Pharmacology of sleep Flashcards
Sleep-wake regulation
ATP (brains metabolic currency) broken down into adenosine during the day = sleep pressure
adenosine acts via adenosine receptors.
When activated these receptors block NET release in particular cholinergic neurons in the basal forebrain
= promote wakefulness, so, if they’re blocked they can’t promote wakefulness
blocked neurons in forebrain = feel sleepy
Sleep pathway
The VLPO is the sleep promoting area, but very importantly it inhibits the NETs involved in arousal
- inhibitory NETs include:
GABA, Galanin
Stimulant/ Sedation feedback loop
waking day can be fuelled by nicotine and caffeine (last in body for a long time)
night time, sleep can be induced by: alcohol or sleeping tablets
(NOT the same as biological sleep!) –> some of the benefits will be impaired
So, we use stimulants the next day = detrimental feedback loop
(can alter individual’s brain chemistry)
–> sending brain mixed signals by consuming both stimulants and sedatives = can result in insomnia = difficulty initiating and maintaining sleep)
Caffeine
- mechanisms of action
- duration of effect (differences)
- Effects on sleep
- withdrawal
most widely used drug in the world
boosts energy and alertness
caffeinism = overindulgence in caffeine
can also affect mood changes and anxiety (can cause disrupted sleep)
increases blood pressure/ heart rate (physiological changes)
MECHANISM OF ACTION:
- caffeine has a similar molecular structure to adenosine; therefore has the ability to bind to receptors
(by binding it blocks them = antagonist =leads to wakefulness)
adenosine = agonist–> activation causes sleepiness
SO, in long term, people who are reliant on caffeine need more as brain responds by increasing the no. of receptors ( = need more caffeine to block more receptors)
- to affect sleep, concentration needs to be 150mg +
- effects can last for 4+ hours (can remain in body for longer if body metabolises slowly)
- ind. differences in effect = more effected = metabolise slowly –> less affected = build up tolerance (need to escalate dose of drug to achieve the same effect, Conroy et al)
EFFECT ON SLEEP
(Garcia et al, 2015)
- INCREASE sleep onset latency
- INCREASE time spent in light sleep// DECREASE SWS
(can lead to more SWS, likely due to disrupted sleep meaning individual is more tired = need more SWS)
- DECREASE REM (due to high arousal and sleep fragmentation –> due to arousal and withdrawal)
- INCREASE wake after sleep onset
- DECREASE total sleep time
- DECREASE sleep efficiency
SLEEP DEPRIVATION
- can reverse the effects of sleep deprivation
- restores performance in task that is degraded by sleepiness, it is NOT producing superior performance
ALSO:
-improve mood
-improve attention
-improve working memory
-improve reaction time
WITHDRAWAL
- DECREASE sleep onset latency
- INCREASE wake after sleep onset (heart rate and anxiety)
- INCREASE REM (rebound) - catch up can take months
- INCREASE total sleep time
(may affect brain chemistry)
Nicotine
- mechanisms of action (direct and indirect)
- effects on sleep
- withdrawal
daily smokers smoke cigarettes to maintain nicotine levels
- over 4000 chemicals
- underlying mechanism v different to caffeine stimulant
MECHANISMS OF ACTION
- in basal forebrain cholinergic activity is present –> acetylcholine acts via its own receptors and when it binds it opens pore enabling the influx of ions = depolarisation = excitation = awake
- nicotine promotes wakefulness by stimulating cholinergic neurotransmission in the basal forebrain
- nicotine activates/ excites acetylcholine receptors which bind with nicotine = enable ions to pass through = action potential which propogates to nucleus accumbens = activates reward circuits in brain = DA released = increase arousal
(acetylcholine + dopamine = wake-promoting NETs)
DIRECT effect on receptors
INDIRECT effect on reward pathways
EFFECTS ON SLEEP
- INCREASE sleep onset latency
- more time in light sleep
- DECREASE SWS
- DECREASE REM (some studies have found no change)
- INCREASE Wake after sleep onset (due to nicotine withdrawal)
- DECREASE total sleep time
- DECREASE sleep efficiency
(Reducing SWS and REM = needed biological functions don’t take place)
WITHDRAWAL
- DECREASE sleep onset latency (decrease nicotine = decrease arousal)
-likely to experience fragmented sleep
- INCREASE sleep after wake onset
- INCREASE REM (rebound)
- INCREASE total sleep time (but may not feel refreshed as it’s fragmented)
