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Neuropharmacology of CNS disorders > Affective disorders > Flashcards

Affective disorders Flashcards

1
Q

breifly what is the monoamine theory of depression?

A

The monoamine hypothesis of depression predicts that the underlying pathophysiologic basis of depression is a depletion in the levels of serotonin, norepinephrine, and/or dopamine in the central nervous system.

Elevating the levels of the Neurotransmitter Available for Signalling improves Mood.

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2
Q

what were the two serendipitous observations that put monoamines at the forefront of depression research?

1960s

A

Iproniazid was in trials for TB and patients reported an elevation in mood.

Imipramine in trials as antipsychotic drugs indication to improve mood.

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3
Q

Diagnosis of psychiatric disorders is largely based on….

A

categorization via clinical observation:

Clinical classification expert view on what you have (inclusion) and don’t have (exclusion).

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4
Q

What diagnostic manual is favoured by Americans?

A

Diagnostic Statistical Manual (DSM currently version V)

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5
Q

what diagnostic manual is used by Britain and Europe?

A

International Classification of Disease (ICD currently version 11)

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6
Q

what are the pros and cons of diagnosing psychiatric disorders using clinical classification inclusion and exclusion ?

A

Pros:
Has improved diagnosis but lacks pathophysiological definition. (where does the issue arise from)
Cons:
Do not consider symptom overlap in distinct classifications (co-morbidities).
Do not resolve specific disease causation hindering mechanism and drug development. - Not good at defining/identifying pathophysiology
it does not take into account the dimensional expression or causes of psychiatric disorder and disease.

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7
Q

What is the Research Domain Criteria (RDoC) basic science approach to diagnosing psychiatric disorders?

A

The RDoC was developed by the National Institute of Mental Health (NIMH) to be a biologically valid approach that incorporated genetics, neuroscience, and behavioral science. Diagnoses must be based on biology as well as on symptoms. Mental disorders involve brain circuitry and therefore are biological illnesses

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8
Q

what are the benefits of the Research Domain Criteria (RDoC) basic science approach ?

A

Better Classification:
- clearer indication of pathology
- help understand and treat.

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9
Q

give an example of how depression is modelled in rodents

A

tank of water, put rodent into tank, when motivated it will struggle and move to try and escape the water (an innate response).
When it gives up, it cant do anything about your situation, you can measure how long it takes a rat to stop struggling. You can test the efficacy of antidepressant drugs using this test .

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10
Q

what is the evolutionary advantage of low mood associated with negative thoughts

A

Averseness = strong reinforcer to modify behaviour, associated with focus “concentration”.
* Thus impart evolutionary advantage (selected for). – aversiveness is a strong way of enforcing a behaviour you don’t want to do again.

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11
Q

when do the primary indicators of depression shift from evolutionarily beneficial to detrimental

A

when they persist for at least two weeks

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12
Q

what are the three primary indicators of depression?

A
  1. Persistent sadness or low mood
  2. Loss of interests or pleasure
  3. Fatigue or low energy most days most of the time
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13
Q

what are the 7 additional associated symptoms of depression

A

4.Disturbed sleep
5. Poor concentration or indecisiveness
6. Low self-confidence
7.Poor or increased appetite
8. Suicidal thoughts or acts.
9. Agitation or slowing of movements
10. Guilt or self-blame.

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14
Q

what three factors need to be present for diagnosis of depression?

A

Primary indicators + persistence + associated symptoms = diagnosis of disease

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15
Q

how many of the primary and associated symptoms correspond to not, mild, moderate or severe depression

A
  • not depressed (fewer than four symptoms)
  • mild depression (four symptoms)
  • moderate depression (five to six symptoms)
  • severe depression (seven or more symptoms, with or without psychotic symptoms)

  • symptoms should be present for a month or more and every symptom should be present for most of every day.
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16
Q

depression emerges as a ___ ______ as a result of ____ ____

A

Depression emerges as a behavioural disfunction as a result of neurological disruption

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17
Q

what is the brain region associated with depressed mood?

