Download Practical Implications of Sleep Neurochemistry

Practical Implications of Sleep
Neurochemistry
Part two
K Hargrave, MD LASM Nov 5 2011
acetylCoA + choline Ach
AchE
Ach----------acetate
+ choline
BuChE
Glutamate
• Glutamate is the most abundant excitatory neurotransmitter
in the vertebrate nervous system
• It is always excitatory, usually due to simple receptors that
increase the flow of positive ions by opening ion-channels.
• In neuroscience, glutamate is an important neurotransmitter
that plays a key role in long-term potentiation and is
important for learning and memory.
• Highest [ ] in hippocampus
http://en.wikipedia.org/wiki/Glutamic_acid
Glutamate
• NMDA receptors
• AMPA receptors
• Kainate receptors
• Metabotropic receptors
NMDA receptors
• Possibly the most complicated of all neurotransmitter
receptors is the NMDA glutamate receptor.
• N-Methyl-D-Aspartate is a synthetic chemical not naturally
found in biological systems, but it binds specifically to the
NMDA glutamate receptor (receptors are frequently named
for artificial substances that bind to the receptor with higher
specificity than their natural neurotransmitter ligands).
NMDA R’s
•
The NMDA receptor is the only known receptor which is
regulated both by a ligand (glutamate) and by voltage.
• There are at least 5 binding sites which regulate NMDA
receptor activity, ie, sites for
• (1) glutamate
• (2) glycine
• (3) magnesium
• (4) zinc and
• (5) a site that binds the hallucinogenic substance
phencyclidine (PCP, "angel dust").
http://www.benbest.com/science/anatmind/anatmd10.html
Histamine
The putative histaminergic neurons of the TMN, the putative
serotonergic neurons of the dorsal raphe nucleus, and the putative
hypocretinergic neurons of the PLH exhibit a wake-active, NREMand REM-off pattern of discharge,
Jaime Monti;S. R. Pandi-Perumal;Christopher M.
Sinton. Neurochemistry of Sleep and Wakefulness
(Kindle Locations 177-178). Kindle Edition.
Serotonin
The putative histaminergic neurons of the TMN, the putative serotonergic
neurons of the dorsal raphe nucleus, and the putative hypocretinergic neurons of
the PLH exhibit a wake-active, NREM- and REM-off pattern of discharge,
Jaime Monti;S. R. Pandi-Perumal;Christopher M. Sinton. Neurochemistry of Sleep
and Wakefulness (Kindle Locations 177-178). Kindle Edition.
Hypocretin/Orexin
http://journals.prous.com/journals/dnp/20031608/html/dn160504/images/DeLeccea_f1.jpg
“If you think about a normal day, 98% of the time is spent
either awake or asleep,” Saper says. “There is a very short
transition period between the two. The brain seems to have a
flip-flop switch that changes the state from wakefulness to
sleep, and orexin acts like the thumb that keeps this switch in
the ‘on’ position.”
A deficiency of orexin causes narcolepsy.
Dopamine
• The role of dopamine in the control of wakefulness is
intriguing and at the same time confusing.
• The most potent wake-promoting substances known
(amphetamines, modafinil) have a common site of action in
inhibiting the dopamine reuptake transporter (DAT), thus
increasing extracellular levels of dopamine (Wisor et al.,
2001).
Jaime Monti;S. R. Pandi-Perumal;Christopher M. Sinton. Neurochemistry of Sleep and Wakefulness (Kindle
Locations 604-608). Kindle Edition.
Dopamine
• However, single-unit recordings from dopamine neurons in
the two largest dopaminergic cell groups projecting to the
forebrain, the substantia nigra (SN) and ventral tegmental
area (VTA), revealed that their average firing rate did not
change across the sleep-wake cycle (Miller et al., 1983).
• Thus, although pharmacological enhancement of
dopaminergic neurotransmission can enhance waking it is
unclear whether dopamine systems in the SN/VTA are actually
involved in causing changes in behavioral state.
