Neurobiology, lecture on Neurosteroids
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
XXX. Neurosteroids 	  

	A. Steroids are accumulated in the brain & produced de novo
		1. Peripheral F/B, P, T, E2 have receptors in specific brain regions
			a. steroid concentrating neurons
		2. converting enzymes like P450aro (= aromatase, T ® E2) also

	B. de novo and metabolic Brain Steroidogenesis

		1. pregnenolone, DHEA, 5aDHP,
		  allopregnanolone=3a5aTHP, THDOC

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

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

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

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

 	D. Non-genomic actions

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

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

		2. allosteric modulators of ion influx

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

				i. unique binding site for steroids

		3. positive allosteric modulators of GABAA Cl- influx
			a. THP = allopregnanolone

			b. THDOC = tetrahydrodeoxycorticosterone

				i. less potent: androsterone (from DHEA)

			c. result: neuronal inhibition

				i. reversible structural regression in hippocampus

				ii. ratio between excitatory & inhibitory
				    steroids shape synaptic activity

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

				i. blunted reaction to stimuli

					(1) antisocial behavior, inclination to substance abuse?

		4. negative allosteric modulators of GABAA Cl- influx

			a. Preg-S = pregnenolone sulfate

				i. less potent : Preg

			b. DHEAS = dehydroepiandrosterone sulfate

				i. less potent: DHEA, androstenedione,  

				ii. binding site distinct from Preg-S,
				    close to barbiturate binding site

			c. positively modulate NMDAGlu-R Ca++ influx

				i. excitatory steroids

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

				i. positive correlations with longevity, vigor,
				   resistance to cancer and cardiovascular diseases

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

	E. may alter neuro-microanatomy

		1. B reduces the number of dendritic spines
		    on hippocampal pyramidal cells
		2. E2 and 5aDHP increase dendritic
		   spines on hippocampal pyramidal cells

	F. affect behavior

		1. E2 increases and B decreases capacity for memory

XXIII. Neuromodulators and Neuropeptides