A

Limbic system/Arousal centres

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18
Q

what is the brain region associated with Irritability?

A

Amygdala/ hypothalamus

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19
Q

what is the brain region associated with low self esteem?

A

Amygdala

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20
Q

what is the brain region associated with modified appetite (+/-)?

A

hypothalamus

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21
Q

what is the brain region associated with hopelessness and guilt?

A

limbic system

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22
Q

what is the brain region associated with weight loss or gain?

A

hypothalamus

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23
Q

what is the brain region associated with decreased ability to concentrate or think?

A

Hippocampus/ Cortex

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24
Q
A
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25
Q

what is the brain region associated with insomnia or hypersomnia?

A

Superchiasmatic nucleus

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26
Q

what is the brain region associated with decreased interest in pleasurable stimuli?

A

Nucleus accumbens/ ventral tegmental area

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27
Q

what is the brain region associated with recurrent thoughts of death and suicide?

A

Amygdala

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28
Q

give 6 statements about the stress pathway inputs to aetiology

A
  1. Stress is a prima facta in triggering depressions.
  2. Dysregulation of the feed back inhibition elevating Corticotrophin Releasing Factor (CRF) and glucocorticoids in depressed patients and animal models of depression.
  3. i. Elevated glucocorticoids kill cells, and cause synapse loss. (Glucocorticoids inhibitory to synaptogenesis and neurogenesis in brain (hippocampus).)
  4. Additionally, CRF1 and CRF2 receptors exist in outside hypothalamic-pituitary axis (e.g. Amygdala).
  5. Changes in CRF receptor levels in post mortem brains of depressed patients.
  6. Antagonists against CRF receptors have some good indications in treatment of depression
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29
Q

elevated glutacorticoids can ____ ____ and cause ______ ____

A

Elevated glucocorticoids kill cells, and cause synapse loss.

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30
Q

describe the hypothalamic-pituitary-adrenocortical stress response

A

When you go through something stressful then the brain will send a signal and the hippocampus will release chemical in response to this, which subsequently signal to the hypothalamus which results in release of Corticotropin releasing factor (CRF). This will facilitate communication between the hypothalamus and the pituitary, the pituitary will then release another neurohormone, Adrenocorticotropic hormone (ACTH), which is released into the blood and channelled through the body. It acts on the adrenal cortex to result in release of glutacorticoids. These are associated with the wide spread effects associated with stress. But also act in the brain in a negative feedback loop (homeostatic response), the steroid hormone acts to decrease the signal coming from the hypothalamus.

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31
Q

what is cortico releasing factor (CRF)

A

the central regulator of the hypothalamic-pituitary-adrenal (HPA) axis, which is the main organizer of the body’s response to stress.

Corticotrophin-releasing hormone also acts on many other areas within the brain where it suppresses appetite, increases anxiety, and improves memory and selective attention. Together, these effects co-ordinate behaviour to develop and fine tune the body’s response to a stressful experience.

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32
Q

what are glucocorticoids?

A

Glucocorticoids are steroid hormones produced from the cortex of adrenal glands (gluco-corti-coids: glucose-cortex-steroids). Glucocorticoids have a pivotal role in the glucose, protein, and fat metabolism of the body.

Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell.

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33
Q

how does Iproniazid cause an elevation in mood?

A

via inhibition of monoamine oxidases (enzymes that metabolize neuroactive forms of monamines)
inhibition increases the bio-availability of neuroactive monoamine

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34
Q

which neurotransmitters does Monoamine oxidase A metabolise?

A

serotonin, noradrenaline, dopamine

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35
Q

which neurotransmitters does Monoamine oxidase B metabolise?

A

dopamine

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36
Q

how does Imipramine improve mood?

