BS42017 L1+2

Question 1

give examples of the following;

1. GABAaR inhibitor
2. GABAaR PAM
3. GABAaR NAM
4. GABAaR antagonist
5. GABAaR agonist

Answer 1

1. bicuculline, picrotoxin
2. diazepam, flunitrazepam, midazolam
3. B-carbolines (e.g. DMCM)
4. flumazenil
5. taurine

Question 2

why do different GABAaRs influence different behaviours?

Answer 2

as they have distinct physiology and pharmacology and exhibit heterogenous expression pattern within the CNS

Question 3

what type of GABAaRs are benzodiazepine sensitive?

Answer 3

a1b1y2

Question 4

which alpha subunits does diazepam enhance the function of?

Answer 4

a1, a2, a3, a5 (not a4 or a6)

Question 5

what effects do GABAaR inhibitors have?

Answer 5

proconvulsant and anxiogenic

Question 6

what effects do GABAaR PAMs have?

Answer 6

anticonvulsant, anxiolytic, sedative and analgesic

Question 7

give an example of a benzodiazepine commonly misused

Answer 7

xanax (alprazolam)

Question 8

what is the difference in composition between GABA neurons and dopamine neurons?

Answer 8

GABA neurons express the a1 subunit but dopamine neurons express a3

Question 9

how do benzodiazepines cause disinhibition of dopamine neurons in the VTA?

Answer 9

• 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

Question 10

what effects does midazolam have on GABA and dopamine neurons?

Answer 10

GABA- decreases firing rate (not on a1H101R mouse)

dopamine- increased firing rate (not on a1H101R mouse)

Question 11

how do opioids act to increase dopamine in VTA-NA pathway?

Answer 11

• 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

Question 12

how do cannabinoids cause disinhibition in the VTA-NA?

Answer 12

• 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

Question 13

how does nicotine act to increase dopamine in VTA-NA?

Answer 13

• Nicotine activates nAChRs (a4b2) expressed on the dopamine neurons
• this causes depolarisation and increases dopamine release

Question 14

how do cocaine and amphetamine act to increase dopamine in VTA-NA?

Answer 14

Cocaine and amphetamine influence dopamine transporters/release and thereby increase the extracellular concentration of dopamine.

Question 15

what behavioural disorders can early life adversity influence?

Answer 15

• depression
• anxiety
• cognitive impairment
• drug abuse later in life

Question 16

which GABA alpha subunit gene polymorphisms are linked to alcohol abuse?

Answer 16

a2

Question 17

what is the NA associated with in terms of behaviours?

Answer 17

reward, depression, stress

Question 18

where are GABAaR a2 subunits expressed in the NA?

Answer 18

in medium spiny neurons (MSN)

Question 19

what does loss of a2 GABAaRs do when administered with cocaine? (ELA mice and a2 0/0 mice)

Answer 19

enhances acute locomotor effects and reduces sensitisation

Question 20

which GABAaR subunit may have a role in the rewarding/reinforcing effects of alcohol?

Answer 20

delta (d)

Question 21

how does alcohol influence GABAaRs?

Answer 21

by increasing synthesis of endogenous neurosteroids

Question 22

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”?

Answer 22

new psychoactive substances (NPS)

Question 23

when did the new drug legislation law come into place?

Answer 23

2016

Question 23

how does DSM-4 differ from DSM-5?

Answer 23

DSM-4 separated into abuser/depender, DSM-5 all substance use disorder
DSM-5 has craving as a criterium

Question 24

rank the order of route of administration of cocaine from highest spike to lowest rise in concentration (4)

Answer 24

smoked/IV snorted (nasal) oral (swallow)

Question 25

what does cocaine do to dopamine reuptake in the NA?

Answer 25

inhibit reuptake through dopamine transporters

Question 26

how does amphetamine increase dopamine efflux in NA?

Answer 26

- 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

Question 27

what are the differences in induction and transporter binding between cocaine and amphetamines?

Answer 27

cocaine has a quicker induction and remains bound for several hours. amphetamine has a slower induction but remains bound for longer

Question 28

what is more addictive- cocaine or amphetamine?

Answer 28

cocaine

Question 29

which route of administration of nicotine is least addictive? 1. cigarettes 2. oral snuff 3. chewing tabacco 4. nicotine gum 5. patch

Answer 29

patch- as it has slow rise and fall of pharmacological curve

Question 30

what is metabolic tolerance?

Answer 30

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.

Question 31

what is functional tolerance?

Answer 31

Functional tolerance is due to changes in responses in the brain so for alcohol this effects the GABAa receptors.

Question 32

what are examples of animal studies that measure reward?

Answer 32

self-administration paradigm and conditioned place preference

Question 33

what effects does alcohol have on GABARs?

Answer 33

it enhances central inhibition

Question 34

which drugs reduce relapse in recovering alcoholics?

Answer 34

disulfiram, acamprosate, naltrexone

Question 35

Which GABAAR subtypes mediate the anxiolytic & sedative effects of diazepam & how was that shown?

Answer 35

anxiolytic- a2 subunit sedative- a1 subunit using the light/dark test

Question 36

What are the clinical uses of benzodiazepines?

Answer 36

used to treat; sleep disorders, anxiety disorders, epilepsy, muscle spasms

Question 37

Contrast the roles played by GABAA receptors & GABAB receptors at an inhibitory synapse.

Answer 37

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.

Question 38

Compare GABAAR-mediated phasic & tonic inhibition

Answer 38

phasic- fast inhibition, mediated by synaptic GABAaRs | tonic- slow inhibition, mediated by extrasynaptic GABAaRs

Question 39

how do extrasynaptic GABAaRs differ from synaptic GABAaRs?

Answer 39

extrasynaptic receptors are less prone to desensitisation and are activated by very low concentrations of GABA that has spilled out of the synapse

Question 40

How does midazolam acting in the ventral tegmental area increase dopamine release in the nucleus accumbens?

Answer 40

midazolam is a PAM and so enhances GABA-ergic inhibition on GABA neurons so reduces inhibition on dopamine neurons, increasing dopamine release.

Question 41

What is the evidence that engagement of both α1- & α2-GABAARs are involved in the self-administration of midazolam?

Answer 41

self-administration paradigm- showed decreased midazolam intake for a1-H101R and a2-H101R mice compared to WT and a3-H125R mice.

Question 42

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?

Answer 42

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.

Question 43

What is the evidence to suggest that the effects of alcohol on inhibitory neurotransmission might be mediated indirectly by GABAAR-active neurosteroids?

Answer 43

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.

Question 44

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?

Answer 44

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