Pineal Gland & Melatonin
replicated the sort of rapid transition to sleep that narcoleptics experience
A drug that blocked orexin might what?
obesity and insulin resistance
Chronic sleep deprivation is a risk factor for what?
-beings in the second decade of life -by age 60, 70% is calcified -descartes called "seat of the soul" -continuous light-onset of sexual development in some places -hamster experiments -remove pineal gland, prevent gonadal regression -melatonin-metabolized in liver for excretion
Discuss calcification of the pineal.
-extracts of pineal glands from cattle were added to water containing tadpoles -interestingly, the tadpoles responded by becoming very light in color or almost transparent due to alterations in melanin pigment distribution -although such cutaneous effects of melatonin are seen in a variety of "lower species" the hormone does not have such effects in mammals or birds
One of the first experiments conducted to elucidate the function of the pineal did what?
"third eye"
The light-transducing ability of the pineal gland has led some to call the pineal the what?
-entrain biological rhythms -important effects on reproductive function of many animals
Ultimately, melatonin has the ability to what?
-proteins produced by a remarkably small number of nerve cells -- a few thousand, at most -- in a single area of the hypothalamus -scientists created KO mice, which lacked the orexin gene -the genetically engineered mice seemed normal in all respects but one: they had trouble staying awake -the scientists got in touch with scientists in Boston who confirmed that orexin regulated the sleep-wake cycle
What are orexins and how were its functions discovered?
LH and FSH (if gonads are removed they get really high because there is no negative feedback -- happens in spaded animals)
What are some hormones that increase with age?
-estrogen -THs
What are some hormones that sharply decline with age?
-caffeine and cocaine as well as amphetamines -they indiscriminately activate all the wakefulness promoting neurons throughout the brain -Modafinil, by contrast, promotes the more selective firing of neuronal circuits in the cerebrum, particularly in the prefrontal cortex, where many of the higher executive functions of cognition and emotion seem to lie
What is the trouble with conventional stimulants and what makes modafinil better?
-1964 HS student kept himself awake for 12 days (rate of thinking and response slowed - no dramatic physiological problems)
When was the record for documented continuous wakefulness set?
-in the absence of such basic medical knowledge, sleep experts caution about the use of drugs like modafinil as a substitute for sleep -they worry that high-acheiving types may be tempted to take them in order to stay awake 2-3 days a week throughout the year -and they worry about abuse among students cramming for exams -in fact, medical consequences of such regular on-off sleep behavior are simply not known, and probably will not known for a long time
Considering many researchers believe that sleep is necessary for the brain to replenish its energy stores, the hypothesis remains unproved, discuss the caution that should be taken in regards to drugs as supplements for sleep.
-only one cerebral hemisphere sleeps at a time -when the left hemisphere is asleep, the right one is awake, and vice versa -Carney believes that working out how the dolphin hemispheres shift between wakefulness and sleep while the animal maintains a basic level of alertness may lead to methods by which cognitive performance might be sustained in human beings
Discuss how Carney is looking at dolphins that never fall asleep.
melatonin declines with age -melatonin peaks in early childhood
Discuss how melatonin levels vary throughout one's lifetime.
-the fundamental pattern observed is that serum concentrations of melatonin are low during the daylight hours, and increase to a peak during the dark "dracula" of hormones because it is high at night -blood levels of melatonin are essentially undetectable during daytime, but rise sharply during the dark -very similar patterns are seen in other species -the duration of melatonin secretion each day is directly proportional to the length of the night
Discuss how synthesis and secretion of melatonin is dramatically affected by light exposure to the eyes.
-flight simulator -6 helicopter pilots -2 40h periods separated by one night of recovery sleep -detailed performance evaluations were conducted at regular intervals -the pilots were ordered to execute precision maneuvers -Caldwells assessed how sleep deprivation affected the pilots performance -military interested in practical uses -MO to Iraq/Afghanistan pilots were given 2-(diphenylmethyl)-sulfinylacetamide aka modafinil and experienced little side effects
Discuss the work of the Caldwell's on sleep studies for the military.