Jaime Monti;S. R. Pandi-Perumal;Christopher M. Sinton. Neurochemistry of Sleep
and Wakefulness (Kindle Locations 604-608). Kindle Edition.
Tyr OH’ase
ddc
MAO (intracellular)
Tyr----L-DOPA----DA-------------HVA
COMT extracellular)
DA B OH’ase
DA --------NE
http://www.benbest.com/science/anatmind/anatmd10.html
Norepinephrine
• LC ‘blue place’ in dorsolateral pons
• a1, a2, B1 receptors
Otto Loewi, after stimulating the sympathetic nerves to the heart, showed
that heart D accelerated its pace, very much like injected adrenaline
(noradrenaline) he called this Acceleransstoff (accelerating substance).
The prefix nor- is likely derived as an abbreviation of the word "normal", used
to indicate a demethylated compound
http://www.cerebromente.org.br/n17/history/neurons5_i.htm
http://pharmrev.aspetjournals.org/content/59/4/289.full
‘Sleep Neurochemistry’
Melatonin
http://pharmrev.aspetjournals.org/content/62/3/343.full
www.biology.lsu.edu/webfac/jstephens/notes/Pineal%20Gland.ppt
GABA
• GABA is the major inhibitory neurotransmitter of the brain,
occurring in 30-40% of all synapses (second only to glutamate
as a major brain neurotransmitter).
• It is most highly concentrated in the substantia nigra & globus
pallidus nuclei of the basal ganglia, followed by the
hypothalamus, the periaqueductal grey matter ("central
grey") and the hippocampus.
• The GABA concentration in the brain is 200-1000 times
greater than that of the monoamines or acetylcholine.
http://www.benbest.com/science/anatmind/anatmd10.html
GABA
GABA A :
Benzo’s
Barb’s
GABA B
presynaptic/autoreceptors
GlucosealphaketoglutarateGlu
GAD
Glutamate-----GABA
Subst Nigra has highest [ ] of GABA
[Glu acid decarboxylase only present in CNS]
Glycine
• Mediates the muscle atony during REM
Adenosine
• Purine nucleoside
• Nucleosides are molecules formed by
attaching a nucleobase to a ribose ring
Prostaglandins
• A prostaglandin is any member of a group of lipid compounds that are
derived enzymatically from fatty acids and have important functions in the
animal body. Every prostaglandin contains 20 carbon atoms, including a 5carbon ring.
DSIP
• If transfused IV or given intra-ventricular from
one who’s asleep to one who’s not,
sleep will ensue about 2 hr later
• Involved with GH secretion
Practical Implications of Sleep Neurochemistry
•Anatomy
•Brain Chemistry
•Conditions
•Drugs
(brain anatomy as it pertains to sleep)
(sleep d.o.’s)
(Rx’s and their effects on sleep)
Insomnia
• Among 902 million outpatient visits that took place in the US in 2006,
• 30 million visits included at least one prescription for insomnia.
• Off-label antidepressants were prescribed more frequently (45.1%)
than nonbenzodiazepine z-hypnotics (43.2%)
and benzodiazepines (11.7%).
Insomnia prescribing patterns were significantly influenced by physician
specialty and physician office settings.
Pediatricians [OR]: 66
and neurologists (OR: 5)
were more likely to prescribe off-label antidepressants than psychiatrists.
Self-paying patients were more likely to receive off-label antidepressants as
treatment for insomnia than patients with private insurance
Drug Healthc Patient Saf. 2011; 3: 27–36
Obstructive Sleep Apnea
• Excess androgen administration may
exacerbate OSA
• Any CNS depressant could theoretically
exacerbate apnea BUT
Xyrem and OSA study
• OSAS patients (n = 48) received 2-week SXB or placebo treatment with psg
at baseline and day 14. The primary outcome measure was change from
baseline in mean AHI. Secondary outcomes included changes from
baseline in SaO(2), and sleep architecture.
