Chapter 17: Anxiety And Anxiolytic Medications

Question 1

Fear

Answer 1

• threat is temporally/ spatially immanent

- requires the amygdala

Question 2

Anxiety

Answer 2

• 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

Question 3

Amygdaloid complex

Answer 3

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

Question 4

CeA orchestrates components of fear

Answer 4

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

Question 5

The amygdala is critical for fear learning

Answer 5

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

Question 6

Nuclei in amygdala

Answer 6

• Lateral nucleus

- basolateral nucleus

Question 7

Nuclei in extended amygdala

Answer 7

• central nucleus

- BNST

Question 8

The medial prefrontal cortex (mPFC) controls amygdala activity

Answer 8

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

Question 9

There are 2 primary reasons the mPFC inhibits fear responses

Answer 9

• escape from the danger is successful

- The threatening stimulus is recoded as “safe”

Question 10

Many transmitter systems are implicated in anxiety

Answer 10

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

Question 11

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

Answer 11

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

Question 12

Stimulation of LC or administration of yohimbine

Answer 12

Induces alerting and fear responses

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

Question 13

CRF acts as both hormone and neurotransmitter

Answer 13

Endocrine control
-cortisol release

Neurotransmitter

• amygdala (CeA)
• locus coeruleus (LC)

*environmental stressors activate the HPA stress axis

Question 14

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

Answer 14

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

Question 15

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

Answer 15

• 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

Question 16

[…] KO mice exhibit an anxious phenotype

Answer 16

5-HT1A KO mice exhibit an anxious phenotype

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

Question 17

5-HT1A autoreceptors

Answer 17

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

Question 18

5-HT1A postsynaptic receptors

Answer 18

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

Question 19

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

Answer 19

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

Question 20

Behavioral Immunization

Answer 20

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

Question 21

[…] is also implicated in anxiety

Answer 21

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

Question 22

Genetic variations in SERT affect brain development and anxiety

Answer 22

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

Question 23

Early life stress confers risk to developing mood and anxiety disorders

Answer 23

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

Question 24

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

Answer 24

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

Question 25

Benzodiazepines are anxiolytics

Answer 25

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

Question 26

Sedative-hypnotics

Answer 26

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

Question 27

Barbituates vs BDZ

Answer 27

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

Question 28

BDZ anxiolytics

Answer 28

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

Question 29

General properties of sedative/ hypnotics

Answer 29

The dose-dependent effects progress from - reduced anxiety - sedation - incoordination - sleep - anesthesia - coma and death

Question 30

Benzodiazepines are grouped by pharmacokinetic properties

Answer 30

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

Question 31

Alcohol, Barbituates, and BDZs are cross-dependent

Answer 31

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

Question 32

Pros of BDZ

Answer 32

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

Question 33

Cons of BDZ

Answer 33

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

Question 34

Use of BDZ in the treatment of anxiety disorders

Answer 34

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

Question 35

BuSpar (buspirone)

Answer 35

- 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

Question 36

Anticonvulsants

Answer 36

``` 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

Question 37

Pharmacological treatment of anxiety

Answer 37

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

Question 38

Dopamine

Answer 38

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

Question 39

Generalized Anxiety Disorder (GAD)

Answer 39

persistent anxiety symptoms for months- years

Question 40

Panic attacks may occur

Answer 40

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

Question 41

Anticipatory anxiety

Answer 41

Anxiety about having attack in place that isn’t safe

Question 42

Agoraphobia

Answer 42

Fear of public places

Question 43

Phobia

Answer 43

Involves fears that individuals recognize as irrational

Question 44

Behavioral Desensitization

Answer 44

Presenting fear-inducing stimuli in gradual increments

Question 45

OCS

Answer 45

Increased activity in caudate nucleus

Question 46

NE Receptor Ligands are used to alleviate physical symptoms of anxiety

Answer 46

Prazosin | Propanolol

Question 47

Prazosin

Answer 47

a1-AR antagonist - increases peripheral vasodilation (decreased bp_ - reduces insomnia and nightmares in PTSD

Question 48

Propanolol

Answer 48

B-AR antagonist - negative chronotropic and inotropic effects on heart - reduces performative anxiety