psychodepressants Flashcards
what are psychodepressants, give some examples and what receptors do they work on
Psychodepressants are a class of psychoactive substances that reduce the activity of the central nervous system (CNS).
Baribiturates (class b)- GABA A Benzodiazepines (class c)- GABA B GBL/GHB (class c)- GABA B Ketamine (class c)- NMDA
PCP- NMDA
GABA neurotransmission
GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).
Approximately one-third of synapses in the CNS utilises GABA as their inhibitory neurotransmitter
Activate ligand-gated ion channel (GABAA) and G-protein coupled (GABAB) receptors
Important roles in mediating inhibitory neurotransmission in local circuit interneurons (hyperopolarisation)
GABAA receptor a key drug target for anxiety disorders and insomnia (amongst other conditions)
GABA receptor
GABA binds to receptor, ion channel leads to influx of chloride ions
leads to hyperopolarisation- membrane potential is more negative than resting potential
inhibits action potential firing by increasing stimulus required to fire action potential
GABA A is post-synaptic. Terminated by GAT
GABA binds between alpha and beta subunit on receptor
but different drugs bind at different targets on the receptor eg. benzodiazepines bind between alpha and gamma
picrotoxin is non competitive antagonist that blocks GABA A receptor ion pore
GA is channel modulator (and so on)
pentameric- 6 alpha, 3 beta, 3 gamma, plus other subunits
most common configuration for GABA A receptor is 2 alpha, 2 beta and a gamma
Multiple binding sites: Agonists/antagonists e.g. GABA - Benzodiazepine binding site - Channel blockers e.g. picrotoxin - Channel modulators e.g. GA - Allosteric modulators e.g. barbiturates
Barbiturate and benzodiazepine binding sites
Each GABAA receptor subunit comprised of four transmembrane domains (M1-M4)
Central channel lined by five a-helical M2 segments of each subunit – this is surrounded by an outer ring of alternating M1 and M3 segments – M4 segments are a component of the outer ring
Benzodiazepines interact with the extracellular a–γ interface.
Barbiturates proposed to interact with the M2 and M3 β-subunit domains – the β-subunit shown to be sufficient for binding.
Introduction to barbiturates
Barbiturates are a class of GABAA receptor positive allosteric modulators that are no longer recommended as anxiolytics and hypnotics.
Barbiturates increase the activity of GABAA receptors – binding increases channel opening beyond that seen with GABA alone to enhance functional response
Responsible for severe depressant effect on the central nervous system (CNS):
direct GABAA agonist
Glycine receptor – stabilises open channel
nAChR & 5-HT3 receptor blockade
AMPA/kainate receptor blockade
barbiturates increase channel opening in GABA A, increasing neuroinhibitory drive
at high doses barbiturates can be a GABA A agonist, but can also interact w glycine receptors (more inhibition)
also block excitatory receptors such as nAChR, 5HT3, APA, kainate
barbiturates used for capital punishment
Introduction to benzodiazepines
Benzodiazepines are a class of GABAA receptor positive allosteric modulators that are widely used as anxiolytics and hypnotics.
Benzodiazepines bind to a distinct regulatory site on GABAA receptors
Benzodiazepines stabilise the GABAA receptor binding site for GABA in the open configuration
Benzodiazepines therefore increases GABA affinity for its binding site and produces a general enhancement of its neuroinhibitory actions
Benzodiazepines are therefore classed as positive allosteric modulators
Benzodiazepines are “cleaner” compounds compared to the barbiturates – do not activate other receptors (e.g. glycine, glutamate receptors)
Antidote available – flumazenil is a competitive antagonist at the benzodiazepine binding site
Duration of action of different benzodiazepines
midazolam, temazepam, lorazepam, anti covulsant, alprazolam, diazepam, chlordiazepoxide
DRUG DURATION OF ACTION MAIN USE
Midazolam Ultrashort (< 6 hours) Anaesthetic
Temazepam Short (12-18 hours) Hypnotic
Lorazepam Short (12-18 hours) Anxiolytic, hypnotic, anti-convulsant
Alprazolam
Medium (24 hours) Anxiolytic
Diazepam
Long (24-48 hours) Anxiolytic, anti-convulsant, treatment for alcohol withdrawal
Chlordiazepoxide Long (24-48 hours) Anxiolytic, treatment for alcohol withdrawal
How baribiturates and benzodiazepines cause tolerance and addiction
Barbiturates and (to a lesser extent) benzodiazepines are associated with unwanted side-effects (e.g., amnesia) and can induce tolerance and withdrawal symptoms
