5. Anxiety and Neurotransmission PDF

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Summary

Anxiety:When fear based/worry based anxious thoughts. Clinical = anxiety which is ‘pathological’ interfering with day to day life In psychiatric literature = anxiety where there is no ‘reasonable’ external cause for anxiety Treatments for anxiety :History of drugs*First line is behavioral therapy ra...

Description

Anxiety: When fear based/worry based anxious thoughts. -

Clinical = anxiety which is ‘pathological’ interfering with day to day life

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In psychiatric literature = anxiety where there is no ‘reasonable’ external cause for anxiety

Treatments for anxiety : History of drugs *First line is behavioral therapy rather than drugs -

Alcohol = Self medication for anxiety (relaxing effects-> depressants)

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Prescription drugs -

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Barbiturates and meprobamate (1960’s) -

Act in a relatively non specific way-> can induce sleep but low evidence that it can help reduce anxiety

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Low therapeutic index -> you can easily overdose + if u overdose, u can die.

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They induce tolerance and dependency

Benzodiazepines (Valium) +

Specific anxiolytic effect -> can actually help anxiety

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Relatively higher therapeutic index (better than 1960’s) : Less chance of dying from overdose

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Induce dependence

Selective serotonin reuptake inhibitors +

Nice guidelines 2011 -> first line of drug treatment for General Anxiety Disorder (GAD)

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Have a delayed onset of action

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Thought of as antidepressants

Drug treatment Disease-centered model “Restore the brain to normal function” -

‘Fix the person like if they were curing a broken leg’

Symptom-centered Having effects on the symptoms of anxiety and making them less disabling. There is no assumption that drug ‘reverses’ some pre-existing abnormality -

Ex: Produce specific changes in aspects of motivation

Nerve cells Drugs and GABA receptor The Gaba receptor is constructed from a series of subunits -

Made up of 5 subunits

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Mkes the action potential less likely to happen because it increases chloride conductance of the membrane. -

Makes the membrane equilibrium potential -65mV

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Cl_ threshold is more negative than -65mV so it makes it less likely to depolarise thus less likely that the new neuron will fire an action potential from it’s soma

Benzodiazepine -

Enhances the effect of the GABA neurotransmitter but has no effect by itself

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This means -

If the neuron is not an inhibitory GABA neuron, it will have no effect

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If it is a GABA neuron, it will stick to the subunit that will help increase how many CL_ ions are released.

Alcohol and Barbiturates -

GABA receptor has separate binding sites for these.

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They work without needing the GABA neurotransmitter to activate the receptor -

This is dangerous because it is not regulated and can cause the inhibitory effect to be TOO strong

Synapse and Benzodiazepine Mohler 2006 -

The GABA receptor subunits are amino proteins that coil up -

The protein structure subtly changes shape when a GABA neurotransmitter is attached to them.

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They open for longer when Benzodiazepine is on them

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Aka they open and close However, some subunits are relatively sensitive to Benzodiazepine which increases the utility of the GABA neurotransmitter with how many Cl _ ions it

can let through.

You can have subunits of GABA receptors that are highly Benzodiazepine receptors and some that are not. -

Some subunits of the GABA receptors are receptive to Benzodiazepine and some are not.

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GABA receptors are made out of 5 subunits (proteins). There are 7 options.

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Called Benzodiazepine sensitive and Benzodiazepine insensitive

If the GABA receptor is filled with the subunit that is highly Benzodiazepine receptive, the Benzodiazepine will be more effective.

So basically, some areas of your brain (aka some neurons) are more receptive to Benzodiazepine while others are not. -

The parts that have the highest receptor density are the hippocampus, amygdala and related structures.

Major classes of GABA receptor subtypes GABAA receptor -

Ion atrophic realtor -

Has ion channels in it

GABAB receptor A metabotropic receptor -

When GABA neurotransmitter is binded, it triggers a biochemical change -

Called the second messenger (first being the neurotransmitter)

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This biochemical change affects the functioning of the postsynaptic cell

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Take a long time to do so

Threat (fear) and The amygdala Used for simple threat conditioning in rats -

Rat hears tone -

Gets a small blood pressure increase

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Gets a mild static footshock right after the tone

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if u play a tone (w/o) the shock

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rat freezes, blood pressure increases Rat gets the same high blood pressure increase and freezing as w/ shock.