-using melatonin alone or in combination with phototherapy to tx sleep disorders (not hugely effective) -there is some indication that melatonin levels are lower in elderly insomniacs relative to age matched non-insomniacs, and melatonin therapy in such cases appears modestly beneficial in correcting the problem (melatonin not regulated by FDA)
Melatonin is probably not a major regulator of normal sleep patterns, but undoubtedly has some effect. One topic that has garnered a large amount of interest is what?
The pineal gland or epiphysis synthesizes and secretes melatonin, a structurally simple hormone that communicates information about environmental lighting to various parts of the body
What is the pineal gland?
-the precursor to melatonin is serotonin, a NT that itself is derived from the amino acid tryptophan -within the pineal gland, serotonin is acetylated and methylated to yield melatonin -melatonin is the 1 hormone produced in the pineal gland (parathyroid is the only other gland to produce 1 hormone)
What is the precursor to melatonin? What is unique about melatonin production in relation to the pineal gland and other glands?
-28 ppl kept up for 4 days and the major consequence was expected decline in cognitive function -other studies of chronic sleep deprivation, where subjects are allowed to sleep for 4 h and are kept awake for 20, found temporary change sin glc metabolism, with an increase in insulin resistance, a condition seen in early diabetes -some of the sleep-deprived subjects also had about a 25% increase in the number of circulating WBCs -clinical significance of such changes is unclear
Where were some more systemic effects that were found to occur with prolonged wakefulness?
-the widespread assumption that sleep is necessary was supported by early studies of sleep-deprived rats; they suffered deterioration not only in behavior but in body metabolism and immune defenses -as repeated experiments have verified, when rodents are prevented from sleeping they often die of sepsis, with some succumbing after only 5d, the hardiest lasting a full month -surprisingly, there is very little hard data showing prolonged sleep deprivation truly has deleterious effects on humans
Will biology permit prolonged wakefulness?
-amphetamines like Dexedrine -Dexedrine had been the standard tx for narcolepsy, and it has had military applications as well: the US Air Force supplied it to most air crews during the Persian Gulf War -more than 60% of the pilots who used the drug said it was "essential" to accomplishing their mission -unfortunately, amphetamines, in addition to a high potential for addiction, cause jitteriness, HTN, rapid and irregular heartbeat, overconfidence, and a negative "rebound" effect -- non-restorative sleep-- when they wear off -what scientists have sought instead is something that would boost wakefulness by replicating the brain chemistry of healthy, well-rested people
until fairly recently, the only "countermeasures" to sleepiness have been conventional stimulants, most notably what?
-(Hcrt-1/OXA, Hcrt-2/OXB) encoded by the same precursor gene and 2 GPCR (Hcrtr1/OXR1, Hcrtr2/OXR2) are currently known -alterations in hypocretin neurotransmission causes the sleep disorder narcolepsy in mice, dogs, and humans -effects on appetite, neuroendocrine, and energy metabolism regulation are also suggested by other studies -hypocretins are uniquely positioned to link sleep, appetitie, and neuroendocrine control, 3 behaviors of major importance in psychiatry
Discuss hypocretin genes, receptors, and effects of alterations.
-only works in some people -production not FDA regulated...may be no active hormone -take 20 minute-1 hour before sleep -tends to improve time takes to fall asleep and wake up less in middle of the night
Discuss melatonin as sleep therapy.
-preserves normal "sleep architecture" -unlike stimulants, modafinil seems to have no potential for addiction; nor have users been known to develop tolerance -indeed, because of modafinil's effectiveness and safety many physicians are experimenting with it for pts with other disorders (ADD and ADHD); modafinil has been shown, for instance, to alleviate drowsiness and fatigue associated with MS, Parkinson's, and depression
Discuss modafinil as a tx for narcolepsy. How is it being looked at for other conditions?
-FDA approved tx for narcolepsy, is not a conventional stimulant, and has almost no detectable effect on people who are fully alert -the drug is at the center of a burgeoning new area of research into the neurochemistry of sleep and wakefulness, which promises to transform the tx of sleep disorders -at the same time, scientists are exploring the prospect that ppl may be able to sustain a state of poised and productive alertness for days on end -some have even raised the question of whether advances in biopharmacology will ultimately make regular sleep unnecessary -scientists in TX identified a new family of NTs called orexins
Discuss modafinil.