• RESULTS: Compared with Placebo, SXB significantly increased reduction in
mean AHI and obstructive apnea index
• with SXB (-0.8 ± 13.3 vs. -8.2 ± 10.0; p = 0.03 and 3.54 ± 11.1 vs. -4.72 ± 7.7;
p = 0.005, respectively)
• and significantly increased change in slow wave sleep duration (5.2 ± 25.0
min vs. 29.4 ± 37.0 min; p = 0.004).
• There were no differences between treatments in SaO2, central apneic
events, or other measures. Adverse events, most commonly headache,
were noted in nine of 27 (33%) and six of 23 (26%) patients receiving SXB
and PBO, respectively.
• CONCLUSIONS: Short-term use of 4.5 g/night SXB did not generate
respiratory depressant effects in OSAS patients as measured by AHI,
obstructive apnea events, central apneas, and SaO2. Extended use of SXB
in higher therapeutic doses in OSAS has not been studied, and merits
caution.
Sleep Breath. 2011 Jan;15(1):13-20. A 2-week, polysomnographic, safety
study of sodium oxybate in obstructive sleep apnea syndrome. George et al
PLMD/RLS
Sleep. 2011 Mar 1;34(3):341-7.
PLMD
Acute and
Emergent Events
in Sleep Disorders
Chokroverty et al
2001
REM Behavior d.o.
RBD
Exac or brought on by:
• SSRI’s
• TCA
• MAOi’s
• AchE inh’s
Treatment:
• 80% success rate w Clonazepam
Nightmare d.o.
Hirshkowitz, in Chokroverty:Acute and Emergent Sleep Disorders 2011.
Parasomnias
Exacerbated or brought on by:
• Li
• SSRI’s
• Atypical antipsychotics
• Hypnotics
– Especially if taken w Etoh and if taken too early
Shift work sleep disorder
• Approximately 1/10 American workers are shift workers
• one out of four hospital nurses of all shift types report being
excessively sleepy and
• night shift work within this population is associated with
increased drug administration errors
Shift work sleep disorder
When behavioral rhythms of feeding and sleeping were 12 hours
out of phase with the endogenous circadian rhythm, subjects
exhibited the most profound alterations in metabolism, including
• increased glucose
• Increased insulin levels,
• decreased leptin levels and
• elevated mean arterial pressure .
Furthermore, a 12 hour misalignment was associated with a
reversal of the cortisol rhythm and reduced sleep efficiency.
Best Pract Res Clin Endocrinol Metab. 2010 Oct;24(5):785-800. Circadian
disruption and metabolic disease: findings from animal models. Arble DM et al
Practical Implications of Sleep Neurochemistry
•Anatomy
•Brain Chemistry
•Conditions
•Drugs
(brain anatomy as it pertains to sleep)
(sleep d.o.’s)
(Rx’s and their effects on sleep)
Drugs
**
Wake Promoters
Hypnotics
Caffeine
Stimulant medications:
Modafanil/Armodafanil
Amphetamines
Methylphenidate
BzdRA’s:
Zolpidem
Eszopliclone
Zaleplon
Benzodiazepines:
Temazepam
Nicotine
Ethanol
Caffeine (1,3,7-trimethylxanthine)
• Blocks adenosine receptors
• Does not affect REM sleep
• Tolerance to the vigilance or wake promoting effects develops
or occurs to some extent in many people and in animal
models
• Increases brain catecholamines and Ach but for the most part
has not been shown to improve learning or memory
•
• Some writers/experts call it a drug of abuse
Nicotine 3-(1-Methyl-2-pyrrolidinyl)pyridine
• Both the tobacco plant (Nicotiana tabacum) and the compound are named
for Jean Nicot, a French ambassador to Portugal, who sent tobacco seeds to
Paris in 1550.
