Anxiety disorders:Neurobiology, neurochemistry and treatment
What is the role of the amygdala?
emotions, memory, decision making
The amygdala receives inputs from which areas of the brain?
sensory cortex and sensory thalamus (and hippocampus)
The amygdala sends outputs to which areas involved in fear response? (3)
lateral hypothalamus = sympathetic activation; tachycardia, pupil dilation, blood pressure elevation
ventral tegmental area: locus coeruleus = activation DA, NE, ACh; behavioural and EEG arousal, increased vigilance
paraventricular nucleus = ACTH release; corticosteroid release (stress response)
ventral tegmental area: locus coeruleus = activation DA, NE, ACh; behavioural and EEG arousal, increased vigilance
paraventricular nucleus = ACTH release; corticosteroid release (stress response)
What is the acute stress response?
aka fight or flight response
when amygdala excites locus coeruleus (VTA) and hypothalamus
when amygdala excites locus coeruleus (VTA) and hypothalamus
What is the HPA axis and when is it activation?
activated as an acute stress response:
fear stimulus to amygdala
project to hypothalamus = release CRH (corticotrpin releasing hormone)
triggers pituitary to release ACTH (adrenocorticotropic hormone)
adrenal cortex releases cortisol = stress hormone
fear stimulus to amygdala
project to hypothalamus = release CRH (corticotrpin releasing hormone)
triggers pituitary to release ACTH (adrenocorticotropic hormone)
adrenal cortex releases cortisol = stress hormone
In the acute stress response what happens in the locus coeruleus?
releases Norepinephrine which triggers ‘fight or flight’ response
What happens in situations of chronic stress?
chronic activation of glucocorticoid receptors in hippocampus; increased entry of Ca2+ into neurons
too much Ca2+ = excitotoxicity = cells die
hippocampus cannot feedback to amygdala to limit cortisol production
too much Ca2+ = excitotoxicity = cells die
hippocampus cannot feedback to amygdala to limit cortisol production
Anxiety disorders may result from what with respect to the hippocampus?
diminished activity of hippocampus
loss of feedback to the amygdala
inappropriate fear responding
evidence = hippocampal volume in PTSD patients reduced
loss of feedback to the amygdala
inappropriate fear responding
evidence = hippocampal volume in PTSD patients reduced
Which type of cell in the hippocampus decreases as a result of chronic stress?
pyramidal cell
What is meant by the push-pull regulation of the HPA axis?
amygdala positive input to HPA axis, hippocampus negative input to HPA axis (inhibitory)
hippocampus has glucocorticoid receptors for cortisol release in response to excitation of the HPA axis and hence cortisol increase will increase the inhibiton of the HPA axis in order to decrease cortisol release
hippocampus has glucocorticoid receptors for cortisol release in response to excitation of the HPA axis and hence cortisol increase will increase the inhibiton of the HPA axis in order to decrease cortisol release
Apart from the amygdala-HPA-hippocampal relationship, which other areas of the brain do the hippocampus and amygdala respond to?
diffuse modulatory systems:
1) noradrenergic system; arousal and attention (fight/flight)
2) serotonergic system; mood and emotion
balance one another out
systems project diffusely throughout the forebrain to cortical and limbic areas and have connections to each other
1) noradrenergic system; arousal and attention (fight/flight)
2) serotonergic system; mood and emotion
balance one another out
systems project diffusely throughout the forebrain to cortical and limbic areas and have connections to each other
Dysregulation of limbic system or their connections may result in what?
inappropriate fear response; due to diffuse modulatory systems that input involved in basal ganglia and linked to amygdala and hippocampus = inappropriate release of cortisol from inappropriate stimulation of HPA axis
can determine pathways by which drugs have anxiolytic effects
can determine pathways by which drugs have anxiolytic effects
Define panic disorder
unrealistic, unfounded fear and anxiety; acute and unremitting terror for variable lengths of time (secs to hours)
Give evidence for the use of benzodiazepines in panic disorder patients?
benzo antagonists eg. flumazenil, produce panic attack in patients with PD , but not in controls
so anxiety disorders may be due to fewer Benzo receptors, or by a neuromodulator that blocks GABA (A) receptor benzo binding site
so anxiety disorders may be due to fewer Benzo receptors, or by a neuromodulator that blocks GABA (A) receptor benzo binding site
Explain what benzodiazepines do?
bdp partial agonists of the GABA(A) receptor, anxiolytic; sedation and sleep induction, reduced muscle tone and coordination, anticonvulsant effects, anterograde amnesia
Apart from benzodiazepines give some other treatments for anxiety disorders?
SSRIs , CBT
In which anxiety disorders do bdps work well and when are they not so effective?
work well in GAD and PD
do not work as well in PTSD and OCD
do not work as well in PTSD and OCD
In which anxiety disorders do SSRIs work well and give a problem with their use?