-pineal tumors are rare, occurring most often in children and young adults -the most common of these are germ cell tumors (germinomas and teratomas), which arise from embryonic remnants of germ cells -these tumors are malignant and invasive and may be life-threatening -tumors of pinealocytes also occur and vary in their potential for malignant change -pineal tumors may cause HAs, vomiting, and seizures due to the increase in pressure within the head that results from enlarging tumor mass -endocrinologic effects may also be observed -some pts may become hypogonadal with regression of secondary sex characteristics
Discuss pineal tumors.
-often find it difficult to adjust to working at night and sleeping during the day -the utility of melatonin therapy to alleviate this problem is equivocal and appears not to be as effective as phototherapy -still another condition involving disruption of circadian rhythms is jet lag -in this case, it has repeatedly been demonstrated that taking melatonin close to the target bedtime of the destination can alleviate symptoms; it has the greatest beneficial effect when jet lag is predicted to be worst (e.g. crossing many time zones)
Discuss sleep disorders experienced by shift workers and jet lag.
-small organ shaped like a pine cone (hence its name) -it is located on the midline, attached to the posterior end of the roof of the 3rd ventricle in the brain -the pineal varies in size among species -in humans it is roughly 1 cm in length, whereas in dogs it is only 1 mm long -to observe the pineal, reflect the cerebral hemispheres laterally and look for a small grayish bump in front of the cerebellum
Discuss the anatomy of the pineal gland.
-in the early 1980s, a French pharmaceutical company, was exploring new txs for somnolence by injecting hundreds of compounds into lab animals and observing the results -in rats and then in humans, modafinil was found to cause wakefulness, yet, unlike stimulants, it did not give rise to hyperactivity -in clinical trials conducted by Cephalon, a PA-based company that licensed the drug, modafinil was demonstrated to be a safe and effective tx for narcolepsy -somehow, it made up for the missing orexin
Discuss the discovery of modafinil. Why was it a good option as tx for narcolepsy?
-seasonal changes in day length have profound effects on reproduction in many species -melatonin is a key player in controlling such events -in temperate climates, animals like hamsters, horses and sheep have distinct breeding season -during the non-breeding season, the gonads become inactive (males fail to produce sperm in any number ), but as the breeding season approaches - gonads must be rejuvenated 10X larger balls during breeding season
Discuss the effects of melatonin on reproductive function.
-hypocretins (orexins) are a newly identified peptide family comprised of two peptides, hypocretin-1 and hypocretin-2 -these peptides play a role in the regulation of behavioral state -when infused into the lateral ventricles in awake animals, hypocretin-1 elicits increased duration of waking beyond that observed in vehicle-treated animals -same true for hypocretin-2, but less potent -rapidly emerging as functionally important NTs
Discuss the family of hypocretins.
-the hypothalamus appeared normal -it was the size of a plum, and had the color and consistency of tofu -they performed immunohistochemistry -no orexin was found -unlike KO mice, the majority of human narcoleptics have normal genes for producing orexin proteins and receptors -researchers think that the orexin neurons are destroyed as part of an autoimmune reaction
Discuss the hypothalamus of a narcoleptic.
-the activity of the rate-limiting enzyme in melatonin synthesis serotonin N-acetyltranserase (NAT) is low during daylight and peaks during the dark phase -in some species, circadian changes in NAT activity are tightly correlated with transcription of the NAT messenger RNA, while in other species, post-transcriptional regulation of NAT activity is responsible -activity of the other enzyme involved in synthesis of melatonin from serotonin -- methyltransferase -- does not show regulation by pattern of light exposure
Discuss the mechanism behind the pattern of secretion of melatonin.
-2 melatonin receptors have been identified from mammals (designated Mel1A and Mel1B) that are differentially expressed in different tissues and probably participate in implementing differing biologic effects -these are GPCR on the cell surface -the high density of receptors have been found in the supraciasmatic nucleus of the hypothalamus, the anterior pituitary (predominantly pars tuberalis) and the retina -receptors are also found in several other areas of the brain
Discuss the melatonin receptors.