A

It causes elevated levels of monoamines by blocking reuptake of release transmitter into cells

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37
Q

give 5 peices of evidence in favour of the monoamine hypothesis

(depression)

A
  • Pharmacological-drugs that increase content or synthesis (tryptophan-Horlicks) or sensitivity to monoamines are antidepressant.
  • Drug that deplete storage (reserpine) or synthesis (alpha-methyltyrosine) of monoamines act as mood depressors.
  • Measuring major metabolites in the CSF or urine equivocal. Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxy indoleacetic acid are elevated in the manic phase of bipolar but are much more varied in CSF plasma, urine of unipolar depressed patients.
  • Measurable but not major alterations in a number of monoamine receptors in particular 5HT 2A in the post mortem tissue of patients.
  • Some genetic mutations associated with deficient serotonin synthesis predispose to depressive episodes (e.g. Serotonergic transporters)
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38
Q

fear is a normal physiological response, how does it help survival?

what viseral reactions does it cause

A

Heightened sensory state, Vigilance HYPER AROUSED, heart rate, metabolic readiness, fight and flight response.
Better still predict danger indeed fearful response is a learnt response.

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39
Q

what are panic attacks?

A

Palpitations, pounding heart, sweating trembling, breathless, feeling of choking chest discomfort abdominal distress, dizzy or faint, feelings of unreality or detached from oneself, fear of losing control or going crazy paresthesias (numbness or tingling sensations), chills or hot flushes. These bouts should peak at 10 minutes.

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40
Q

What is agoraphobia?

A

extreme or irrational fear (panic attack symptoms) of entering open or crowded places, of leaving one’s own home, or of being in places from which escape is difficult.

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41
Q

what is panic disorder?

A

Recurrent panic attacks 10 minute peak. Or remain anxious about them recurring for up to month after an attack. May be associated with Agoraphobia. Not due to drug abuse. Are not better explained by co-morbid conditions.

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42
Q

what are specific phobias?

A

Excessive fear to a specific cue often recognized by sufferer not the case for children. Anticipation of cue or avoidance of it interferes with normal life routine. Not explained by other conditions.

43
Q

what is social phobia?

A

Anxious state induced by social situation many criteria as for specific phobia. In children they must exhibit otherwise normal ability for social interaction in familiar setting. If aligned with another disorder this can not underlie social phobia.

44
Q

what is obsessive compulsive disorder (OCD)?

A

Recurrent obsessive thoughts or images intrusive and inappropriate to time or place. Try to neutralize intrusion by distracting routines. Patient recognize the obsessive nature. Compulsions respective behaviours (e.g. hand washing) or inappropriate/excessive behaviours designed to reduce distress. Recognition of the excess. Time consuming routines 1 hour a day Interfering with social or working relations. Not due confounding condition. Define if patient has poor or good insight into their condition. (fearful outcome if they do not do the behaviour, inappropriate expression of the fear circuit)

45
Q

what is post traumatic stress disorder (PTSD)?

A

Experienced traumatic or near death experience in which intense fear response ensued. Intrusive recurring memory, dreams or sense of event. Intense response to internal or external cues associated with event. Physiological response by event cues. Persistent avoidance of cue. Diminished expectations quality of life (e.g. career, family etc). Irritability, insomnia, hyper vigilant difficulty concentrating. Impact on social function and symptoms persist for greater 1 month. 1-3 months (ACUTE); >6 months (Chronic), appears 6 months post traumas (Delayed Onset)

46
Q

what is acute stress disorder?

A

Cause and ensuing outcomes similar to PTSD. Shorter term classified lasting between 2 days and 4 weeks and occurs within 4 weeks of trauma. Individual shows dissociative behaviour during or following trauma, amnesia, depersonalization. No substance abuse or other underlying cause.

47
Q

what is generalised anxiety disorder (GAD)?

A

Anxiety or worry for more days than not for 6 months. Uncontrolled worry Associated with restlessness, fatigue, lack of concentration blank mind, irritability, muscle tension, sleep disturbances. Anxiety can not be specified but brings about disruption of normal life. Is not part of an associated syndrome.

