Insomnia

Insomnia

The most common sleep disorder in the with underlying mechanism not clearly understood.

Risk factors: stress, shift work, ageing, and drug/alcohol abuse

Synptoms: becoming more irritable, feeling tired, and having difficulty remembering. So concentration, reasoning, and reaction time can become severely impaired. 

What is main focus of insomnia treatments?

Combination of pharmacological approaches and non-pharmacological measures like cognitive behavioural therapy and relaxation therapy.

1) Block wake promoting pathways

2) Enhance sleep inducing pathways

What pathways are relevant to sleep disorders?

-the suprachiasmatic nucleus (SCN) involved in circadian rhythm

-hypothalamus involved in wakefulness

-brainstem reticular formation for arousal and consciousness. 

What are the primary neurotransmitters to target, in the treatment of sleep disorders?

Histamine, GABA, dopamine, noradrenaline and serotonin.

Where are histaminergic neurons located?

Tuberomammillary nucleus of the hypothalamus

What is the role of histaminergic neurons?

-Wake promoting pathway (arousal)

-Feeding

-Thermogenesis

-Learning

-Memory

What is the correlation between firing and arousal state?

Highest when alert, slower when asleep and silent during REM sleep

What types of neurons are found in outputs to the cortex involved in wakefulness?

Cholinergic neurons of the basal forebrain

What other sites does the histaminergic neurons of the tuberomammillary nucleus communicate with?

Other pontine wake promoting nuclei like…

-locus coeruleus (NA)

-raphe nuclei (5-HT)

-ventral tegmental area (DA)

Where are inhibitiory inputs for sleep promoting centres?

In ventrolateral preoptic nucleus in hypothalamus

Which two histamine receptors are relevant to sleep?

H1 and H3

Diphenhydramine

Centrally acting antagonist of H1 receptor which is excitatory due to Gq coupling

clozapine

H1 antagonists produce sedation - side effect of anti-psychotics

Zolpidem

Z drug

Enhances GABA-A signalling

Use limited by risk of dependence, tolerance and withdrawal syndrome

Short half life for sleep treatment so reduced risk of tolerance and hangover effect

Has a sedative rather than anxiolytic effects and are less addictive than benzodiazepines due to it’s selectivity of alpha-1 subunit over alpha-2

Which GABA receptors are sensitive to benzodiazepines?

Must contain alpha 1,2,3,5 and gamma-2 subunits

What is the relevance of the combination of subunits of the GABA receptor?

Each subunit has distinct functions and thus leads to specific side effects

What is the function of α1 subunit?

anticonvulsant, sedative/hypnotic and addictive effects

What is the function of α2 subunit?

anxiolytic effects

What is the function of the α2, α3 and α5 subunits?

muscle relaxation

What is the relevance of the α5 subunit?

Mice lacking the α5 subunit have improved learning/memory and thus an α5 subunit selective inverse agonist could potentially be memory enhancing. For example, diazepam (Valium)

Lorazepam

used for its sleep-inducing effects and produces less tolerance than a longer acting drug.

Orexin

Stimulates wake promoting circuitry by activating VGCaC activity and decreases potassium channel activity.

Where are orexin containing neurons found?

At lateral hypothalamus

Suvorexant

Orexin (OX1 and OX2) receptor antagonist

OX1- Gq coupled

OX2- Gq/Gi coupled

Ramelteon

melatonin MT1 and MT2 receptor agonist.

Both receptors are Gi coupled

Acts on neurons of the hypothalamic suprachiasmatic nucleus.

Melatonin

Sleep inducing hormone that sets bodys circadian rhythm

Pitolisant

a H3 inverse agonist promotes wakefulness used in the treatment of narcolepsy.

H3 is an inhibitory autoreceptor

Caffeine

non-selective antagonist of adenosine receptors.

narcolepsy

The transitions from wakefulness to sleep are abnormally rapid and are associated with onset of sleep paralysis. 

-Narcoleptic attacks are irresistible and can be triggered by positive emotional states. 

-The cause of narcolepsy was unknown for many years, but in 2001, it was found to be due to destruction of hypothalamic neurons containing the peptide transmitter orexin (also called hypocretin).

Adenosine

endogenous somnogen whose levels rise in brain during neural activity

Triggers sleep by:

- inhibiting wake promoting signal: inhibits orexogenic neurons via A1 receptors

-enhances sleep promoting signals: stimulates GABAergic neurons in the VLPO via activation of A2a receptor

What is the role of NA in wakefulness?

Activation of noradrenaline neurons induces alertness and vigilance and is importance for maintaining arousal and attention. Directly involved in: 

• Sleep-wake cycle. 

• Sensory stimuli. 

• Central control of blood pressure. 

• Mood.

Amphetamine (dexamphetamine)

NET/DAT +VMAT substrate

enhances wake- promoting action of noradrenergic neurons. Also used to treat ADHD.

Lead to mania and psychosis (DA)

Methylphenidate (Ritalin)

NET/DAT inhibitor

used to treat ADHD, may also be used to treat narcolepsy

Modafinil

Weak DAT inhibitor + enhances 5-HT, glutamate, histamine release and inhibits GABA release

used to treat narcolepsy

Amantadine

antiviral with weak DAT inhibitor and NMDA antagonist activity

used to treat fatigue in MS (also used in Parkinson’s disease)

Serotonin

Has dual function: both to promote wakefulness and suppress REM sleep, depending on the receptor subtype involved.

Buspirone

acts as a partial agonist at the 5-HT-1A receptor to act as an anxiolytic and is structurally distinct from benzodiazepines and SSRIs.

Not a major sleep promoting drug but helps with easing other factors like stress and anxiety which affect sleep.