Endocrinology, lecture on Hormones from the Brain
USD Department of Biology
Endocrine Glands
2nd Messengers
Nuclear Receptors
Genetic Regulation
Hormone Synthesis
Receptor Regulation
Hypothalamo-Hypophysial Communication
Tropic Hormones
Neurohypophysial Nonapeptides
Thyroid Axis
Adrenal Axis
Adrenal Medulla
Osmo-Pressure Balance
Reproductive Endocrinology
Somatic Axis
Growth Factors
Immune System
Ca++, PO4 Homeostasis
Pancreatic Hormones
GI Hormones
Guts 'n Brains
Brain Hormones
Figures for Endocrionology
text:Vertebrate Endocrinology4th Edition - David O. Norris:
Read pages 3-12 for this lecture
acronyms    end
XXIX. Brain Hormones 			

	A. Peripheral hormones effect the brain
		1. Steroids and Thyroid hormones pass through the Blood-Brain-Barrier
		2. Active uptake
			a. tanycytes in the median eminence
				i. deliver to CSF
		3. de novo synthesis
			a. monoamine hormones/neurotransmitters
				i. indoleamines
					(1) serotonin (5-HT) made in the brain is a neurotransmitter
					(2) hormonal melatonin from the pineal
				ii. catecholamines are neurotransmitters
			b. neurosteroids
			c. neuropeptides
	B. Melatonin

		1. synthesized from 5-HT in the pineal gland			

				æ5-HT-N-acetyltransferase ä 	æHIOMT (hydroxyindole-O-methyltransferase )ä
			a. 5-HT        ®         N-acetyl 5-HT         ®         melatonin

			b. the  pineal is connected to a 3rd eye:
			   parietal eye in some vertebrates

				i. fishes, amphibians, and some reptiles
				   have a photoreceptive pineal organ

				ii. glandular pineal in birds and mammals
			c. melatonin is also produced by the parietal eye
				i. by the retina in the lateral eyes
				ii. may be necessary for photoreception
			d. production and release is circadian
				i. daily pattern, even without exogenous cues

		2. production and secretion of melatonin inhibited by light

			a. photic information in mammals delivered via the lateral eyes,
			   suprachiasmatic nucleus, to the PVN, spinal cord and
			    superior cervical ganglion ® pineal

				i. melatonin synthesis is stimulated by
				   a-adrenergic activation (NE)

			b. pronounced diurnal rhythm

				i. production and secretion stimulated by darkness

			c. melatonin strongly affects and is affected by
			   endogenous biological rhythms

				i. endogenous rhythms generated in mammals by
				   the suprachiasmatic nucleus

					(1) circannual, circadian, and ultradian rhythms

				ii. pineal melatonin may play a central role in the circadian
				    organization of fishes, lizards and some birds

					(1) e.g. pinealectomy in house sparrows abolishes freely
					    running circadian rhythms of both locomotion and body  To

					(2) but pinealectomy in the Japanese quail does not
					    affect rhythms at all

		3. Seasonal Affective Disorder and Depression

			a. long nights, as in winter, stimulate more melatonin production
			   and is correlated with depression = SAD

			b. treatment can be affected with strong lights in the morning

				i. administration with melatonin in the evening
				   is not effective

					(1) does not stimulate obvious endocrine changes

					(2) makes people sleepy

						(a) possible jet lag remedy

		4. Reproduction

			a. plays a role in regulating the GnRH pulse generator

				i. an ultradian oscillator with frequency code

					(1) may ¯ the amplitude or frequency of GnRH secretion

				ii. affects sensitivity to steroid feedback

				iii. regulation is seasonal
				    (i.e. affected by circannual rhythms)

			b. seasonally breeding animals

				i. melatonin signals change depending upon environmental lighting

					(1) times reproductive cycles by adjustment to seasonal
					    photophase (daylength) and scotophase (darkness) changes

						(a) winter = longer nights ®   melatonin
						      melatonin® ¯ GnRH pulse frequency ®
						  ® ¯ LH pulse frequency ® ¯ E2 for positive feedback

						(b) melatonin stimulates reproduction in
						     short day breeders (e.g. deer, sheep)

			c. puberty

				i.  melatonin levels are high in humans from ages 1 to 5,
				    and then decrease until puberty

				ii. lesions of the pineal result in precocious puberty

					(1) those with secretory pineal tumors exhibit delayed puberty

		5. has an anti-MSH effect in fishes and amphibians

			a. melatonin influences color change as in background adaptation
			    by controlling melanophore responses

			b. melatonin decreases pituitary MSH in mammals as well

				i. melatonin induces the differentiation of a winter/white
				   pelage in weasels

