle tone
180
Sedation of patients occurs with the lowest doses of benzodiazepines, T or F?
T
181
What are the effects of benzodiazepines on sleep?
Hypnosis - reduced latency of sleep onset, increased stage 2 non-REM sleep, decreased duration of REM and slow-wave sleep
182
What are the effects of benzodiazepines on memory?
Benzodiazepines result in anterograde amnesia that results in short term memory loss and the prevention of memory formation for the duration of the benzodiazepines effects
183
Benzodiazepines given at high concentrations acts as anticonvulsants, T or F?
T
184
Explain the allosteric regulation of the GABAA receptors by benzodiazepines?
Benzodiazepines increase the activity of GABAA receptors increasing Cl- influx and a greater inhibition of postsynaptic activity
185
The binding of benzodiazepines to the GABAA receptors is irreversible, T or F?
F – its reversible
186
Name an antagonist of the allosteric site of the GABAA receptor?
Flumazanil
187
How do benzodiazepines lead to an increase in the GABA receptor activity?
Benzodiazepines increase the frequency of opening of the GABA receptors rather than changing the conductance or mean open time
188
Why are benzodiazepines when taken alone, not very dangerous?
They don’t directly activate channels by themselves, they only increase the activity of channels already open
189
At high concentrations barbiturates are also positive allosteric modulators of the GABAA channels, T or F?
F – at low concentrations barbiturates are positive allosteric modulators of GABAA however, at high concentrations they directly cause an opening of the channels
190
Describe how barbiturates lead to an increase in activation of the GABAA receptors?
Barbiturates increase the mean open time of the receptors this giving rise to bigger Cl- currents
191
What is meant by the background constitutive activity of the GABA receptor?
The GABA receptors are capable of spontaneously adopting an active conformation in the absence of an agonist
192
What is the role of GABA receptor inverse agonists?
Inverse agonists stabilise the GABA receptor in the closed or inactive conformation, stopping it from opening by itself
193
Name a family of compounds that are inverse agonists of the GABA receptors?
β-carbolines increase memory and learning
194
What three aspects of the pharmacokinetics of benzodiazepines are influenced by lipid solubility?
Determines the onset of actions, redistribution and accumulation
195
What factors determine the benzodiazepine half-life in the body?
Renal function, age and microsomal enzyme activity induction
196
How can benzodiazepine metabolism actually lead to an increase in duration of action?
First phase metabolism of some benzodiazepines can produce other active metabolites
197
How can plasma protein binding influence a benzodiazepines effects?
Binding to plasma proteins may increase the time it takes for the drug to get into the central nervous system. Competitive binding of multiple drugs for plasma proteins can result in wild fluctuations in drug concentrations in the blood
198
Define epilepsy?
Unprovoked seizure activity in the brain characterised by high frequency discharge as a result of an imbalance between excitatory and inhibitory neurotransmission
199
What are the two treatment options for epilepsy and which neurotransmitters do these target?
? Increase inhibitory neurotransmission by increasing GABA or GABAA activity. Decrease excitatory neurotransmission by decreasing glutamate levels or receptor activity
200
What are the two main types of epilepsy and how do they differ?
Partial and generalised epilepsy. Partial epilepsy has its effects localised to only one hemisphere of the brain whereas generalised effects both
201
List some of the causes of epilepsy?
Head trauma, infection, tumour, local lesions, genetics
202
Mutations in which classes of proteins are often responsible for epilepsy?
Voltage-gated Na+ channels, GABAA receptors and nAchRs
203
Seizure activity in the motor cortex results in convulsions in regions of the body innervated by that region of the brain, T or F?
T
204
What is the result of seizure activity in the hypothalamus?
Autonomic discharge e.g. salivation and increase secretion
205
Seizure activity in which region of the brain is responsible for the loss of consciousness sometimes seen in epilepsy?
Reticular formation
206
Which technique is often used to diagnose epilepsy?
Electroencephalogram
207
What is the main difference seen in the EEGs of patients with generalised and partial epilepsy?
General epilepsy EEGs will show high frequency brain activity all over the brain picked up by all the electrode, whereas partial epilepsy patients EEGs will only show abnormal electrical activity picked up by some electrodes due to the limited spread
208
How do absent type epilepsy EEGs differ from tonic-clonic types?
he EEGs show slow synchronised oscillatory behaviour whereas the tonic-clonic type shows rapid high frequency activity followed by rhythmic wave type activity
209
What type of protein is usually mutated in patients with absent epilepsy?