PET imaging study in humans (Isenberg et al) Stroop task w/ chill words and threat related words. -

Greater activation in the amygdala w/ threat related words

Neural circuits for fear Outputs from the amygdala can modulate different aspects of fer -

Automatic symptoms :

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Hormonal changes : Hypothalamus

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Blood pressure heart rate

Increase adrenaline, cortisol

Processing fear-related stimuli

Is amygdala needed for humans to feel fear? Feinstein et al (2013) -

3 individuals who had bilateral amygdala damage (both sides of amygdala was damaged)

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They + 12 control participants, were given high concentration of CO 2

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All 3 experienced panic attacks and some of the control experienced panic attacks

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This causes panic attacks

The people who experienced panic attacks were around equally panicked

So no, amygdala is not needed for humans to fear

Benzodiazepines may modulate GABA inputs to amygdala Fear related aspects and Benzodiazepines The inhibitory effect of Benzodiazepines has an effect on the panic and phobia (fear related aspects ) of the amygdala. -

Modulation of amygdala -

5HT (Serotonin)

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GABA

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Glutamate

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CRF : Catrophy releasing factor -

Important in hormone control for cortisol release

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NE ( Noradrenaline)

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Voltage gated ion channels

Neuronal circuits for worry Complex loops run between the cortex, the striatum and thalamus (CSTC loops) -

Responsible for modulation of motor output and cognition, visual processing

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One Of these loops, in the dorsolateral prefrontal cortex (DLPFC) -

May be important for worry and anxiety

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Gaba is one of the main neurotransmitters in that loop therefore Benzodiazepines has an effect on free flowing worry. (General anxiety)

Overlap between depression (MDD) and anxiety (GAD) Symptomatic approach = both anxiety and depression have many same symptoms -

Therefore many anti depression drugs help anxiety

Non-Benzodiazepines anxiolytics Selective serotonin reuptake inhibitors -

Enhance inhibition in both amygdala and CSTC related circuits

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This class of drug is also widely prescribed for depression

Buspirone -

A serotonergic drug which is similar to the SSRIs but does it in a dif way

Gabapentin and pregabalin -

Modulators of voltage sensitive calcium channels (VSCCs)

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Reduce excitatory glutamate transmission in the amygdala and CSTC related circuits

Noradrenergic antagonists (beta blockers) -

May reduce noradrenergic inputs that normal enhance vigilance (sustained concentration) -

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Via effects on the hippocampus and the amygdala

Can reduce the autonomic components of anxiety (blood rush)

Serotonin anxiolytics -

Serotonin aka -

5 hydroxytryptamine

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5-HT

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Has diff subtypes that mediate its effects

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Selective serotonin reuptake inhibitors = Prozac

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7 major families and subtypes within the families. Slow the removal of serotonin from the synaptic cleft (enhancing its action)

Busiporone acts as a partial agonist at some types of serotonin receptors -

So it binds to cetrain serotonin receptors to make them work better

Noradrenaline modulates Amygdala ‘fear’ circuits -

Noradrenaline is a peripheral stress hormone and a central neurotransmitter -

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The local coeruleus (hindbrain) constraints noradrenaline cell axons that project forward to the cortex and the amygdala

Selective chemogenetic stimulation of these neurons delays the extinction of a simple fear response in rats

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The fear in rats of the tone goes away if you repeatedly play the tone w/o shocking the rat.

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However, with the selective chemogenetic stimulation (Stress) in the hind brain, the extinction of the fear is delayed

HOWEVER, propranolol stops the effect of stress to delay and instead allows the fear to go extinct -

Propranolol is a noradrenergic beta receptor antagonist (especially relevant to PTSD patients)...