48
Q

what is the major serontinergic nuclei?

A

Dorsal raphe

49
Q

what are the major dopaminergic nuclei?

A

ventral tegmental area
substantia nigra

50
Q

what is the major adrenergic nuclei?

A

locus coeruleus

51
Q

give two examples of a trycyclic antidepressant

A

Imipramine (Tofranil)
Clomipramine

52
Q

give two examples of selective serotonin reuptake inhibitors

A

Fluxetine (Prozac)
Fluovoxmine

53
Q

what is the mode of action of tricyclic antidepressants?

A

they bind to monoamine transporters

54
Q

what is the structure of tricyclic antidepressants?

A

The chemical structure of a TCA comprises a 3-ringed arrangement with an attached secondary or tertiary amine.

55
Q

what is the mode of action of selective serotonin reuptake inhibitors

A

these bind selectively to serotonin receptors (although they bind to the other monoamine receptors, they bind serotonin reuptake recpetors which much higher affinity, better efficacy at one)

56
Q

describe the structure and function of monoamine transporters

autoreceptors

A

Membrane proteins with 12 Transmembrane domains (TM)
Substrate binds within central TM ( monoamine, transported from outside of cell to inside of cell)
They are secondary transporters - co-transport Na+ and Cl- into cell with the substrate.

the critical transmemebrane domains, 1 and 6 come together in space to create the substrate binding pocket
extracellular loops 4B and 4A are also critical, these are helical structures that sit on top of this cavity. When allosteric site is occupied this flips down to make it more difficult for things to escape.

57
Q

how is citalopram different from other SSRIs?

A

Allosteric SSRIs such as citalopram, occupies the substrate binding site to stop reuptake, however it has an additional quality where it binds to a alloateric site (one distinct from the one the substrate uses) so that it closes up the release eof the transmitter from the binding site. Slowing release of drug preventing the reuptake, this prolongs the mode of drug action

58
Q

what three ways do Noradrenalin Serotonin selective antidepressant (NaSSA) work?

A
  • Selective increase in Noradrenalin by autoreceptor block
  • Selective increase in Serotonin by heteroreceptor block (autoreceptor but on a downstream neuron (not the one that it was released from)(you can have organisation via connectivity)
  • Additional blocking or activating on sub-classes of receptor
59
Q

what is the broad efficacy of antidepressants?

A

Offer good efficacy in 40-50% (full recovery) with some efficacy in up 80%.

60
Q

give three examples of monoamine oxidase inhibitors

A

Ipronazid
Phenelzine
Meclobemide

61
Q

give an axample of an NaSSA, its mechanism of action and the side effects/notes

A

Mirtasepine
Blocks alpha 1, H1, 5HT2 and muscarinic receptor - elevating monoamines by preventing inhibition of release
Dry mouth and sedation
Faster acting that other actidepressants

62
Q

what happens to your brain in short term follow antidepressants?

A

Inhibit uptake monoamine (e.g. serotonin) causing increased signalling in Raphe nucleus, locus coeruleus and cortex
Locally this can inhibit neuronal firing (cell body) and release (nerve terminals) by activating negative autoreceptors ( e.g.5HT1A) that Inhibit firing or release

63
Q

what happens to you brain medium term following antidepressants?

A

Prolonged treatment leads to down regulation of auto receptors reduced feedback
Inhibition leading to increase neuron firing and chemical transmission (release).
Autoregulation in the face of sustained signalling
Other noted changes include:
* Down regulation b2 postsynaptic receptors
* Down regulation of a2 auto receptors
* Down regulation of 5HT2 receptors.
Overall sense of a homeostatic response of pathways returns to signalling to pre-treatment levels

64
Q

what happens to your brain long term following antidepressant

A

Other almost structural changes in response to altered neurotransmitters, particularly in experimental settings
Above indicative of an adaptive response after treatment and serotonin (monoamine signalling) has been implicated in longer term and possibly more sustained changes supported by GROWTH FACTOR EXPRESSION (e.g. BDNF).
This is associated with synaptic plasticity neurogenesis and synaptogenesis.
Sustained rewiring of circuits associated with mood.