Ca2+ channel
210
Where is absence type epilepsy more commonly seen and how is it characterised?
Absent epilepsy is more often seen in children and is characterised by a brief loss of attention
211
What are the three types of targets for antiepileptic’s at the inhibitory synapses?
Increase GABAA activity and increase inhibitory neurotransmission. Block GABA uptake back into presynaptic terminal to increase the duration of GABAs effects and this the duration of inhibition. Decrease GABA metabolism by inhibiting enzyme responsible for its breakdown
212
Which target for the treatment of epilepsy gives specificity?
GABAA receptor activation
213
How do benzodiazepines work? Benzodiazepines are allosteric regulators of the GABAA receptors. They increase the activity of the GABAA receptors by increasing the frequency of opening of the GABA channels. This increases Cl- currents across the membrane and thus the inhibition of the neuron
Benzodiazepines are allosteric regulators of the GABAA receptors. They increase the activity of the GABAA receptors by increasing the frequency of opening of the GABA channels. This increases Cl- currents across the membrane and thus the inhibition of the neuron
214
Give some examples of benzodiazepines?
Diazepam, clonazepam, clobazam
215
What are the problems of benzodiazepine use for the treatment of epilepsy?
Sedation, tolerance and withdrawal
216
How do barbiturates work?
At low concentrations they are positive allosteric modulators of GABAA receptors. They increase the mean open time of the channels to give rise to bigger Cl- currents thus resulting in greater inhibition. At high concentrations barbiturates can directly cause opening of GABAA channels and leads to a massive inhibition of brain activity.
217
Give some examples of barbiturates?
Phenobarbitone, primidone
218
What are the problems of barbiturate use in the treatment of epilepsy?
Low therapeutic index, sedation and complex pharmacokinetics
219
In which metabolic process is GABA a by-product of?
Kreb Cycle
220
What is the name of the enzymes that converts glutamate to GABA?
Glutamic acid decarboxylase
221
How does valproate act to treat epilepsy?
Increases the level of GABA in the brain most likely at due to working at the level of transcription controlling enzymes involved in GABA synthesis
222
What is the main target for the treatment of epilepsy at the excitatory synapses/neurons?
Inhibition of glutamate receptors and decrease excitation
223
What class of channels can also be targeted to decrease excitation and treat epilepsy?
Inhibition of voltage-gated Na+ that drive depolarisation and the rising phase of the action potential will lead to less excitatory neurotransmission
224
How do Na+ channel blockers work?
Na+ channel blockers stabilise the voltage-gated Na+ channels in the inactivate state thus preventing the neuron from depolarising.
225
Na+ channel blockers are non-sedative, T or F?
T
226
Give examples of Na+ channel blockers used in the treatment of epilepsy?
Phenytoin, carbamazepine
227
What is the most widely used anti-epileptic drug?
Carbamazepine
228
What type of Ca2+ channels are implicated in absence type seizures and what is unusual about them?
T-type Ca2+ channels – can mediate the rising phase of the action potential in some brain regions instead of Nav channels
229
Name some examples of T-type Ca2+ channel blockers used in the treatment of epilepsy?
Ehtosuximide, GABApentin – binds to accessory α2δ subunit that controls T-type Ca2+ channel trafficking to the membrane
230
Levetiracetam is a new drug found to be effective in treating epilepsy, how does it work?
Decreases the exocytosis and release of glutamate containing vesicles by binding to synaptic vesicle protein-2A
231
Which conditions is depression commonly associated with?
Insomnia, anxiety and addiction
232
What are the two categories of depression and how do they differ?
Bipolar disorders – where patients alternate between low and over-exuberant moods. Unipolar disorders – where patients have consistent low mood
233
What is meant by endogenous and reactive depression?
Endogenous depression is where there is a constant low mood that doesn’t seem to have a clear cause or trigger. Reactive depression is usually caused by a stressful event
234
Describe the peripheral aspect of depression?
Increase in cortisol levels as wells as gherlins and leptins associated with feeding behaviour
235
Describe the classical symptoms of depression?
Low mood (anhedonia), negative thoughts, pessimism and misery, diminished ability to think/concentrate, loss of libido, rapid increase or decrease in weight, apathy, low self-esteem
236
Depression is more common in males than female, T or F?
F – twice as likely in females
237
What is the recommended treatment for depression?
Antidepressant drugs in combination with counselling
238
After the cause of depression has been alleviated, a patient’s depression will not subside, why is this?
