Segment  6  

Wake  &  REM:  GABA  

Neurobiology of Sleep and Wakefulness

•  Learning Points & Defining Behavioral States •  Historical Overview: Brainstem & Forebrain •  Wakefulness and REM Sleep: Monoamines,

Acetylcholine & GABA, Hypocretin/Orexin •  NREM Sleep: GABA, Adenosine •  Summary

GABA •  Major inhibitory transmitter in brain

•  Most drugs used clinically to produce sleep, sedation, or general anesthesia enhance transmission at GABAA receptors

•  Activation of GABAB receptors also causes sleep

Hall-Porter et al., Sleep Med Clin 5:609-625, 2010

Agent (Trade name) Class Flurazepam (Dalmane) Benzodiazepine Quazepam (Doral) Benzodiazepine Estazolam (Prosom) Benzodiazepine Temazepam (Restoril) Benzodiazepine Triazolam (Halcion) Benzodiazepine Zolpidem (Ambien) Imidazopyridine (BZ site agonist)

Zolpidem CR (Ambien CR) Imidazopyridine (BZ site agonist) Zaleplon (Sonata) Pyrazolopyrimidine (BZ site agonist) Eszopiclone (Lunesta) Cyclopyrrolone (BZ site agonist) Ramelteon (Rozerem) Propionamide Doxepin (Silenor) Antihistamine

•  HOWEVER, preclinical studies show that the effects of GABA on sleep and wakefulness are brain-region specific

•  For example, GABA in the pontine reticular formation (PRF, PnO) actually increases wakefulness and inhibits sleep, particularly REM sleep

GABA

GABAA Receptor Agonist in Mouse PnO Increases Wakefulness and Decreases Sleep

Flint et al., J Neurosci 30: 12301-9, 2010

Extrasynaptic GABA-A Receptors in Rat PnO Promote Wakefulness

Vanini & Baghdoyan Sleep 36:337-343, 2013

NPA

!  !  

A   B  

Blocking GABA Uptake Increases Extracellular GABA Levels  

NPA

!  !  

A   B  

Increasing Endogenous GABA in Rat PnO Increases Wakefulness and Decreases Sleep

Watson et al., Sleep 31:453-464, 2008

B  

Blocking GABA Synthesis Decreases Extracellular GABA Levels  

A  !  B   3-MPA

Decreasing Endogenous GABA in Rat PnO Decreases Wakefulness and Increases Sleep

Watson et al., Sleep 31:453-464, 2008

Blocking GABAA Receptors in Mouse PnO Increases Sleep and Decreases

Wakefulness

Flint et al., J Neurosci 30:12301-12309, 2010

Blocking GABAA Receptors in Mouse PnO Increases Acetylcholine Release

Flint et al., 2010 J Neurosci 30: 12301-12309

Marks et al., Neuroscience 156:1-10, 2008

GABA-Ach Interaction in PnO Modulates REM Sleep

Vehicle GBZ Atr/GBZ

Tim

e in

REM

Sl

eep

(min

)

40  

20  

30  

10  

0  N=5  

*  

+  

Interpretation •  GABAA receptors in the pontine reticular

formation promote wakefulness and inhibit REM sleep

• 

•  Mechanism by which GABA in the pontine reticular formation inhibits REM sleep involves inhibition of acetylcholine release

GABA Levels in the Pontine Reticular Formation are Greatest in Wakefulness

Vanini et al., J Neurosci 31:2649-2656, 2011

     

ACh Release in the Pontine Reticular Formation is Greatest during REM Sleep

Leonard and Lydic, Neuroreport 6:1525-1529, 1995 Kodama et al., Neurosci Lett 114:277-282, 1990

WAKE NREM REM

pmol

ACh

/10

min

(mea

n +

SD

)

0.0

0.2

0.4

0.6

0.8 ✻  

GABA and ACh in the PRF Show Differential State-Specific Changes

Vanini et al., J Neurosci 31:2649-2656, 2011

0.3  0.9  1  

PRF GABA Can Increase Wakefulness: Clinical Relevance

•  Benzodiazepines increase total sleep time but some decrease the amount of REM sleep and increase REM sleep latency (Avidan and Zee, Handbook of Sleep Medicine, 2006, p. 52)

•  Increasing pontine GABAergic transmission may be one mechanism by which some benzodiazepines decrease REM sleep

•  Benzodiazepines sometimes produce paradoxical excitation (Brown et al., N Engl J Med 363:2638-2650, 2010)

•  The finding that enhancing GABAergic transmission in the pontine reticular formation promotes wakefulness suggests a possible mechanism

PRF GABA Can Increase Wakefulness: Clinical Relevance