Week 5: Anxiolytics

Question 1

What are the areas of the brain affected by generalized anxiety disorder?

Answer 1

-passive activity: have increased metabolic rates in occipital, temporal, and frontal lobes, and in cerebellum and thalamus
-vigilance tasks: increased activity in basal ganglia
-overall: hyperactive brain circuits in GAD
Role of other parts of brain
-amygdala=anxiety way station that mediates incoming stimuli from environment (form thalamus and sensory cortex) and stored experience (frontal cortex and hippocampus)

Question 2

What is involved in the panic response pathway in the periphery (descending pathways)?

Answer 2

• Sympathetic nervous system response

- ANS sends impulses from CNS to peripheral organs

Question 3

What brain circuits are implicated in GAD?

Answer 3

• hypofunction of serotonergic neurons arising from dorsal rap he nucleus and GABAergic neurons–> lack of inhibitory effect on GAD pathway
• overactivity of noradrenergic neurons from locus coeruleus–>excessive excitation

Question 4

What is the importance of GABAergic and serotonergic (5-HT) modulation of CNS activity?

Answer 4

• GABAergic neuron activity decreased in GAD
• 5-HT neuron activity in prefrontal cortex, basal ganglia, and limbic region reduced in GAD
• GABA=main inhibitory neurotransmitter in CNS
• Serotonergic nuclei found in rostral and caudal raphe nuclei

Question 5

What are the 3 main classes of anxiolytics?

Answer 5

• anxiolytics cause CNS depression=reduced activity
  1. Benzodiazepines (BZs)- e.g. Valium
  2. Barbiturates - not used much anymore
  3. Buspirone and SSRI/SNRI - 1st line treatment for anxiety disorders, act on serotonin/norepineprhine reuptake.

Question 6

How do GABA neurotransmission work?

Answer 6

• bind to receptor site on Cl- channel
• Cl- channels open and Cl- flow inward–>hyper polarization
• increases intracellular negative charge and reduces probability of firing
• Specific subunits in GABA A receptors confer functional diversity on the receptor
• GABAergic synapses confined to neural tissues

Question 7

What is the mechanism of action of BZ?

Answer 7

• BZ receptor agonists increase the affinity of GABA to its receptor
• causes allosteric modification of the receptor that allows for Cl- to flow in per unit time
• excitability of target neurons is decreased

Question 8

What is the mechanism of action of 5-HT1a receptor agonist (Buspirone)?

Answer 8

• 5-HT1A receptors have inhibitor effect on neurotransmission when bound by an agonist
• Buspirone is a serotonin mimic
• Buspirone is an agonist of 5-HT1a
• 5-HT1a receptors activate K+ channels via G proteins and allows K+ outflow to hyper polarize the cells and reduce excitability
• there are 5-HT1a receptors on pre synaptic neuron that reduces serotonin release also

Question 9

What is the mechanism of action of SSRIs (5-HT reuptake inhibition)?

Answer 9

• increase 5-HT concentration at the synapse and acts on pre and post synaptic 5-HT1a receptors
• result is similar to Buspirone (activation of K+ channels–>K+ outflow and hyper polarization)

Question 10

What is the dose dependent effect of BZs and barbiturates?

Answer 10

• increase in dose higher than needed of hypnosis may lead to a state of general anesthesia
• higher doses, sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death

Question 11

Describe the influence of metabolism on duration of action of BZ?

Answer 11

• Most BZs are metabolized
• metabolites are inactive, polarity and water solubility increases and speeds up excretion
• Some older BZs are metabolized to active compounds, e.g. Clorazepate
• active metabolites of Diazepam have CNS depressant actions, extends half life to days

Question 12

What are the advantages of SSRIs over BZs for long-term treatment?

Answer 12

• physiological dependence occurs in susceptible individuals with BZ and barbiturates (not buspirone of SSRIs)
• acquired tolerance develops with BZ and barbiturates
• BZs actions are lost within 2 weeks (dose increases, increases chance of overdose)
• physical dependence and withdrawal syndrome including rebound anxiety and insomnia with BZ and barbiturates

Question 13

Define anxiolytics, sedatives, and hypnotics.

Answer 13

• anxiolytics=CNS depression without causing drowsiness, work in amygdala/limbic/forntal cortical structures
• sedatives=relax and induce drowsiness
• hypnotics=produce drowsiness and encourage sleep
  1. Barbiturates=hypnotic/sedative/anxiolytic
  2. BZs=anxiolytic, sedative, hypnotic
  3. Buspirone and SSRI/SNRI =used as anxiolytics