OCD, PTSD, PD, GAD
but can be anxiogenic in short term; first few days of treatment
anxiolytic effects may not become apparent for weeks
but can be anxiogenic in short term; first few days of treatment
anxiolytic effects may not become apparent for weeks
What is buspirone and what is it used to treat?
a 5-HT1A receptor partial agonist
works for GAD but takes 4-6 weeks to exert therapeutic potential
works for GAD but takes 4-6 weeks to exert therapeutic potential
What effect do drugs increasing GABA activity have on anxiety and name some partial and indirect agonists?
anxiolytic
partial agonists = alcohol, barbiturates
indirect agonist = benzodiazepines
partial agonists = alcohol, barbiturates
indirect agonist = benzodiazepines
What effect do drugs decreasing GABA activity have on anxiety and name an antagonist and where it acts?
anxiogenic
antagonist = benzodiazepine antagonist eg. flumazenil
drugs act on the GABA(A) ionotropic receptor
antagonist = benzodiazepine antagonist eg. flumazenil
drugs act on the GABA(A) ionotropic receptor
Explain the drug action on GABA (A) R both agonist and antagonist?
GABA (A) Cl- channel
response of neuron to GABA when bdp eg. diazepam, is present is increased Cl- conductance and increased hyperpolarization current
GABA antagonists prevent Cl- conductance in spite of benzodiazepine presence
response of neuron to GABA when bdp eg. diazepam, is present is increased Cl- conductance and increased hyperpolarization current
GABA antagonists prevent Cl- conductance in spite of benzodiazepine presence
Give some evidence for GABAergic dysfunction in anxiety disorders?
PET study using radiolabelled Flumazenil; indicates Bdp binding sites; Flumazenil is bdp antagonist binds bdp sites on GABA(A) ionotropic receptor
patients with panic disorder have fewer bdp binding sites
therefore PD patients lack sufficient inhibitory control (via agonizing inhibitory GABA(A) ) in cortical and limbic regions to suppress inappropriate fear responses and subsequent panic attack
frontal cortex normally shows increased activity during periods of anxiety
patients with panic disorder have fewer bdp binding sites
therefore PD patients lack sufficient inhibitory control (via agonizing inhibitory GABA(A) ) in cortical and limbic regions to suppress inappropriate fear responses and subsequent panic attack
frontal cortex normally shows increased activity during periods of anxiety
Describe the link between anxiety and depression?
comorbid 85% depressed display GAD symptoms,
both treatable with SSRIs, both weeks before therapeutic actions are visible
both treatable with SSRIs, both weeks before therapeutic actions are visible
Why is there a delay between the onset of drug treatment for anxiety and depression and the therapeutic effect?
SSRIs ; effect not just due to raised synaptic levels of serotonin
otherwise changes would be seen on initiation of treatment
instead as a result of adaptive changes by the nervous system to the chronically elevated levels of serotonin;
intracellular cascades downstream of 5HT receptor lead to changes in neuronal plasticity and morphology eg. neurogenesis in adult hippocampus
otherwise changes would be seen on initiation of treatment
instead as a result of adaptive changes by the nervous system to the chronically elevated levels of serotonin;
intracellular cascades downstream of 5HT receptor lead to changes in neuronal plasticity and morphology eg. neurogenesis in adult hippocampus
Describe the opposing functions of serotonergic and norepinephrine systems in panic disorder?
NE release stimulates arousal and alertness, 5HT inhibits NE release
shifted NE pathway balance may be basis for panic attacks
SSRIs boost 5HT release = increased inhibition NE, inhibit arousal and alertness
shifted NE pathway balance may be basis for panic attacks
SSRIs boost 5HT release = increased inhibition NE, inhibit arousal and alertness
What is OCD?
frequently occurring, uncontrollable, anxiety-producing thoughts and impulses. Responding to them dissipates associated anxiety
OCD patients recognize that their thoughts and behaviors are senseless
different categories of compulsions eg. counting, checking, avoidance
OCD patients recognize that their thoughts and behaviors are senseless
different categories of compulsions eg. counting, checking, avoidance
What is the incidence of obsessive compulsive disorder?
12% incidence
What causes OCD? (environmental and genetic)
could be genetic eg. monozygotic > dizygotic
common underlying genotype Tourette’s and OCD
common underlying genotype Tourette’s and OCD
could be environmental eg. streptococcal infection
experience plays a role eg. family health history
Which area of the brain is associated with OCD?
May be a disorder of the basal ganglia; repeated behaviors – following rituals, Tourettes also locus in bg, imbalance between indirect and direct pathways through basal ganglia
Describe the role of the direct pathway in the basal ganglia?
controlling previously learned behavioural sequences so they become automatic and can be rapidly executed
Describe the role of the indirect pathway in the basal ganglia?
suppressing automatic behaviours so the individual can switch to more adaptive behaviours (behavioural flexibility)
What is the relationship between the indirect and direct pathways of the basal ganglia and OCD?
overactivity of direct pathway may lead to these compulsive behaviours without being able to switch them off
Explain the link between caudate hyperactivity and OCD?
caudate sends GABAergic inhibitory projections to globus pallidus which sends inhibitory projections to the thalamus, which then projects to the OFC
disinhibition leading to activity in this circuit may cause OCD
disinhibition leading to activity in this circuit may cause OCD
Give some evidence for OCD and OFC dysfunction?
underactivation of OFC in a reversal learning task in patients with OCD
What is the best treatment strategy for anxiety disorders?
SSRIs initially anxiogenic
BDP good immediate effects but tolerance, abuse, withdrawal anxiety
combine SSRIs and BDP initially, taper off BDP as the SSRIs take effect
BDP good immediate effects but tolerance, abuse, withdrawal anxiety
combine SSRIs and BDP initially, taper off BDP as the SSRIs take effect