SLEEP DEPRIVATION
quitting smoking (cessation) leads to sleep disruption which can cause sleepiness and dysphoria (restlessness/ irritability/ dissatisfaction with life) = v common to relapse
(could just be the act of quitting causing these feelings)
Alcohol
- mechanisms of action
- effect on sleep
it has both a stimulating and sedative effect
- stimulating (due to interaction with nervous system) via excitatory neurotransmission
- proposed that its sedative effects are due to increased GABA activity, but it may not be its primary mode of action some suggest its is via adenosine (literature is complex = not fully understood)
- proposed that its sedative effects are due to increased GABA activity, but it may not be its primary mode of action. Some suggest it is via adenosine (literature is complex = not completely understood)
MECHANISMS OF ACTION
- via adenosine
- adenosine binds to receptors = decrease NETs = sleepy
- alcohol increases extracellular adenosine. MORE adenosine = increase adenosine receptor activity = more sleepy
EFFECTS ON SLEEP
- acute alcohol intoxication effects on sleep are dose dependent, but, ALL doses reduced sleep onset latency (Garcia, 2015)
-more time in deep sleep in first half of night
- wake up a lot in 2nd half of the night
- a lots more time in REM (more dreams in 2nd half)
(WHY? 1st half = sedated, 2nd half = REM/ dreaming/ fragmented)
FIRST HALF:
- DECREASE sleep onset latency (due to sedative effects)
- INCREASE SWS
- DECREASE REM
SECOND HALF:
- INCREASE REM (rebound)
- INCREASE wake after sleep onset
Alcohol is metabolised quickly (=why effects differ over span of night)
Sedative effect wears off = resulting in arousal
WITHDRAWAL
- INCREASE sleep onset latency
-DECREASE SWS
-INCREASE REM (rebound) - sacrifice SWS
- INCREASE WASO
-INCREASE total sleep time
- DECREASE sleep efficiency
= experienced by regular drinkers
- effects of these disturbances depends on how long you’ve been consuming them (can become mentally and physically exhausting)
SUMMARY
alcohol, nicotine, caffeine
ATP –> adenosine (builds up in basal forebrain)
adenosine acts via adenosine receptors = blocks NET release (particularly cholinergic neurons)
ALCOHOL –> increases extracellular adenosine levels = increasing adenosine activity = sleepy
CAFFEIENE –> blocks adenosine receptors (antagonise) = increases arousal
NICTOINE –> increases cholinergic neurotransmission = stimulating effect - this has a knock on effect on reward circuits increasing dopaminergic neurotransmission
ALL 3 substances are working on the same pathway. If you consume all 3 = mixed messages to brain which impairs the pathway
Cannabis
over 60 cannabinoids
the way you consume cannabis affects how it is metabolised = difficult to research
complex mechanisms
2 most common compounds explored in terms of sleep:
1) CBD
2) THC
–> both act via CB1 receptors
- CB1 receptors are linked to REM sleep and are found in high concentration in frontal cortex, cerebellum and basal ganglia
- CB1 receptors activate a variety of signal transduction pathways and interact with numerous NETs and neuromodulators
CBD = blocks CB1 receptors = INCREASE WAKEFULNESS (antagonist)
THC = activates CB1 receptors = INCREASE SLEEPINESS
(both bund but have opposing function due to one being an agonist, and one being antagonist)
EFFECTS ON SLEEP
- low doses:
- DECREASE sleep onset latency
- INCREASE SWS
- DECREASE REM
- INCREASE total sleep time
–> sedative properties at low doses (helps relax)
- high doses:
- INCREASE sleep onset latency
- DECREASE SWS
- DECREASE REM
- DECREASE total sleep time
–> stimulating effect on brain
- chronic ingestion of THC = long term suppression of SWS
WITHDRAWAL
- INCREASE sleep onset latency
- DECREASE SWS
- INCREASE REM (strange dreams) - usually occur 24-72 hours of discontinuation and persist for 6-7 weeks = exhaustion/ confusion -> can lead to relapse
- change brain chemistry = hard to give up
Treatments to reduce withdrawal effects
Pharmacological therapy (potential for abuse)
- Gabapentin (used to treat insomnia) - increases the concentration of GABA (Conroy et al)
- -> BUT, should we be treating with drug if caused by drug?
CBT
- developing behavioural and cognitive strategies to consolidate sleep at night time
Mindfulness
- likely to be beneficial as it usually helps sleep in general (v. early days)
Sleep hygiene
- a combination of these might be used
- patients have to be in treatment for several months to see benefits
