Lecture 5 Flashcards
anxiety - clinical aspects
a feeling of fear or dread
clinical anxiety = anxiety which is ‘pathological’ interfering with others activities or priorities
fear = panic or phobia worry = anxious misery/ apprehensive expectation/ obsessions
drug treatments of anxiety
a ‘disease-centered’ model =
- suggests that a drug restores the brain to normal function
- analogy: treatment with insulin restores relative physiological normality to people with type 1 diabetes
a ‘symptom-centered’ model =
- suggests drugs such as anxiolytics produce specific changes in aspects of mood, motivation and cognition that make condition less disabling
the GABAa synapse and Benzodiazepines
- GABA within vesicles in the presynaptic terminal
- depolarisation leads to GABA release which will act ar postsynaptic GABA receptors
- then transported back into presynaptic terminal or adjacent glial cells by reupauke pump
the reuptake mechanism is responsible for inactivating the NT after release
benzodiazepines and GABAa receptor
a benzodiazepine enhances the effect of GABA but has ‘no’ effect alone
the GABAa receptor also has separate binding sites for alcohol and barbiturates
action potential in detail
early phase:
- sodium enters and the axon depolarises
late phase:
- K+ leaves axon repolarises and briefly hyper polarises (refractory period)
GABA increases chloride conductance of membrane
if GABA impedes depolarisation of cell, this will make action potentials less likely = inhibitory effect
benzodiazepines enhance action of GABA at the GABAa receptor
suppose a drug were developed that reduced the effect of GABA at receptor then might expect drug to promote anxiety
benzodiazepines and GABAa receptor subtypes
GABAa receptor is made up of 5 separate subunits -
each is a protein and coded by different gene
the subunits are slightly variable in their structure, altering the sensitivity of receptor to benzodiazepines
differences through the brain in expression of these subunits
GABA receptor subtypes
GABAa = an ionotrophic receptor composed of 5 subunits, with considerable variability in detailed sub-unit structure
GABAb = a metabotrophic receptor - G-protein coupled
fear and amygdala
- involved in fear conditioning in rats
- rats hears tone = small increase in blood pressure
- tone precedes mild foot shock which causes larger increase in blood pressure
- tone alone now elicits blood pressure increase
- conditioning process is decreased in rats with damage to the amygdala
neural circuits for fear
outputs from amygdala can modulate different aspects of fear, including autonomic symptoms, hormonal changes and processing of fear-related stimuli
noradrenaline modulates amygdala fear circuits
noradrenaline is both peripheral stress hormone and central NT
the locus coeruleus in hindbrain contains noradrenergic cell bodies that project forwards to cortex and also sub-cortical structures including amygdala
selective chemogenetic stimulation of these neurone delays extinction of simple fear response
effect blocked by propranolol and noradrenergic beta receptor antagonist which is relevant in PTSD
neural circuit for worry
complex neural loops run between cortex, striatum and thalamus (CSTC loops) are responsible for modulation of motor output and cognition
one of these loops, from dorsolateral pre-frontal cortex may be of special importance in worry and anxiety
non-benzodiazepine anxiolytics
SSRIs enhance serotonergic inhibition in both amygdala and CSTC related circuits and are prescribed for depression
noradrengeric antagonists may reduce noradrenergic inputs that normally enhance vigilance