• Stimulates pre and post synaptic nAchR’s in brain, which then, indirectly
increase or modulate GABA, Glu, DA, NE,
• Nicotinic antagonists abolish the G in PGO waves
http://www.galaxygoo.org/biochem/nicotine/what_is_nicotine.html
http://iibce.edu.uy/escuela/pdf/Molecular_and_Cellular_Mechanisms_of_Action_of_nicotine_in_the_CNS.
pdf
Ethanol
• One consistent finding from multiple studies is that REM sleep
was reduced on the alcohol night. Other studies similarly have
shown a decrease in REM sleep with low and moderate
alcohol doses.
• Findings regarding the effects of a single dose of alcohol on
subsequent sleep latency and NREM sleep are less consistent
Sleep. 2011 Feb 1;34(2):195-205. Does timing of alcohol
administration affect sleep? Van Reen E, et al (Carskadon)
• The present study examined the effects of a moderate dose of
alcohol compared to placebo given at four different circadian
phases and at three different homeostatic loads on sleep
stage and spectral EEG characteristics using a 20-hour forced
desynchrony protocol.
• ‘We hypothesized that the homeostatic and circadian
processes would interact to influence the effects of alcohol on
subsequent sleep.
Sleep. 2011 Feb 1;34(2):195-205. Does timing of alcohol
administration affect sleep? Van Reen E, et al (Carskadon)
• ‘The findings of this study did not support our hypothesis,
which was based on previous literature that reported
increased SWS and decreased SOL with alcohol administered
at a high homeostatic load at the start of the circadian night
(i.e., 22:00).
• ‘On the other hand, we found that when alcohol was
administered at 04:00 with the highest homeostatic load,
alcohol increased minutes of wake, and there was a trend for
reduced minutes of stage 2 sleep compared to alcohol
administered at 16:00.
Sleep. 2011 Feb 1;34(2):195-205. Does timing of alcohol
administration affect sleep? Van Reen E, et al (Carskadon)
as compared to non Etoh preferring rats, the Etoh preferring rats
were more susceptible to sleep disruptions after binge
ethanol treatment.
In addition, the preferring rats exhibited insomnia-like
symptoms observed during abstinence from alcohol in human
subjects.
Neuroscience. 2010 September 29; 170(1): 22–27. Sleep-wakefulness in
alcohol preferring (P) and non-preferring (NP) rats following binge
alcohol administration Mahesh M. Thakkar, PhD
Vigilance agents
•
•
•
•
Armodafanil
Modafanil
Methylphenidate
Amphetamines
Armodafanil
• Methylphenidate
• Amphetamines
Antidepressants used as Hypnotics
• SSRI’s
– Trazodone
– Serzone
– Mirtazapine
• TCA’s
– Amitriptyline
– Doxepin
Antipsychotics: Quetiapine (Seroquel)
• RESULTS: Adjunctive quetiapine therapy did not significantly alter sleep
efficiency, sleep continuity, or Pittsburgh Sleep Quality Index scores. RDI and %
of total time in REM sleep decreased and the % of total time in non-REM sleep,
and duration of Stage 2 and non-REM sleep significantly increased after 2-4 days
of quetiapine treatment. Illness severity significantly decreased over time.
• CONCLUSIONS: Adjunctive quetiapine treatment alters sleep architecture in
patients with major depressive disorder or bipolar disorder, which may partially
explain its early antidepressant properties.
• Changes in sleep architecture are more robust and significant within two to four
days of starting treatment.
Neuropsychiatr Dis Treat. 2010; 6: 501–508. Effects of quetiapine on
sleep architecture in patients with unipolar or bipolar depression.
Laura Gedge, et al
Non benzo BZDRAs
• Zolpidem
• Zaleplon
• Eszopiclone
Sodium Oxybate (Xyrem)
• GABA-B receptors probably
• Helps EDS and Cataplexy
Antihistamines
Watanabe. Tohoku J Exp Med. 2001 Dec;195(4):197-217.
Diphenhydramine
Br J ClinPharmacol. 2008 Jun;65(6):811-21.
Chlorpheniramine