GABA and addiction

Question 1

The GABAa receptor is an important clinical target for numerous drugs, name some of these

Answer 1

• Benzodiazepines (diazepam, flumazenil)
• Barbituates (pentobarbital)
• Steroids (allopregnanolone)
• Volatile anaesthetics and alcohols (halothane)
• IV anaesthetics (etomidate, propofol)

Question 2

Diazepam is an example of a ‘PAM’ benzodiazepine. What does this mean?

Answer 2

• PAM = positive allosteric modulator
• Enhances the effects of GABA when bound to the GABAa receptor.
• Anxiolytic, sedative, muscle relaxant, anticonvulsant

Question 3

Beta-carboline is an example of a ‘NAM’ benzodiazepine. What does this mean?

Answer 3

• NAM = negative allosteric modulator
• Inhibits effects of GABA when bound to the receptor.
• Anxiogenic, pro-convulsant

Question 4

What kind of BZD is flumenazil?

Answer 4

• Antagonist
• No effect alone but blocks the effects of both diazepam and beta-carboline

Question 5

What type of BZA binding site is sensitive to classical BZDs e.g. diazepam?

Answer 5

alpha 1

Question 6

What are BZDs used to treat?

Answer 6

Sleep disorders, anxiety disorders, epilepsy, muscle spasms

Question 7

What are some common side effects of BZDs?

Answer 7

Sedation, amnesia, dependence, addiction

Question 8

How long does BZD addiction take to occur and what are some of the features of this?

Answer 8

• After a few weeks physical dependence may occur, manifest as a withdrawal syndrome, including; sleep disturbance, irritability, anxiety and panic attacks
• Addiction is associated with chronic use and often occurs in conjunction with other substance abuse e.g. heroin

Question 9

Which 2 areas of the brain are highly involved in addictive behaviours?

Answer 9

• Nucleus accumbens
• Ventral tegmental area

Question 10

Which subunit of the GABAa receptor do GABA neurons express but dopamine neurons do not?

Answer 10

alpha 1 subunit

Question 11

What do BZDs do to the dopamine neurons in the VTA?

Answer 11

• Cause disinhibition.
• BZDs enhance phasic inhibition on the GABA-ergic interneuron, causing a decreased GABA release onto the dopamine neuron.
• This increased inhibition causes an increased excitation of the dopamine neurons thereby increasing DA release in the nucleus accumbens

Question 12

L838,417 exhibits functional selectivity across GABAa receptor subtypes, describe which subtypes it binds to

Answer 12

L838,417 binds similarly to alpha 1, a2, a3 and a5 GABAa receptors but does not influence the function of alpha1-GABAaRs i.e. it is a PAM of a2, a3 and a5 but a BZD antagonist of a1-GABAaRs

Question 13

How do opioids act on the VTA-nucleus accumbens pathway?

Answer 13

Decrease the release of GABA on to DA neurons via mu opioid receptors probably by opening K channels (hyperpolarisation) and/or decreasing the opening probability of voltage-gated Ca channels

Question 14

How do cannabinoids act on the VTA-nucleus accumbens pathway?

Answer 14

Decrease the release of GABA on to dopamine neurons via cannabinoid CB1 receptors acting to decrease the opening probability of voltage gated Ca channels

Question 15

How does GHB act on the VTA-nucleus accumbens pathway?

Answer 15

Activates GABAb receptors to open K channels (hyperpolarisation) and thereby decrease the release of GABA

Question 16

How does nicotine act on the VTA-nucleus accumbens pathway?

Answer 16

Activates nicotinic ACh receptors expressed on the DA neurons causing their depolarisation and increased release of DA

Question 17

How do cocaine and amphetamine act on the VTA-nucleus accumbens pathway?

Answer 17

Influence DA transporters/release and thereby increase the release of DA

Question 18

What are thought to be 2 of the most important factors in causing drug abuse?

Answer 18

• ELS - early life stress
• GABAR2 - alpha 2 GABAa receptor has been linked with alcohol, cocaine and heroin addiction

Question 19

Where does the nucleus accumbens fit into drug abuse associated with ELS and GABAR2?

Answer 19

• The NAc is associated with reward and stress
• The majority of NAc neurons are GABA-ergic
• Synaptic alpha2-GABAaRs are expressed in the NAc medium spiny neurons

Question 20

How can early life stress affect expression of the alpha 2 subunit?

Answer 20

In the nucleus accumbens of adult mice, prior ELS selectively decreases the expression of the a2 subunit resulting in compromised phasic inhibition

Question 21

What can a combination of alpha 2 subunit deletion and ELS do in terms of cocaine use?

Answer 21

Enhance the acute locomoter effects of cocaine and suppress sensitisation to cocaine

Question 22

What effect does a mutation in the GABAa receptor subunit beta1 subunit cause in mice?

Answer 22

Causes a preference for ethanol and increased ethanol consumption