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Neuropharmacology > Chapter 17: Anxiety And Anxiolytic Medications > Flashcards

Chapter 17: Anxiety And Anxiolytic Medications Flashcards

1
Q

Fear

A
  • threat is temporally/ spatially immanent

- requires the amygdala

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2
Q

Anxiety

A
  • Threat is temporally/ spatially remote
  • extended amygdala (BNST) maintains fear response
    - BNST doesn’t require constant stimulation
  • worry about something that could happen in future
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3
Q

Amygdaloid complex

A

Amygdala and limbic cortex (insular and anterior cingulate cortex, hypothalamus, and hippocampus)

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4
Q

CeA orchestrates components of fear

A

ANS activation, enhanced reflexes, increased vigilance’s activation of HPA axis

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5
Q

The amygdala is critical for fear learning

A

Sensory input

  • thalamus
  • sensory cortex

Amygdala

  • US and CS inputs converge in amygdala
  • coordinates fear responses

Hypothalamus and Brainstorm

  • autonomic and endocrine systems
  • freezing, startle

*fear learning is a form of associative (Pavlovian) learning

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6
Q

Nuclei in amygdala

A
  • Lateral nucleus

- basolateral nucleus

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7
Q

Nuclei in extended amygdala

A
  • central nucleus

- BNST

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8
Q

The medial prefrontal cortex (mPFC) controls amygdala activity

A

The mPFC integrates and evaluates several kinds of information

  • sensory, context, emotional salience, motivation
  • cognition; subjective experience (feelings)

mPFC controls amygdala processing, largely through modulating GABAergic neurotransmission

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9
Q

There are 2 primary reasons the mPFC inhibits fear responses

A
  • escape from the danger is successful

- The threatening stimulus is recoded as “safe”

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10
Q

Many transmitter systems are implicated in anxiety

A

CRF- responsible for inducing anterior pituitaryto release ACTH in blood,which increases release of glucocorticoids (ex. cortisol) from adrenal cortex

Norepinephrine and serotonin- antidepressants

GABA- benzodiazepine and anxiolytics

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11
Q

HPA axis is activated by release of […] from […]

A

HPA axis is activated by release of CRF from paraventricular nucleus of hypothalamus

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12
Q

Stimulation of LC or administration of yohimbine

A

Induces alerting and fear responses

  • yohimbine (a2-AR antagonist)
    - produces panic attacks in patients with panic disorder or PTSD
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13
Q

CRF acts as both hormone and neurotransmitter

A

Endocrine control
-cortisol release

Neurotransmitter

  • amygdala (CeA)
  • locus coeruleus (LC)

*environmental stressors activate the HPA stress axis

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14
Q

CRF neurons in CeA project to LC and activate the adrenergic component of stress response

A

Stress increases activity in CRF-releasing neurons from the CeA that drive high-tonic firing in LC neurons

LC neuronal activity enhances SNS activity and further drives the CeA

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15
Q

Stress and CRF induce high-tonic firing of LC neurons and increase anxiety-like behavior

A
  • restraint stress increases neural activity (c-fos expression) in the LC that is inhibited by Ga1-coupled DReADD
  • activating the Ga1-coupled DReADD in TH+ LC neurons prior to restraint stress inhibits stress-increased anxiety-like behavior
  • high-tonic firing of LC neurons increases anxiety-like behavior on the elevated plus maze in rodents that is blocked by B but not a1-AR antagonists
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16
Q

[…] KO mice exhibit an anxious phenotype

A

5-HT1A KO mice exhibit an anxious phenotype

  • 5-HT1A receptors are both postsynaptic receptors and somatodendritic (activity-modulating) autoreceptors
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17
Q

5-HT1A autoreceptors

A
  • dorsal and median raphe
  • inhibit neuronal firing and 5-HT release
  • agonists are anxiolytic
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18
Q

5-HT1A postsynaptic receptors

A
  • many brain area, eg. Hippo and amygdala
  • emotional and cognitive aspects
  • agonists are anxiogenic
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19
Q

Inability to control stressors enhances […], and sensitizes […]

A

Inability to control stressors enhances 5-HT release, and sensitizes anxiety-like behavior

  • reduced inhibition by 5-HT1A autoreceptors is responsible for increased 5-HT release in target areas
  • vmPFC detects controllability
  • Glu pyramidal neurons project to DRN
  • activates GABAergic interneurons

*behavioral immunization

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20
Q

Behavioral Immunization

A

Experience with ES before IS blocks the behavioral and neurochemical consequences of IS

21
Q

[…] is also implicated in anxiety

A

SERT is also implicated in anxiety

Acute SSRI

  • can elicit anxiety
  • activation of postsynaptic 5-HT receptors

Chronic SSRI

  • is anxiolytic
  • desensitizes 5-HT1A autoreceptors
22
Q

Genetic variations in SERT affect brain development and anxiety

A

Short allele

  • smaller amygdala and subgenual anterior cingulate cortex (sgACC)
  • increased amygdala activity
  • greater symptom severity in anxiety disorders

Developmental mechanisms

  • short allele is low- expressing (more synaptic 5-HT)
  • SERT KO or 5-HT1A KO mice are more anxious
23
Q

Early life stress confers risk to developing mood and anxiety disorders

A

Short SERT: Prefrontal Cortex

  • smaller mPFC volume
  • loss of top-down control
  • not as effective in reuptake grade 5-HT (functions as though it is already partially blocked)