2 different systems in the brain that make up wakefulness 1. vigilance -where one is tensely alert to potential threats in the environment -the physiology of vigilance seems to involve the dopamine, NE, and serotonin pathways: stimulating these pathways results in hyperactivity and a reduction of reaction time 2. calm -one is attentive and engaged in so-called "executive functions" able to focus on cognitive tasks -such wakefulness may involve the histamine pathways
Discuss the pathways that modafinil acts on the brain.
-orexin-A and B were identified as endogenous ligands for the orexin-1 (HCRT1) and orexin-2 (HCRT2) GPCRs -these peptides are identical to 2 hypothalamic peptides that share a high degree of homology with secretin, designated hypocretin-1 and hypocretin-1 -ICV administration of orexin-A and B stimulated food intake in rate -reports suggest a role in the sleep-wake cycle -calm wakefulness not vigilant wakefulness
Discuss the relation of orexin A and B to hypocretins.
-identical twins -discorded for obesity (1 normal and 1 obese) -got the obese one to lose weight and they now weight the same -no difference in diet or exercise -sill had different energy expenditure -the one that used to be fat had less energy expenditure -as you lose weight, energy expenditure goes down
Discuss the study of identical twins and obesity.
-histologically, the pineal is composed of "pinealocytes" and glial cells -in older animals, the pineal often contains calcium deposits ("brain sand")
Histologically, what does the pineal gland contain?
anti-gonadotropic -in other words, melatonin inhibits the secretion of the gonadotropic hormones LH and FSH from the anterior pituitary -much of this inhibitory effect seems due to inhibition of GnRH from the hypothalamus, which is necessary for secretion of the anterior pituitary hormones
How can you summarize the effect of melatonin on reproductive systems?
-light exposure to the retina is first relayed to the suprachiasmatic nucleus of the hypothalamus, an area of the brain well known to coordinate biological clock signals -fibers from the hypothalamus descend to the spinal cord and ultimately project to the superior cervical ganglia, from which post-glanglionic neurons ascend back to the pineal gland -thus, the pineal is similar to the adrenal medulla in the sense that it transduces signals from the SNS into a hormonal signal -all tissues have a biological clock
How does the retina transmit information about light-dark exposure to the pineal gland?
decrease motor activity, induce fatigue and lower body temperature, particularly at high doses -the effect on body temperature may play a significant role in melatonin's ability to entrain sleep-wake cycles, as in patients with jet lag
In various species including humans, administration of melatonin has been shown to what?
-artificially manipulate cycles in seasonal breeders -for example, sheep that normally breed only once per year can be induced to have two breeding seasons by tx with melatonin -tx and take away induces breeding (lack of melatonin induces)
One practical application of melatonin's role in controlling seasonal reproduction is found in its use to what?
-melatonin has important effects in integrating photoperiod and affecting circadian rhythms -consequently, it has been reported to have significant effects on reproduction, sleep-wake cycles and other phenomena showing circadian rhythm
What are the biological effects of melatonin?
-only 2% of our time is in the switch between being asleep and awake and orexin acts as the thumb on the switch that keeps us awake -a deficiency of orexin causes narcolepsy
What is a good analogy for how orexin works and what can a deficiency of it cause?
arousal state
What is a main pharmacologic effect of orexins?
-have trouble falling asleep -estimated that 30% of the population has significant insomnia on occasion -10-15% it is a regular condition -some researchers believe that the orexin pathway may point toward a new-generation sleeping pill that would not have disadvantages of the conventional sleeping pills, which almost always degrade the quality of the sleep they induce
What is one of the the reasons so many Americans have trouble staying awake? What is the prevalence of insomnia in society?
-photoperiod -the pineal gland is able to measure day length and adjust secretion of melatonin accordingly -a hamster without a pineal gland or with a lesion that prevents the pineal from receiving photo information is not able to prepare for the breeding season
What is the most important cue allowing animals to determine which season it is? How does this affect breeding season in hamsters?
