Chapter 17: Anxiety And Anxiolytic Medications Flashcards
Fear
- threat is temporally/ spatially immanent
- requires the amygdala
Anxiety
- 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
Amygdaloid complex
Amygdala and limbic cortex (insular and anterior cingulate cortex, hypothalamus, and hippocampus)
CeA orchestrates components of fear
ANS activation, enhanced reflexes, increased vigilance’s activation of HPA axis
The amygdala is critical for fear learning
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
Nuclei in amygdala
- Lateral nucleus
- basolateral nucleus
Nuclei in extended amygdala
- central nucleus
- BNST
The medial prefrontal cortex (mPFC) controls amygdala activity
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
There are 2 primary reasons the mPFC inhibits fear responses
- escape from the danger is successful
- The threatening stimulus is recoded as “safe”
Many transmitter systems are implicated in anxiety
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
HPA axis is activated by release of […] from […]
HPA axis is activated by release of CRF from paraventricular nucleus of hypothalamus
Stimulation of LC or administration of yohimbine
Induces alerting and fear responses
- yohimbine (a2-AR antagonist)
- produces panic attacks in patients with panic disorder or PTSD
CRF acts as both hormone and neurotransmitter
Endocrine control
-cortisol release
Neurotransmitter
- amygdala (CeA)
- locus coeruleus (LC)
*environmental stressors activate the HPA stress axis
CRF neurons in CeA project to LC and activate the adrenergic component of stress response
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
Stress and CRF induce high-tonic firing of LC neurons and increase anxiety-like behavior
- 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
[…] KO mice exhibit an anxious phenotype
5-HT1A KO mice exhibit an anxious phenotype
- 5-HT1A receptors are both postsynaptic receptors and somatodendritic (activity-modulating) autoreceptors
5-HT1A autoreceptors
- dorsal and median raphe
- inhibit neuronal firing and 5-HT release
- agonists are anxiolytic
5-HT1A postsynaptic receptors
- many brain area, eg. Hippo and amygdala
- emotional and cognitive aspects
- agonists are anxiogenic
Inability to control stressors enhances […], and sensitizes […]
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
Behavioral Immunization
Experience with ES before IS blocks the behavioral and neurochemical consequences of IS
[…] is also implicated in anxiety
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
Genetic variations in SERT affect brain development and anxiety
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
Early life stress confers risk to developing mood and anxiety disorders
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
[…] are the first-line medications in the treatment of anxiety disorders
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
Benzodiazepines are anxiolytics
CNS Depressants- Barbituates
Sedative/ Hypnotics- hypnotics
Anxiolytics- BDZ
Sedative-hypnotics
Enhance function of GABA, causing sedation, reduced anxiety, and anticonvulsant effects
Barbituates vs BDZ
Barbituates keep GABA-activated Cl- channels longer than BDZs to
- increases number of microsomal enzymes
BDZ anxiolytics
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
General properties of sedative/ hypnotics
The dose-dependent effects progress from
- reduced anxiety
- sedation
- incoordination
- sleep
- anesthesia
- coma and death
Benzodiazepines are grouped by pharmacokinetic properties
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
Alcohol, Barbituates, and BDZs are cross-dependent
Withdrawal from any one of them can be terminated by administration of any others
Pros of BDZ
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
Cons of BDZ
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
Use of BDZ in the treatment of anxiety disorders
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
BuSpar (buspirone)
- 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
Anticonvulsants
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
Pharmacological treatment of anxiety
1st line: SSRI, SNRI, buspirone
2nd line: TCA, BDZ
Adjunct: prazosin, propranolol, gabapentin, pregabalin, atypical antipsychotic
Dopamine
- mesolimbic DA cells are activated by stressful/ threatening stimuli
- released DA on D1 or D1-R in amygdala, decreased GABA inhibition
Generalized Anxiety Disorder (GAD)
persistent anxiety symptoms for months- years
Panic attacks may occur
- In response to particular environment
- Total without warning in unexpected fashion
- In situation where an attack occured
Anticipatory anxiety
Anxiety about having attack in place that isn’t safe
Agoraphobia
Fear of public places
Phobia
Involves fears that individuals recognize as irrational
Behavioral Desensitization
Presenting fear-inducing stimuli in gradual increments
OCS
Increased activity in caudate nucleus
NE Receptor Ligands are used to alleviate physical symptoms of anxiety
Prazosin
Propanolol
Prazosin
a1-AR antagonist
- increases peripheral vasodilation (decreased bp_
- reduces insomnia and nightmares in PTSD
Propanolol
B-AR antagonist
- negative chronotropic and inotropic effects on heart
- reduces performative anxiety
