BS42017 L1+2 Flashcards
give examples of the following;
- GABAaR inhibitor
- GABAaR PAM
- GABAaR NAM
- GABAaR antagonist
- GABAaR agonist
- bicuculline, picrotoxin
- diazepam, flunitrazepam, midazolam
- B-carbolines (e.g. DMCM)
- flumazenil
- taurine
why do different GABAaRs influence different behaviours?
as they have distinct physiology and pharmacology and exhibit heterogenous expression pattern within the CNS
what type of GABAaRs are benzodiazepine sensitive?
a1b1y2
which alpha subunits does diazepam enhance the function of?
a1, a2, a3, a5 (not a4 or a6)
what effects do GABAaR inhibitors have?
proconvulsant and anxiogenic
what effects do GABAaR PAMs have?
anticonvulsant, anxiolytic, sedative and analgesic
give an example of a benzodiazepine commonly misused
xanax (alprazolam)
what is the difference in composition between GABA neurons and dopamine neurons?
GABA neurons express the a1 subunit but dopamine neurons express a3
how do benzodiazepines cause disinhibition of dopamine neurons in the VTA?
- GABA neurons produce GABA onto the dopamine neurons
- BZs enhance phasic inhibition of GABA neurons which subsequently release less GABA onto the dopamine neurons
- dopamine neurons now release more dopamine onto the NA
what effects does midazolam have on GABA and dopamine neurons?
GABA- decreases firing rate (not on a1H101R mouse)
dopamine- increased firing rate (not on a1H101R mouse)
how do opioids act to increase dopamine in VTA-NA pathway?
- Opioids decrease the release of GABA onto dopamine neurons via u-opioid GPCR receptors
- they do this by either; opening of K+ channels (hyperpolarisation) and/or decreasing the opening probability of the Ca2+ channels
how do cannabinoids cause disinhibition in the VTA-NA?
- Cannabinoids decrease the release of GABA onto dopamine neurons via cannabinoid GPCR CB1 receptors
- they do this by acting to decrease the opening probability of voltage-gated Ca2+ channels
how does nicotine act to increase dopamine in VTA-NA?
- Nicotine activates nAChRs (a4b2) expressed on the dopamine neurons
- this causes depolarisation and increases dopamine release
how do cocaine and amphetamine act to increase dopamine in VTA-NA?
Cocaine and amphetamine influence dopamine transporters/release and thereby increase the extracellular concentration of dopamine.
what behavioural disorders can early life adversity influence?
- depression
- anxiety
- cognitive impairment
- drug abuse later in life
which GABA alpha subunit gene polymorphisms are linked to alcohol abuse?
a2
what is the NA associated with in terms of behaviours?
reward, depression, stress
where are GABAaR a2 subunits expressed in the NA?
in medium spiny neurons (MSN)
what does loss of a2 GABAaRs do when administered with cocaine? (ELA mice and a2 0/0 mice)
enhances acute locomotor effects and reduces sensitisation
which GABAaR subunit may have a role in the rewarding/reinforcing effects of alcohol?
delta (d)
how does alcohol influence GABAaRs?
by increasing synthesis of endogenous neurosteroids
what is a “new narcotic or psychotropic drug, in pure form or in preparation, that is not controlled by the United Nations drug conventions, but which may pose a public health threat comparable to that posed by substances listed in these conventions”?
new psychoactive substances (NPS)
when did the new drug legislation law come into place?
2016
how does DSM-4 differ from DSM-5?
DSM-4 separated into abuser/depender, DSM-5 all substance use disorder
DSM-5 has craving as a criterium
rank the order of route of administration of cocaine from highest spike to lowest rise in concentration (4)
smoked/IV
snorted (nasal)
oral (swallow)
what does cocaine do to dopamine reuptake in the NA?
inhibit reuptake through dopamine transporters
how does amphetamine increase dopamine efflux in NA?
