531 Lec 35

Understand the role of the hypothalamic-pituitary-adrenal (HPA) axis in anxiety.

Causes an increase in cortisol secretion to the adrenal cortex

Understand the influence of different areas of the brain on the HPA in anxiety.

amygdala goes off when there is a perceived threat, usually there’s a balancing event when that is not a real threat

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hippocampus files events - can lead to perceiving memories as if they are happening now

What molecule is this

GABA

What molecule is this

Glutamate

Know the role of glutamate and gamma-aminobutyric acid (GABA) in the CNS.

Glutamate is an excitatory NT

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GABA is an inhibitory NT(calming)

Understand the GABA shunt, why it is relevant to our anxiety discussion, and the reactions and enzymes involved

GABA shunt reactions are responsible for the synthesis, conservation and metabolism of GABA

How is glutamate transported from glia cells without causing depolarization ?

1) Glutamate from the Glia cell gets converted into inert glutamine that can travel between Glia cells and presynaptic neurons so that we don’t have loose glutamate hanging around binding things

2)In the presynaptic neuron glutamine gets converted into glutamate then GABA then released into the synaptic cleft

GABAa Receptors

Ionotropic- Ligand gated ion channels

Fast acting

GABAb Receptors

Metabotropic receptors

G protein coupled receptors

Slow acting

What do ionotropic receptor subunit subtypes do?

modulate the pharmacology of the receptor

Know where GABA binds on each of its receptor types.

Gaba binds at the nexus at alpha 1 and beta 2 ( need 2 to bind)

Know what effect benzodiazepine binding has on chloride flux and what results.

Open the Cl Ion channel

Cl- flux stabilizes the membrane so it’s desensitized against stimuli

baclofen

GABA-B receptor agonist

→ increased k+ flux, long lasting inhibitory postsynaptic potentials

→ reduced calcium influx, helps GABA autoreceptors inhibit presynaptic GABA release

→Suppress Adenylate cyclase activity→ decreases cAMP concentrations

→Activation of K+ channels through GABAb coupled G proteins inhibits neuron firing

Know where Baclofen binds on its receptor

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Know the activity and side effect profile of benzodiazepines

Used as sedative hypnotics, muscle relaxants, anxiolytics, anticonvulsants

Nonselective with respects to alpha subunit

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Side effects:

Sedation

Respiratory depressant depending on dose and duration

Anterograde amnesia

Withdrawal syndrome

Accumulation leads to tolerant

Potential for physical dependence with chronic use

Nearly all BZs cause dose-dependent behavioral changes

For what indications are benzodiazepines generally prescribed?

Sleep aids, Muscle relaxants, anxiolytics, anticonvulsants

Know what alpha subunits of GABA-A are associated with sedative vs anxiolytic effects.

alpha 2,3, and 5 subunits mediate anxiolytic and muscle relaxant properties

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alpha 1 subunit mediate sedative effects

Know where and under what circumstances benzodiazepines bind on the GABA receptor.

Binds between alpha 1 and gamma 2 subunits of GABA ionotropic receptors

Know the general effect of an agonist at the GABA-A receptor.

Anticonvulsant (anti muscle spasms), anxiolytic, sleep aid, muscle relaxant

Know the general effect of an antagonist at the GABA-A receptor.

Convulsant (causing muscle contractions)

Diazepam (Valium)

Anxiolytic, Sedative, Muscle Relaxant, Anticonvulsant and Amnestic effects

Increased risk of abnormalities in preggo

Passes into breast milk

N alkylation

Metabolized to N-desmethyldiazepam

Chlordiazepoxide (Librium)

Anxiolytic

Sedative properties

Oral tablets

Light sensitive

Metabolized to N-desmethyldiazepam

N-desmethyldiazepam

Active metabolite of Valium and Librium