65
Q

Prefrontal cortex has an important executive role
what regions of the brain doe sit connect to
(involved in depression)

A

connects to dorsal raphe (5HT), locus coeruleus (adrenergic), prefrontol cholinergic system (cholinergic) and ventral tegmental area (dopamine)

66
Q

give an example of a surrogate for measuring depression (animal model)

A

measuring motivation

67
Q
A
68
Q

describe the experiment where they used an animal model of motivation to model/measure depressionusing optogenetics

A

Put a magnetic bar on the leg of the rodents and with a magnet quantified the movement of the animal by breaks in the magnetic feild
When they move they are motivated, When float they have given up (model despair).
Via channel rhoposin (from seeweed) a membrane protein activated by light and opens an ion channel – if you introduce this into a neurons you have an artificial way of activating the neurons through light exposure
1. Package channel rhodopsin into a virus and inject it into the executive centre, the prefrontal cortrex.
2. The channel rhodopsin travels to the membrane of the neurons, so that the neurons is now light sensitive. Sometimes the rhosopsin will be retained at the cell surface, or released to distant areas of the brain that are connected via axons, Therefore you are able to send the virus to all the areas of the brain that are connecteed to the prefrontal cortex and also selectively activate the neurons at the sites of which channel rhodopsin is expressed
3. Use light senstive fibres, inject light into brain and look for change in behaviour in response to the light

shining light on the cell bodies of neurosn in the prefrontal cortex shows no change. But when you shine it on to the dorsal raphe nucleus, you see a change
When lights off it stops moving, but when light is on you recover the motivation and it starts moving again

This shows that there can be selectivity in the neurotransmitter that’s elevated globally across the brain based on where its acting within a given circuit

69
Q

what two major things does the success of a drug depend on?

A

depend on it having beneficial effects (efficacy) and the willingness or ability of patient to take the drug (acceptibility)

70
Q

ketamine have dose dependent impacts on behaviour, what behavioural states does this produce and how

A

Anaethesia, ~3mg/kg, inhibits thalamic regions
Dissociative symptoms, ~1mg/kg, limits subcortical inhibition
Antidepressant, 0.5mg/kg

71
Q

describe the experiment that compared ketamine to midazolam (a sedative benzo)
- what were the results?

A

Comparative, midazolam is a benzodiazpien that associated with anxiety release.
Recruited; flushed of existing medication and assigned to either treatment.
Given a baseline rating of depression. (using a scoring system, here a Montgomery asper depression system)
Infused with drug and then assessed after 1 day for antidepressant activity.
Some follow up based on time that patients remained responders

  1. Antidepressant effect with 50% reduction of the MADRS. Supported self reporting scores.
  2. Hints at longer term effect based on relapse below 50% reduction (note fall out).
  3. Adverse effects (e.g. dizziness nausea for both groups and 15% reported dissociative symptoms for ketamine only).

Ketamine - Strong antidepressant effect seen sustained (20-25days) after single dose

72
Q

describe the experiment that tested the biological explanation of ketamine activity using the forced swim test

A

using an animal model, forced swim test, the animal was given three separate drugs that act on NMDA receptors, differentially
Ketamine NMDA channel block, CPP NMDA competitive inhibitor, MK801 NMDA channel block (no sustained effect)

ketamine selectively induces acute and allow sustained (1week) antidepressant activity pointing to an effect on plasticity and the production of things that bring about structural changes

73
Q

describe the experiment that investigated ketamines ability to sustain antidepressant effects

A

BDNF was knocked out of animals, and then ketamine was infused
immobility was measured and showed that BDNF knock out animals do not show ketamine induced antidepressant activity

74
Q

how does ketamine cause a sustained antidepressant effect?