imbalance between GABA and glutamate (excitatory)
GABA levels are often low in those with symptomatic anxiety
allosteric modulators of GABA a receptor, general enhancement of GABA A receptor
individual can develop tolerance
perhaps due to addition of glutamate receptors in membrane
individual needs higher dose to investigate this imbalance
if individual was to withdraw: too much glutaate- leading to heightened anxiety and convlusions
GABA B receptor
GABA B is a metabotropic or GPCR 7 transmembrane domain strucutre intracellular c terminal domain made as heterodimers with GABA B1 and GABA B2 subunit
neurotransmitter binding activates G protein which dissociates from GABA B receptor G protein activates secondary messenger inhibiting adenyl cyclase reduces cAMP activating potassium channels efflux of positive potassium ions out of cell blocking of VGCC cause hyperpolarisation
Describe GHB
γ-hydroxybutyrate (GHB) was first synthesised as an anaesthetic agent – it was subsequently discovered that GHB is a short-chain fatty acid that occurs naturally in the brain and acts as a neurotransmitter and neuromodulator
GHB- developed as anaesthetic agent
also a short chain fatty acid acting in brain acting naturally in brain, liver, kidney and heart
GHB was used in anaethesia but was limited due to inadequate analgesia, due to side effects such as delirium and convulsive effect
sodium salt of GHB used in treating narcolepsy- sudden muscle weakness
misues of GHB increased greatly in western countries (party drug), taken alongside alcohol- exacerbating depressive effects on CNS
date rape drug (drug has sedative effects)
Describe GBL
γ-butyrolactone (GBL) is a precursor of GHB that, when ingested, is rapidly metabolised into GHB, exerting the same clinical effects as GHB
GBL- a precursor of GHB which when ingested has same effect as GHB after metabolism . industrially sold as stain remover and paint stripper
GHB mechanism of action
GHB has dual effect on GHB receptor and GABA B receptor
high affinity for GHB receptor (GPCRs in brain)
low affinity at GABA B receptor
when concentrations of GHB are high through drug use, GHB receptor desensitises. GHB acts as competitve agonist at pre synaptic GABA B
Endogenous concentrations of GHB too low to activate GABAB receptors
However, when concentrations of GHB in the brain rise (e.g., drug use), the GHB receptor desensitises and GHB acts as a competitive agonist at pre-synaptic GABAB receptors
GHB endogenously increases dopamine at GHB receptor- with stimulatory effect
but when there are high concentrations of GHB in drug use, GHB can inhibit dopamine release in GABA B receptors.
increasing GHB can inhibit mesocortical pathway (i.e the dpoaminergic neurons ranging from VTA projecting to the frontal cortex)- involved in cognitive control, motivation and emotion
high concentrations therefore inhibit cognition motivation and emotion
GHB dual mechanism of action
Result of dual mechanism of action of GHB
GHB initially causes an increase in dopamine secretion due to the activation of GHB receptors
At increasing concentrations, GHB can subsequently inhibit dopamine secretion due to the activation of GABAB receptors
Increasing concentrations of GHB can inhibit the mesocortical pathway, which has important roles in:
cognitive control, motivation and emotion
NMDA receptor
Three subunit types (plus alternate splice variants):
GluN1 (or NR1)
GluN2 (or NR2)
GluN3 (or NR3)
Hetero-tetrameric
“Dimer of dimers”
ketamine and PCP function by interacting with NMDA receptor
this is a receptor for glutamate- major excitatory receptor
NMDA receptor is both voltage gated and ligand gated ion channel, influx of sodium and calcium ions
the ligands for NMDA receptor are glutamate, glycine, D-serine
Glutamate binds to GluN2, whilst glycine and D-serine bind to GluN1 subunits
All binding sites need to be occupied
voltage gated: magenisum ion block at resting potential. Only depolarisation event will lead to magensium ion exiting and enabling ion channel to open and allow influx of positively charged ions
3 subunit types: GluN1,2,3 they are hetero-tetrameric usually 2 GluN1 subunitd, and 2 GluN2/3 GluN3 is non functional NMDA receptors are both ligand and voltage gated
Describe PCP
Phencyclidine (PCP) is a non-competitive antagonist of the NMDA receptor with anaesthetic and analgesic properties – associated with prolonged emergence delirium
PCP act on the NMDA receptor
non competetive antagonist
anaesthetic and analgesic
associated with intense prolonged emergence delirium- a state of marked irratation and dissociation after using anaesthesia