Depression causes changes in brain chemistry that can only be reversed though medication
239
What are the three main classes of antidepressants and how do they differ?
MOAIs -inhibit the breakdown of monoamine neurotransmitters and increase the levels in the synapse. Tricyclic antidepressants – generally inhibit monoamine neurotransmitter reuptake with no selectivity. Selective reuptake inhibitors – selectively inhibit the uptake of monoamine transmitters into the neurons
240
Give an example of an SSRI?
Fluoxetine/Prozac
241
What additional class of molecules are being investigated as antidepressants?
Monoamine receptor antagonists
242
Which type of MOA is found in the central nervous system and is responsible for the metabolism of 5-HT and noradrenaline thus making it the main target of antidepressant drugs?
MAO-A
243
Explain the side effect of MAOIs known as the cheese effect?
Tyramine is an amine derivative of tyrosine that is also broken down by MAO. Inhibition of MAO leads to a build-up of tyramine which triggers the release of monoamines in the peripheral nervous system thus resulting in hypertension
244
Give an example of an MAOI?
Moclobemide
245
How do tricyclic antidepressants (TCAs) act?
Non-selectively inhibit the reuptake of monoamines back into the neurons
246
What are the side effects of TCA use and why is this?
TCA side effects are due to the result of their antagonism of the mAchRs leading to a dry mouth, blurred vision and constipation
247
Give an example of a tricyclic antidepressant?
Amitryptyline, clomipramine
248
SSRIs have far fewer side effects than TCAs, T or F?
T – due to their selectivity
249
Give an example of an SNRI?
Reboxetine
250
Where is the main source of noradrenergic neurons located in the brain?
Locus serealus
251
The function of noradrenaline can be remembered using the acronym P.A.A.M, what does this stand for?
Pain, attention, arousal, mood
252
Recall the monoamine biosynthesis pathway?
Tyrosine à L-Dopa à Dopamine à Noradrenaline à Adrenaline
253
Which enzyme is responsible for the breakdown of noradrenaline?
MAO-A
254
Which enzyme is responsible for the breakdown of noradrenaline in the cytoplasm as well as terminating its action?
Catechol-O-Methyltransferase
255
What is the rate limiting step, and its accompanying enzyme, in the monoamine neurotransmitter synthesis pathway? Conversion of tyrosine à L-Dopa – Tyrosine hydroxylase
Conversion of tyrosine à L-Dopa – Tyrosine hydroxylase
256
Stimulation of the α1 adrenoceptors has been known to stimulate 5-HT neurons in the raphe nucleus, T or F?
T
257
Where are the majority of serotonergic neuronal cell bodies found in the brain?
Raphe nucleus
258
What are some of the roles of 5-HT?
Sleep and wakefulness, mood and emotion, feeding behaviour
259
How can 5-HT actions be linked to anhedonia?
5-HT has a role in regulating limbic processing, thus decreased 5-HT levels may result in decreased emotion to normally pleasurable experiences
260
What is the precursor in 5-HT synthesis and where is it obtained?
Tryptophan amino acid precursor obtained in the diet from chocolate and protein rich foods
261
What is the rate determining step and the enzyme involved in the synthesis of 5-HT?
Conversion of tryptophan to 5-hydroxytryptophan – catalysed by tryptophan hydroxylase
262
Serotonin has a huge array of receptors, but what classes of receptors are these?
GPCRs and ligand-gated ion channels
263
The 5HT1A receptors are inhibitory receptors, what type of G protein are they coupled to?
Gi
264
How do acute and chronic increases in 5-HT levels differ at the level of the 5HT1A receptor?
Acute increases in 5-HT leads to increase activation of the 5HT1A receptors and a decrease in neuronal firing and subsequent 5-HT release. Chronic increase in 5-HT levels leads to a desensitisation to the neurotransmitter. This occurs by the internalisation and degradation of the 5HT1A receptors leading to a loss of inhibition and more action potential firing
265
Serotonin is also known to have an effect on neurotrophins, explain this effect?
5-HT neurons regulate the expression of brain-derived neurotrophic factor (BDNF) which is responsible for synaptic stabilisation, particularly in the dendritic spines. Phosphorylation of CREB by PKA leads to increased translocation to the nucleus and increased BDNF transcription. Activation of the 5HT1A receptors leads to a decrease in PKA and thus a decrease in CREB activation
266
How does the neurotrophin hypothesis link to depression?
The decreased levels of 5-HT seen in in depression leads to a decrease in BDNF and thus a reduced synaptic stability therefore results in depression
267
What class of molecules are used to treat psychosis?