A

Ketamine seems to be activating the system for controlling brain state leading to upregulation of BDNF which results in structural changes (existing BDNF mRNA)
Ketamine activity requires the acute induction of BDNF protein that depends on translational (protein synthesis) but not transcriptional (new gene expression) control

Confirmed or reinforced by experiments showing that translation inhibitors (anisomycin)but not transcriptional inhibitors prevent ketamine effects.

75
Q

describe how ketamine works on specific NMDA receptors to bring about its effects

A

Ketamine by its nature can selectively targets inhibitory subtypes of NMDA receptors,

excitatory neurons release glutamate stimulating inhibitory neurons release of GABA - anatomically it is hooked back to feed onto excitatory neurons thereby Activate an inhibitory neurons which inhibits the original activation – simple circuit of self regulation.

When ketamine blocks NMDA receptors on inhibitory neurons it is keeping the excitatory neurons more active

Still a change in state of the circuit but mediated by a selective targeting of the inhibitory component that drives the system.

76
Q

what is the target, effect, side effect and wider impact of

A
77
Q

what is anxiety in relation to fear?

A

Anxiety would be the activation of fear responses to neutral or emotionally ambiguous cues. This interpretational aspects suggests important cognitive component.
Anxiety is a pathophysiological state that detract from normal function and likely impede an organisms success. Thus, a medical condition.

78
Q

what animal model is used to study the fear circuit?

A

fear conditioning

Fear conditioning: unsignalled and signalled. Both require an interaction and recognition of the environment and detection of a fearful response associated with it.

79
Q

give an example of fear conditioning

A

Rodent placed in cage with blue floor, animal given modest electric shocks through foot. Repeat and ingender a fear response in the animal when it is in the same environment. Length of time for frozen is a measurement of fear. Another expression is the erection of hair.
If place same animal in cage distinct from environment in which it received the shock you don’t get a fear response.
Secondary, an experiment that represents a learning even associated with a cue. – here the animal is placed in the cage and a bell is rung at the same time as the electric shock, within this context the animal will show an appropriate response. If put into the same environment it will show a fear response,
Independently put into a new environment and ring a bell the rodent remembers the associated and exhibits a fear response.

80
Q

what three things does fear conditioning do/show?

A
  1. Accessing the core fear circuit.
  2. Implicating additional modulation.
  3. Making a clear case for neuronal plasticity.
81
Q

what inputs does the core fear centre have?

model

A

association pathways
-ve modulation
+vs modulation

82
Q

what is the fear centre of the brain?

A

the amygdala

83
Q

where is the amygdala in the brain and what are the main connections it makes

A

Amygdala lies adjacent to the hippocampus (in the midbrain).
It has input from the hypothalamus, the hippocampus, olfactory lobe and interaction with the cortex, thalamic regions and the cingulate gyrus

84
Q

the emotional response output from the amygdala feeds into which areas of the brain and why

A
  • orbital cortex (choice bahviour and emotional memory)
  • hippocampus (learning, place)
  • central amygdala, bed nucleus stria terminalis (autonomic responses, attention)
  • striatum (avoidance behaviour)
85
Q

what regions of the brain feed into the amygdala?

A
  • brainstem
  • hypothalamus
  • prefrontal cortex
  • septum
  • sensory cortex
  • thalamus
  • hippocampus
86
Q

what is the current preferred treatment route for anxiety disorders?

