GABA and addiction Flashcards
The GABAa receptor is an important clinical target for numerous drugs, name some of these
- Benzodiazepines (diazepam, flumazenil)
- Barbituates (pentobarbital)
- Steroids (allopregnanolone)
- Volatile anaesthetics and alcohols (halothane)
- IV anaesthetics (etomidate, propofol)
Diazepam is an example of a ‘PAM’ benzodiazepine. What does this mean?
- PAM = positive allosteric modulator
- Enhances the effects of GABA when bound to the GABAa receptor.
- Anxiolytic, sedative, muscle relaxant, anticonvulsant
Beta-carboline is an example of a ‘NAM’ benzodiazepine. What does this mean?
- NAM = negative allosteric modulator
- Inhibits effects of GABA when bound to the receptor.
- Anxiogenic, pro-convulsant
What kind of BZD is flumenazil?
- Antagonist
- No effect alone but blocks the effects of both diazepam and beta-carboline
What type of BZA binding site is sensitive to classical BZDs e.g. diazepam?
alpha 1
What are BZDs used to treat?
Sleep disorders, anxiety disorders, epilepsy, muscle spasms
What are some common side effects of BZDs?
Sedation, amnesia, dependence, addiction
How long does BZD addiction take to occur and what are some of the features of this?
- 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
Which 2 areas of the brain are highly involved in addictive behaviours?
- Nucleus accumbens
- Ventral tegmental area
Which subunit of the GABAa receptor do GABA neurons express but dopamine neurons do not?
alpha 1 subunit
What do BZDs do to the dopamine neurons in the VTA?
- 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
L838,417 exhibits functional selectivity across GABAa receptor subtypes, describe which subtypes it binds to
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
How do opioids act on the VTA-nucleus accumbens pathway?
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
How do cannabinoids act on the VTA-nucleus accumbens pathway?
Decrease the release of GABA on to dopamine neurons via cannabinoid CB1 receptors acting to decrease the opening probability of voltage gated Ca channels
How does GHB act on the VTA-nucleus accumbens pathway?
Activates GABAb receptors to open K channels (hyperpolarisation) and thereby decrease the release of GABA
How does nicotine act on the VTA-nucleus accumbens pathway?
Activates nicotinic ACh receptors expressed on the DA neurons causing their depolarisation and increased release of DA
How do cocaine and amphetamine act on the VTA-nucleus accumbens pathway?
Influence DA transporters/release and thereby increase the release of DA
What are thought to be 2 of the most important factors in causing drug abuse?
- ELS - early life stress
- GABAR2 - alpha 2 GABAa receptor has been linked with alcohol, cocaine and heroin addiction
Where does the nucleus accumbens fit into drug abuse associated with ELS and GABAR2?
- 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
How can early life stress affect expression of the alpha 2 subunit?
In the nucleus accumbens of adult mice, prior ELS selectively decreases the expression of the a2 subunit resulting in compromised phasic inhibition
What can a combination of alpha 2 subunit deletion and ELS do in terms of cocaine use?
Enhance the acute locomoter effects of cocaine and suppress sensitisation to cocaine
What effect does a mutation in the GABAa receptor subunit beta1 subunit cause in mice?
Causes a preference for ethanol and increased ethanol consumption