		6. Thermoregulation

			a. pineal involvement in body temperature regulation is more
			   readily demonstrated in more classes of vertebrates than
			   any other function of melatonin

			b. hot and cold result in cytological changes in the pineal
			   (mammals + reptiles)

			c. NAT + HIOMT activity change with temperature
			   (mammals, reptiles, amphibians)

			d. removal of parietal eye in lizards elevates behaviorally selected Tob

				i. pinealectomy lowers Tob

				ii. melatonin injection lowers panting threshold

			e. pinealectomy abolishes circadian Tob rhythms in sparrows

				i. also results in abnormally high Tob

				ii. hyperthermia may be reversed by melatonin 

			f. melatonin induces hyperthermia in rats, but hypothermia in mice

				i. pinealectomy   Tob of sheep and rabbits,  ¯ Tob  of  rats

				ii. Brown adipose tissue may be regulated by the pineal

					(1) catabolism of brown fat produces heat

						(a) thermogenic response

					(2) melatonin stimulates increased brown adipose tissue

						(a) pinealectomy reduces brown fat reserve

			h. hibernation

				i. pineal may regulate cycles of  Tob changes in hibernators

	B. Neurosteroids

		1. Steroids are accumulated in the brain from peripheral sources
		    and  produced de novo

			a. P450scc, 3b-HSD, 5a-reductase, 3a-oxidoreductase
			   present centrally in glia

		2. Peripheral steroids bind to classical cytoplasmic/nuclear receptors
		   to activate genomic actions

			a. especially immediate-early genes with products important for
			   neurochemical and endocrine function

				i. code for G-proteins, receptors,
				   protein kinases, transcription factors...

		3. Non-genomic actions

			a. de novo central neurosteroids bind to
			   ionotropic receptors, especially GABAA

				i. ligand-gated channels for ions (Cl-, Ca++)

			b. allosteric modulators of ion influx

				i. ionotropic receptors have multiple membrane spanning
				   subunits (usually 5) with
				   more than one ligand binding site

					a. unique binding site for steroids

			c. positive allosteric modulators of GABAA Cl- influx

				i. THP = allopregnanolone

				ii. THDOC = tetrahydrodeoxycorticosterone

					(1) less potent: androsterone (from DHEA)

				iii. result: neuronal inhibition

					(1) reversible structural regression in hippocampus

					(2) ratio between excitatory & inhibitory steroids
					   shape synaptic activity

				iv. effects: anxiolytic, antiaggressive,
				    anesthetic, sedative, hypnotic

					(1) blunted reaction to stimuli

						(a) antisocial behavior, inclination to substance abuse?

			d. negative allosteric modulators of GABAA Cl- influx

				i. Preg-S = pregnenolone sulfate

					(1) less potent : Preg

				ii. DHEAS = dehydroepiandrosterone sulfate

					(1) less potent: DHEA, androstenedione,  

					(2) binding site distinct from Preg-S,
					    close to barbiturate binding site

				iii. positively modulate NMDAGlu-R Ca++ influx

					(1) excitatory steroids

				iv. effects: enhance neuronal and glial survival &
				    structural growth, neuronal differentiation,  neuroprotective, 
					enhance memory,   anxiety,  basal CNS arousal 
					 convulsions,  seizures,  sedation threshold

					(1) positive correlations with longevity, vigor,
					    resistance to cancer and cardiovascular diseases

			e. specific G-protein mediated receptors
			    have been discovered for B, P & E2

	C. Neuropeptides

		1. Many peptide hormones are also secreted within the brain
		   to modulate neural actions

		2. Classes of neuropeptides:

			a. opiates: Met-enkephalon, Leu-enkephalon, b-endorphin, dynorphin

			b. gut-brain: SP, VIP, CCK, NT, NPY, galanin, insulin, glucagon,
			      GRP/bombesin, gastrin, secretin, motilin

			c. hypothalamic: CRH, GHRH, GnRH, TRH, somatostatin

				i. neurohypophysial: AVP, Oxy

			d. pituitary: ACTH, GH, LH, a-MSH, PrL, TSH

			e. other: Ang2, ANP, CGRP, bradykinin

		3. Functional roles (examples):

			a. opiates: analgesic, anxiolytic, sedative

			b. gut-brain:  CCK is anxiogenic
						 SP ® pain transmission

			c. hypothalamic:
			       CRF ® coordinates neural control of stress responses
			      TRH ® stimulant (antagonizes sedative drugs  arousal and locomotion )

				i. neurohypophysial: AVP  learning, memory and aggression

					(1) OT  sexual receptivity and behavior
					    + parental behavior

			d. pituitary: ACTH ® anxiogenic, depression

XXX. Neurosteroids