Dopamine antagonists
268
What is Schizophrenia?
A psychotic disease characterised by disturbances in area of the brain associated with thought perception, attention, motor behaviour and emotion
269
Give some examples of the negative symptoms of Schizophrenia?
Blunting of emotions, withdrawal from social contact, flattening of emotional responses, reluctance to perform everyday tasks
270
Give some examples of the positive symptoms of Schizophrenia?
Hallucinations, delusions, thought disorders, delusions of grandeur, bizarre behaviours and stereotypes movements
271
List some of the causes of Schizophrenia?
Genetic and environmental factors, can also be associated with drug use (methamphetamine, cannabis, cocaine and opiates)
272
Glutamate and serotonin receptors have also been implicated in Schizophrenia, T or F?
T
273
What are the four dopamine pathways in the brain?
Nigrostriatal pathway, mesocortical and mesolimbic pathway, tuberohypohyseal pathway and the medullary trigger zone
274
Loss of dopamine neurons in the SN is associated with Parkinson’s Disease, T or F?
T
275
What is the link between dopamine and psychotic disorders?
Excess activity of the dopamine system is associated with Schizophrenia, ADHD and drug dependence
276
What is the precursor of dopamine?
Tyrosine
277
Recall the synthesis of dopamine from its precursor?
Tyrosine à L-Dopa (catalysed by tyrosine hydroxylase). L-Dopa à Dopamine (catalysed by dopa-decarboxylase)
278
Which step is the rate limiting step in dopamine synthesis?
Conversion of tyrosine to L-Dopa
279
Dopamine receptors are of the GPCR and ligand-gated ion channel varieties, T or F?
F – dopamine receptors are only GPCRs
280
How many subtypes of dopamine receptors are there?
5
281
All dopamine receptors are excitatory, T or F?
F – D2 and D4 are inhibitory
282
What is the effect on stimulation of dopamine receptors on cAMP levels?
Stimulation of D1, D3 or D5 receptors leads to an increase in cAMP levels whereas stimulation of D2 or D4 receptors results in a decrease in cAMP levels
283
Explain how the dopamine receptors can autoregulate?
Explain how the dopamine receptors can autoregulate? The D2 receptors control the function and release of other dopamine releasing neurons
284
Which enzyme is responsible for the metabolism of dopamine in the mitochondrial membrane?
MAO-B
285
Which enzyme is responsible for the metabolism of dopamine in the cytosol?
Catechol-O-Methyltransferase
286
Give an example of a dopamine receptor agonist?
Apomorphine
287
Which dopamine receptor is the most suitable target for antipsychotics?
? D2 receptors
288
D2 receptor agonists are used in the treatment of Schizophrenia, T or F?
F – D2 antagonists are used
289
Give an example of a classical antipsychotic used in the treatment of Schizophrenia and that is a member of the phenothiazine compounds?
Chlorpromazine
290
What are the side effects of first generation antipsychotics?
Motor disturbances, prolactin secretion
291
What is meant by extrapyramidal effects of antipsychotics?
Effects on pituitary hormone secretion such as prolactin due to their interference with the tuberohypophyseal dopamine pathway
292
Atypical antipsychotics have a lower incidence of extrapyramidal effects, name one?
Clozapine, sulpiride
293
Explain why prolonged use of antipsychotics leads to neurotoxicity?
Prolonged antipsychotic drugs use leads to accumulation of toxic metabolites within the neurons resulting in the degeneration of aminergic neurons
294
Stimulation of which dopaminergic pathway leads to the euphoria and excitement associated with dopamine receptor antagonists?
Mesocortical and mesolimbic pathway
295
Explain how acute use of antipsychotics can lead to increased blood pressure and decreased gut motility amongst other side effects?
Dopamine antagonists can displace noradrenaline in the peripheral nervous system leading effects of sympathetic nervous system stimulation
296
Which dopaminergic pathway is the target of antipsychotic drugs?
Mesocortical and mesolimbic pathway
297
Only a small number of D2 receptors need to be occupied in order to alleviate the symptoms of Schizophrenia, T or F?
F – 80% occupancy is required in order to effectively remove symptoms
298
Sedation is another common side effect of dopamine receptor antagonist use, what is the hypothesised cause of this?
Interferences with other amine systems such as histamine receptors
299
How can D2 antagonists lead to abnormal breast development in males?
Stimulation of the tuberohypophyseal pathway leading to hyperprolactin secretion
