7.3. Sedative-hypnotics: Neurobiology and GABA transmission

Sedative-hypnotics: Pharmacodynamic mechanism

Sedative-hypnotics enhance chloride influx through GABAA receptors

Pharmacodynamic mechanisms: Barbs and benzos

Unique binding sites on GABAAreceptor

Pharmacodynamic mechanisms: Alcohol

Unknown mechanism at GABAA receptor

• Similar spectrum of behavioral effects

• Similar increase in chloride currents

• Cross-tolerance and cross-dependence

GABA

- GABA is the most important inhibitory neurotransmitter in the adult, vertebrate brain.

- Found throughout the brain in high concentrations (many neurons and nuclei)

- Important role in regulating excitation.

GABA synthesis

GABA is formed from glutamate (the immediate precursor) via the enzyme glutamic acid decarboxylase (GAD).

GABA transmission and inactivation

- Packaged into vesicles via the vesicular GABA (and glycine) transporter VGAT.

- After release, transported out of synapse (i.e., inactivated) via GABA transporters GAT-1, GAT-2, and GAT-3 (on neurons and glia).

- Metabolism/degradation in neurons and glia via the enzyme GABA amino-transferase (GABA-T).

GABAa receptors are

- Ionotropic

- Ligand-gated Cl- channels

- Pentameric (5 subunits)

GABAb receptors are

- Metabotropic

- Unlike most GPCRs, GABA-B receptors need two different subunits

- Used as the autoreceptor on GABA terminals.

GABAA receptors: Composition

- GABAA receptor: 5 subunits (Cl- ion channel)

- Most GABAA receptors have 2α subunits, 2β subunits, and γ (or δ).

GABAA receptors: Pharmacology

GABA binding to GABAA receptor increases Cl- conductance, leading to hyperpolarization (inhibition) and IPSPs.

Mechanism of action: Barbs/benzos

Barbs and benzos act at different sites on GABAA receptor, and a different site than GABA

GABA + diazepam (benzo)

- Benzos cause GABAA channels to open more frequently.

- Need GABA; benzos have no effect alone; benzos are positive allosteric modulators.

GABA + phenobarbital (barb)

- Barbs cause GABAA channels to stay open for longer duration.

- Barbs have some direct agonist effects without GABA.

Benzodiazepine binding site

- BZ binding site

- Benzo binding correlates with anxiolytic effects

Benzo inverse agonists

- inverse agonists, β-carbolines

- Benzos positively modulate GABAA receptor; β-carbolines negatively modulate

- β-carbolines are found in psychedelic drug ayahuasca:

GABAA subunits: Benzo behavioral effects

GABAA receptors with different subunits are differentially involved in various behavioral effects of benzos

α2 subunit: Anxiolytic effects of benzos

Conclusion: Anxiolytic effects of benzos require α2-containing GABAA receptors

α1 subunit: Rewarding effects of benzos

- Benzos increase firing of VTA dopamine neurons via disinhibition

Conclusion: Rewarding effects of benzos require α1-containing GABAA receptors

Alcohol effects in nervous system:

- At low to moderate doses, specific effects

- At high doses, nonspecific effects

Alcohol Glutamate mechanisms: Acute

Inhibits glutamate transmission; reduces effectiveness of glutamate actions at NMDA receptor, resulting in memory loss during intoxication.

Alcohol Glutamate mechanisms: Chronic

Upregulation of NMDA receptors; hyperexcitability during withdrawal

Alcohol GABA mechanisms: Acute

Increases GABA-induced Cl- influx at GABAA receptors

Alcohol GABA mechanisms: Chronic

Reduces GABAA-mediated Cl- influx; hyperexcitability during withdrawal

Alcohol DA mechanisms: Acute

- Increases DA transmission

- Alcohol self-administration reduced, but not blocked, by DA antagonist or 6-OHDA lesions.

Alcohol DA mechanisms: Chronic

Reduction in DA transmission; withdrawal-induced negative affect and reduction in DA

Alcohol opioid mechanisms: Acute

- Increases endogenous opioids

- Alcohol self-administration decreased by opioid antagonist or μ opioid receptor knockout

Alcohol opioid mechanisms: Chronic

Reduces opioid production

Alcohol treatment options: Detoxification

Benzodiazepine replacement

Alcohol treatment options: Psychosocial

Self-help groups

Alcohol treatment options: Pharmacotherapy

- ALDH inhibitor

- μ opioid receptor antagonist

- Partial NMDA antagonist