Practical Implications of Sleep Neurochemistry

1. Practical Implications of Sleep Neurochemistry Part two K Hargrave, MD LASM Nov 5 2011

2. acetylCoA + choline Ach Ach----------acetate + choline AchE BuChE

3. 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

4. Glutamate • NMDA receptors • AMPA receptors • Kainate receptors • Metabotropic receptors

5. 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).

6. 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

7. 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, 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.

8. 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.

9. Hypocretin/Orexin http://journals.prous.com/journals/dnp/20031608/html/dn160504/images/DeLeccea_f1.jpg

10. “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.

12. 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.

13. 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.

14. Tyr----L-DOPA----DA-------------HVA DA --------NE Tyr OH’ase MAO (intracellular) ddc COMT extracellular) DA B OH’ase

15. http://www.benbest.com/science/anatmind/anatmd10.html

16. 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

17. ‘Sleep Neurochemistry’

18. Melatonin http://pharmrev.aspetjournals.org/content/62/3/343.full www.biology.lsu.edu/webfac/jstephens/notes/Pineal%20Gland.ppt

19. 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

21. GABA GABA A : Benzo’s Barb’s GABA B presynaptic/autoreceptors

22. GlucosealphaketoglutarateGlu Glutamate-----GABA [Glu acid decarboxylase only present in CNS] SubstNigra has highest [ ] of GABA GAD

23. Glycine • Mediates the muscle atony during REM

24. Adenosine • Purine nucleoside • Nucleosides are molecules formed by attaching a nucleobase to a ribose ring

25. 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 5-carbon ring.

26. 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

27. Practical Implications of Sleep Neurochemistry Anatomy (brain anatomy as it pertains to sleep) Brain Chemistry Conditions (sleep d.o.’s) Drugs (Rx’s and their effects on sleep)

28. 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

29. Obstructive Sleep Apnea • Excess androgen administration may exacerbate OSA • Any CNS depressant could theoretically exacerbate apnea BUT

30. 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).

31. 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

32. PLMD/RLS Sleep. 2011 Mar 1;34(3):341-7.

33. PLMD Acute and Emergent Events in Sleep Disorders Chokroverty et al 2001

34. REM Behavior d.o.

35. RBD Exac or brought on by: • SSRI’s • TCA • MAOi’s • AchEinh’s Treatment: • 80% success rate w Clonazepam

36. Nightmare d.o. Hirshkowitz, in Chokroverty:Acute and Emergent Sleep Disorders 2011.

37. Parasomnias Exacerbated or brought on by: • Li • SSRI’s • Atypical antipsychotics • Hypnotics • Especially if taken w Etoh and if taken too early

38. 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

39. 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

40. Practical Implications of Sleep Neurochemistry Anatomy (brain anatomy as it pertains to sleep) Brain Chemistry Conditions (sleep d.o.’s) Drugs (Rx’s and their effects on sleep)

41. Drugs ** Caffeine Nicotine Ethanol Wake Promoters Stimulant medications: Modafanil/Armodafanil Amphetamines Methylphenidate Hypnotics BzdRA’s: Zolpidem Eszopliclone Zaleplon Benzodiazepines: Temazepam

42. 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

43. Nicotine 3-(1-Methyl-2-pyrrolidinyl)pyridine • Both the tobacco plant (Nicotianatabacum) 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

44. 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)

45. 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)

46. ‘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)

47. 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

48. Vigilance agents • Armodafanil • Modafanil • Methylphenidate • Amphetamines

49. Armodafanil

50. Methylphenidate • Amphetamines