A
  1. SSRI. Selective serotonin reuptake inhibitors (increase 5HT levels)
  2. Tricyclic antidepressant drugs (increase 5HT and Noradrenalin levels)
  3. Benzodiazepines (Potentiate GABA mediated inhibition in CNS and periphery)(increase acitvitiaty of GABA A receptor, and inhibitory iontropic receptor)
  4. Anticonvulsant drugs (Stabilize nerve activity, e.g. valporate)(down regulation in a nonspecific way can help anxiety)
  5. Monoamine Oxidase inhibitors (elevate 5-HT levels) not favoured.

the route prioritises an order of treatments

87
Q

how were benzodiasepines intially discovered for the treatment of anxiety

A

Benzodiazepines- 1960 classical anxiety treatment grew out of efficacy of Chlordiazepoxide: accidental synthesis that had calmed agitated animals

88
Q

what is the mechanism of action of benzodiazepines?

A

acts as an inverse agonist by allosterically binding GABA receptors
it works in collaboration with GABA - turns up the effect (elevating inhibition)

Modulate the levels of inhibition in the nervous system
Turning up the gaba response by allosterically binding to the GABA receptor

89
Q

How can modulation of general transmitter pathway selectively modify specific pathophysiology?

A

due to the relative abundance of some receptor combiantion types in some areas of the brain compared to others

90
Q

what are the pros and cons of benzodiazepines

A

Pros
Rapidly acting (cf the SSRI that require long treatments >8-12 weeks for full efficacy).
Anxiolytic, sedative, hypnotic, muscle relaxant (now know these effects are through distinct GABAA receptor types.
Receptors expressed broadly in the anatomical regions of the circuit including BZ sensitive GABA receptors in amygdala.
Excellent efficacy but amnesic. Very limited toxicity (cf barbiturates that they superseded)

Cons
Big problem associated with protracted use of the drug – withdrawal symptoms can persist for years and years
Use has become restricted due to tolerance and withdrawal problems.

91
Q

what non drugs therapies are there for anxiety?

A

psychoanalysis, mindfullness
cognitive behavioural therapy,
family therapy

92
Q

what is the basic premise and evidence for changes in brain structure and function for psychoanalysis

A

unconscious mind
evidence for and against

93
Q

what is the basic premise and evidence for changes in brain structure and function for mindfullness

A

live in the present
meditation changes brain state

94
Q

what is the basic premise and evidence for changes in brain structure and function for cognitive behavioural therapy ?

A

rationalising organising thought process
fMRI some evidence for activity changes

95
Q

what is the basic premise and evidence for changes in brain structure and function for family therapy

A

defining life events and social organisation
reward MRI signals associate with family scores

96
Q

how can benzodiazepines have anxiolytic and anxiogenic effects?

A

Inhibit nerve activity by GABA induced Cl- flux BZ agonist increase flux (anxiolytic)
BZ inverse agonist decrease flux (anxiogenic)

97
Q

what subunit is required for GABA receptors to be sensitive to benzodiazepine

A

gamma

98
Q

what GABA receptor (subunits) make up the majority

A

a1b2g2

60% in cortex (layer1-VI) broadly

99
Q

what subunits can make up GABA receptors?
how many potential combinations are there?

A
  • Alpha (a) subunit 1-6
  • Beta (b)subunit 1-3
  • Gamma (g) 1-3
  • Delta (d) 1
  • Epsilon (e) 1
  • Theta (q) 1

200 potential combinations

100
Q

Physiologically, why do GABA receptors containing gamma subunits have different sensitivity to those that dont

A

Gamma containing subunits require micromolar doses (relatively high)
Receptors that lack the gamma subunit have nm affinity

Those containing gamma are sensitive to synaptically released gaba as it is high for a short moment. Those without gamma see the synaptically released gaba once it is distributed and at lower levels –

101
Q

what gaba receptors are successfully expressed in the amygdala?
what parts?

A

alpha 2 containing receptors

102
Q

describe how benzodiazepine activity interact with the amygdala

A

The critical parts of the fear pathway the Central and basolateral amygdala communicate with each other
Input into the BL and output coming from Ce

Strong staining of the alpha 2 containing receptors in the central amygdala means it is sensitive to activation by the benzodiazepines downregulating output by increasing inhibition.

103
Q
A

Neuropharmacology of CNS disorders (8 decks)

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