- amphetamine gets taken up by DAT
- amphetamine then blocks the VMAT (transports dopamine into vesicles)
- rise in intracellular dopamine causes efflux out of DAT into the synaptic cleft
what are the differences in induction and transporter binding between cocaine and amphetamines?
cocaine has a quicker induction and remains bound for several hours.
amphetamine has a slower induction but remains bound for longer
what is more addictive- cocaine or amphetamine?
cocaine
which route of administration of nicotine is least addictive?
- cigarettes
- oral snuff
- chewing tabacco
- nicotine gum
- patch
patch- as it has slow rise and fall of pharmacological curve
what is metabolic tolerance?
This is when a drug causes an increased expression of the enzymes that are responsible for metabolising it. I.e. alcohol causes an increase in p450 enzymes.
what is functional tolerance?
Functional tolerance is due to changes in responses in the brain so for alcohol this effects the GABAa receptors.
what are examples of animal studies that measure reward?
self-administration paradigm and conditioned place preference
what effects does alcohol have on GABARs?
it enhances central inhibition
which drugs reduce relapse in recovering alcoholics?
disulfiram, acamprosate, naltrexone
Which GABAAR subtypes mediate the anxiolytic & sedative effects of
diazepam & how was that shown?
anxiolytic- a2 subunit
sedative- a1 subunit
using the light/dark test
What are the clinical uses of benzodiazepines?
used to treat; sleep disorders, anxiety disorders, epilepsy, muscle spasms
Contrast the roles played by GABAA receptors & GABAB receptors at
an inhibitory synapse.
GABAa- fast communication, cause fast hyperpolarisation of post-synaptic membrane as they are transmitter gated ion channels.
GABAb- slower communication, cause slow hyperpolarisation of post-synaptic membrane to add to fast hyperpolarisation from GABAa. additionally cause autoinhibition on pre-synapse.
Compare GABAAR-mediated phasic & tonic inhibition
phasic- fast inhibition, mediated by synaptic GABAaRs
tonic- slow inhibition, mediated by extrasynaptic GABAaRs
how do extrasynaptic GABAaRs differ from synaptic GABAaRs?
extrasynaptic receptors are less prone to desensitisation and are activated by very low concentrations of GABA that has spilled out of the synapse
How does midazolam acting in the ventral tegmental area increase dopamine release in the nucleus accumbens?
midazolam is a PAM and so enhances GABA-ergic inhibition on GABA neurons so reduces inhibition on dopamine neurons, increasing dopamine release.
What is the evidence that engagement of both α1- & α2-GABAARs are involved in the self-administration of midazolam?
self-administration paradigm- showed decreased midazolam intake for a1-H101R and a2-H101R mice compared to WT and a3-H125R mice.
In mice which GABAAR subtypes are expressed in the medium spiny neurons (MSNs) of the nucleus accumbens, how were they identified & what role do the different subtypes play in GABA-ergic inhibition?
To find which subunits were present in MSN NA neurons they compared mice of different transgenes. These were done in combo with the drugs that are selective for different types of subunits.
Using electrophysiology (whole cell patch clamp) techniques, they found that synaptic receptors are either a1by2 or a2by2 but the MSN also express extrasynaptic receptors comprised of a4bd subunits.
A4bd are BZ insensitive and synaptic ones are BZ sensitive.
What is the evidence to suggest that the effects of alcohol on inhibitory neurotransmission might be mediated indirectly by GABAAR-active neurosteroids?
hippocampal rat slices recorded using whole-cell patch clamp technique show delayed effect of ethanol on IPSC decay and this effect is blocked by finasteride.
In the nucleus accumbens medium spiny neurons extrasynaptic
α4βδ GABAARs mediate a tonic current. What is the evidence that the expression of this receptor subtype in the accumbens & the magnitude of the tonic current influences ethanol intake?
Micro perfusion of GABAaR antagonist (bicuculline) into the accumbens, reduces ethanol self-administration. Accumbal injection of siRNA to decrease expression of either the d or a4 subunit decreases ethanol intake in rats