Short SERT: Midbrain

  • higher 5-HT (5-HT1A)
  • smaller amygdala volume
  • increased neural activity
24
Q

[…] are the first-line medications in the treatment of anxiety disorders

A

Antidepressants are the first-line medications in the treatment of anxiety disorders

Anxiety and depression are related:

  • the occurrence of an anxiety disorder increases the risk of major depression
  • people with depression often experience sever anxiety

Antidepressant medication are also anxiolytic

  • SSRI, SNRI
  • TCA
25
Q

Benzodiazepines are anxiolytics

A

CNS Depressants- Barbituates
Sedative/ Hypnotics- hypnotics
Anxiolytics- BDZ

26
Q

Sedative-hypnotics

A

Enhance function of GABA, causing sedation, reduced anxiety, and anticonvulsant effects

27
Q

Barbituates vs BDZ

A

Barbituates keep GABA-activated Cl- channels longer than BDZs to
- increases number of microsomal enzymes

28
Q

BDZ anxiolytics

A

BDZs are positive allosteric modulators of GABAa receptors (enhanced GABA transmission)

  • bind at the interface of a-g subunits of GABAa
  • increase affinity of B subunit for GABA
  • increase Po and gCl
29
Q

General properties of sedative/ hypnotics

A

The dose-dependent effects progress from

  • reduced anxiety
  • sedation
  • incoordination
  • sleep
  • anesthesia
  • coma and death
30
Q

Benzodiazepines are grouped by pharmacokinetic properties

A

Long-acting

  • metabolites are psychoactive
  • Librium (chlordiazepoxide)
  • Valium (diazepam)
  • half-life: 60 hours

Shorter-acting

  • metabolized in one step
  • Xanax (alprazolam)
  • Ativan (lorazepam)
  • Klonopin (clonazepam)
  • half-life 10-12 hours

Short-acting

  • Rohypnol (flunitrazepam)
  • Versed (midazolam)
  • half-life: 1-2 hours
31
Q

Alcohol, Barbituates, and BDZs are cross-dependent

A

Withdrawal from any one of them can be terminated by administration of any others

32
Q

Pros of BDZ

A

Relatively high safety margin (relative to Barbituates)
- respiratory depression is rare, unless mixed with alcohol or CNS depressants

Little to no liver enzyme induction
- little metabolic tolerance; few drug interactions

33
Q

Cons of BDZ

A

Abuse liability is a concern

  • often associated with poly drug abus
  • a history of drug abuse is risk factor
  • can be used during abstinence/ withdrawal phase of substance abuse

Retrospective studies suggest risk of Alzheimer’s detention with long-term, high dose use. Prospective studies suggest no risk

May impair long-term therapeutic outcomes

34
Q

Use of BDZ in the treatment of anxiety disorders

A

Generally acceptable use

  • short- term (2-4 mo); fill-in
  • pre- anesthetic
  • emergence of panic attack, as needed

Other justifiable use

  • long-term use risks abuse/ dependence
  • GAD; PTSD; contraindicated unless alcohol use is rules out
  • phobia; social anxiety disorder generally not acceptable
35
Q

BuSpar (buspirone)

A
  • a non-BDZ anxiolytic; does not act on GABAa receptors
  • buspirone is a partial agonist of 5-HT1A receptors
  • anxiolytic effects are slow, follow a “ therapeutic lag”
  • not useful for people who have used BDZ

Useful for cognitive symptoms

  • treating comorbid anxiety and depression
  • relief of worry, poor concentration; less effective on physical symptoms

No sed/ hypnotic side-effects; no abuse potential
Doesn’t enhance CNS-dependent effects of alcohol

36
Q

Anticonvulsants

A 
Neurontin (gabapentin)
Lyrica (pregabalin)
- block active calcium channels (a2d)
- reduces excitatory neurotransmission 
- off-label use

Side effect:

  • mental fogginess; cognitive slowing
  • memory deficits
  • dizziness
  • sleepiness, drowsiness
  • weakness/ lethargy
37
Q

Pharmacological treatment of anxiety

A

1st line: SSRI, SNRI, buspirone
2nd line: TCA, BDZ
Adjunct: prazosin, propranolol, gabapentin, pregabalin, atypical antipsychotic

38
Q

Dopamine

A
  • mesolimbic DA cells are activated by stressful/ threatening stimuli
  • released DA on D1 or D1-R in amygdala, decreased GABA inhibition
39
Q

Generalized Anxiety Disorder (GAD)

A

persistent anxiety symptoms for months- years

40
Q

Panic attacks may occur

A
  1. In response to particular environment
  2. Total without warning in unexpected fashion
  3. In situation where an attack occured
41
Q

Anticipatory anxiety

A

Anxiety about having attack in place that isn’t safe

42
Q

Agoraphobia

A

Fear of public places

43
Q

Phobia

A

Involves fears that individuals recognize as irrational

44
Q

Behavioral Desensitization

A

Presenting fear-inducing stimuli in gradual increments

45
Q

OCS

A

Increased activity in caudate nucleus

46
Q

NE Receptor Ligands are used to alleviate physical symptoms of anxiety

A

Prazosin

Propanolol

47
Q

Prazosin

A

a1-AR antagonist

  • increases peripheral vasodilation (decreased bp_
  • reduces insomnia and nightmares in PTSD
48
Q

Propanolol

A

B-AR antagonist

  • negative chronotropic and inotropic effects on heart
  • reduces performative anxiety

Neuropharmacology (15 decks)

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