Chronopharmacology and circadian drug interactions Flashcards
Why is a circadian rhythm necessary?
• Living in a cyclical environment necessitates a biological clock. Cycles include:
o Day/night (light/dark) cycle
o Weather patterns
o Food availability – there are flowers which open during the day and close during the night
Which organisms have biological clocks?
all organisms have a biological clock: o Bacteria o Plants o Fungi o Animals
Name the 5 types of circadian rhythm, their time durations, and give an example of each.
o Circadian = 20-28hour cycles Daily cycles – sleep/wake o Ultradian = <20hour cycles Sleep stages o Infradian = >28hour cycles Pre-menstrual syndrome o Circamensual = ~30 day cycle Menstrual cycle o Circannual = annual/seasonal Hibernation period, migration patterns
The master circadian clock is found in which area of the brain?
the suprachiasmatic nucleus
o Part of the hypothalamus consisting of ~35,000 cells
Patterns of neuronal activity and firing change throughout the day in response to light levels, thereby regulating the activity of the hypothalamus and other brain areas to control physiological processes and behaviours (e.g. sleep)
o Found above the optic chiasm
• Responsible for synchronising physiology and behaviour with the day/night cycle
What does zeitgeber mean?
time giver
How does the zeitgeber affect circadian rhythms?
Cells become most active during daylight hours and least active during night-time hours; this is regulated by light intensity.
Can the SCN be influenced by the zeitgeber?
Yes - this is how the SCN is responsible for synchronising physiology and behaviour with the day/night cycle
How do you establish if biological activity has an endogenous circadian rhythm?
eliminate light input – when you’ve done this, if the behaviour still occurs cyclically, it’s a circadian rhythm
Name the 4 components of the endogenous clock
o The main components are BMAL1, CLOCK, PER, and CRY
How does the endogenous clock work?
• The endogenous clock works through “genetic cogs”, engaged in a transcription-translation feedback loop
Explain how the endogenous clock works on a molecular level.
BMAL and CLOCK form a dimer, then translocates to the nucleus to stimulate the production of a PER-CRY dimer; this in turn inhibits the production of the BMAL-CLOCK dimer.
Protein production varies throughout the day and night, and this in turn affects cell activity.
Hall, Rosbash, and Young won the 2017 Nobel Prize in Physiology or Medicine for determining this.
You can track these changes over time (day and night); in an animal without a clock, this doesn’t occur – this animal cannot endogenously tell time. Oscillation of protein levels changes neuronal activity during the day and night
Why do cells need to be in-phase? Which neurotransmitters and cells are important for this?
• Cells need to be in-phase (ensemble) to effectively tell time
o Important neurotransmitters for this are:
GABA
AVP (arginine vasopressin)
VIP – ventral cells
o This is what breaks down during old age and disease
Which external factors can influence a circadian rhythm?
o Light-dark exposure, regular eating patterns, and scheduled exercise –> synchronised mechanics –> synchronised internal clock
o These mechanics may need to be adjusted and in synchrony with the environment around us
Describe photic input.
• Originates from the retina
o Fires along the retino-hypothalamic tract to the SCN
o Glutamatergically signals to the intergeniculate leaflet, which it turn fires down the geniculohypothalamic tract (using neuropeptide Y) to the SCN
o Retinohypothalamic tract uses glutamate and PACAP signalling to pass information to the SCN
Describe non-photic input
- Mainly comes from the median raphe nucleus, serotonergically firing to the SCN
- Dorsomedial hypothalamic nucleus is involved too
Which other inputs to the circadian system are there?
• Circulating factors such as glucose and leptin impact on SCN signalling
What do these inputs lead to?
rhythmic outputs from the SCN, regulating cell firing and chemical release
On the physiological level, what do biological clocks regulate?
o Memory o Reward o Sleep-wake cycles o Body temperature o Metabolism o Feeding behaviour o Immune response o Detoxification o Liver o Heart o Lungs o Spleen o Fat tissue o Muscle o Intestine
On the cellular level, what do biological clocks regulate?
o Cell cycle progression o DNA damage repair o Cellular energy metabolism o Cell detoxification o Neuronal excitability
What happens if there is not a master clock?
The numerous rhythmic biological systems are why we require a master clock; otherwise they would operate asynchronously to potentially pathogenic effect
