Fear and anxiety 1 Flashcards
How is fear a useful and innate response?
When exposed to a threatening stimuli we freeze, the flight/flight reaction kicks in, and we response as appropriate. Freezing is the first of the fight/flight response to assess the situation.
How are anxiety disorders a product of inappropriate fear responses?
Excessive or maladaptive fear responses (e.g. phobias/panic disorder).
Constant fear-related behaviour (e.g. generalised anxiety).
Studying the maladaptive state allows us to work out which processes are important in the healthy adaptive state.
Is there evidence of GABAergic dysfunction in anxiety disorders?
Patients with Panic Disorder have less benzodiazepine binding sites.
Flumazenil = GABA antagonist. If have binding of flumazenil, will indicate number of GABA a receptors. May be a reduction which may mediate the symptoms associated with AD.
GABA is the main inhibitory receptor in the brain - fluxes chloride, and inhibits brain firing. Lacking of this means a lack of suppression of the fear response.
What are the properties of the GABA a receptor?
GABA a receptors are channels that sit across the cell membrane. When GABA binds it changes configuration, so it is able to flux chloride. Many types of GABA a receptor depending on different combination of sub-units. This changes the properties of the cell as well. Also changes where it is expressed. Most common are alpha 1 and alpha 2 subunits.
What drugs increase GABA a receptor activity to reduce anxiety (anxiolytic)?
Agonists = alcohol and barbiturates.
Indirect agonists = benzodiazepines.
What drugs decrease GABA a receptor activity and increase anxiety (anxiogenic)?
Antagonist = Flumazenil
Inverse agonist = beta-CCM (methyl-beta-carboline-3-carboxylate).
What happens when benzodiazepines are present?
In the presence of benzodiazepines: GABA molecules are more effective at opening the Cl- channel, greater influx of chloride, greater hyperpolarisation, more inhibition.
Having binding sites of the GABA a receptor, and modify receptor (doesn’t change the flux of chloride, but change the GABA response on that receptor. Will get bigger hyperpolarisation at the membrane).
Benzodiazepines are the best for treating anxiety as they have a medium effect - too much of an effect can lead to sedation, too little will not decrease symptoms.
What are other effects of benzodiazepines?
They act as an anxiolytic, anticonvulsant, sedative, muscle relaxant, and amnestic. An ideal anxiolytic would only have an anxiolytic effect, so want to find a drug that doesn’t have the side effects that benzodiazepines have, e.g. sedation.
What GABAa subunit may be important in anxiety?
Alpha 1 is expressed pretty much everywhere in the brain (60%) - highest in the cortex.
Alpha two is much less in the cortex but expressed elsewhere in high levels, e.g. limbic structures, the hippocampus, and the amygdala. Are expressed in brain areas which we know are involved in anxiety.
This therefore may point to alpha 2 as being the subunit for anxiety.
What are animal models for studying anxiety?
Elevated maze. Unconditioned response to a potentially dangerous environment. Anxiety measured by the degree to which the animal avoids the open arms of the maze. Effect of diazepam = increases the amount of time mouse spends in the aversive open arms of the maze.
What are the anxiolytic properties of drugs selective for the alpha 2 subunit?
TPA023: agonist at alpha 2/3 subunit containing GABAA receptors. Drug is experimental drug which as shown to be a agonist at alpha 2/3, very little at alpha 1. Tests a range of dose of that drug to test its anxiolytic response.
What are animal models for studying anxiety (2)?
Conditioned emotional response. Mice trained to press one level for food, and if they press another level they don’t get food. One condition has CS paired with mild footshock, the other condition has presentation with no consequence. Will respond less for the footshock conditioned stimulus.
What are anxiolytic properties of drugs selective for 2 subunit containing receptors?
L-838417: agonist at alpha 2/3 subunit containing GABAA receptors. Another experimental drug. Look at suppression ratios in how much they stop pressing. If give drug that is alpha 2 specific, it reduces how much they suppress their responding – have a reduction in their anxiety response in seeing that conditioned stimulus.
What happens if we remove the receptor?
GABAa alpha2 subunit knockout mouse. No difference in acquisition or level pressing for food. Still respond to the shock (have same perception of the shock), but change their fear response to getting the response. Can activate alpha 2 receptor to induce anxiety response. As increasing dose of benzodiazepine, wild mice are less concerned about the CS+ and see a back to normal responding = in knockout mouse they stabilise.
What happens if we genetically “turn off” the benzodiazepine binding site?
Knockout mice never had alpha 2 receptors - this could therefore have changed how their brains developed. Therefore other tools can use to manipulate these receptors by changing properties to analyse their function.
Alpha 4 and alpha 6 cannot bind benzodiazepines. If take the others (a2, 3, 5) which are sensitive, the amino acid on its own able to change the properties of the receptor to make benzodiazepines unable to bind.
Made mice where genetically manipulated so amino acid changed – those receptors now insensitive to benzodiazpeines. Allows to determine which subtypes do what.
