Summers

Neurobiology text: Principles of Neural Science - Kandel, Schwartz and Jessell: Read pages 283-284 for this lecture end

XIX. Indoleamines and Histamine  			back to XVIII. Catecholamines

	A. Synthesis of Indoleamines (2 ring structure)


		1. precursor: tryptophan (Trp)


			a. increasing dietary tryptophan will increase transmitter 


				i. active uptake into the brain


					(1) carrier process open to competition


					(2) brain Trp levels are determined by plasma 
					     levels of Trp and other amino acids


			b. rate limiting


			c. converted by tryptophan hydroxylase (TrH; oxidase)


				i. TrH never saturated by Trp


				ii. rate limiting of the 2 enzymes


				ii. requires O2


		2. 5-HTP (5-hydroxytryptophan)


			a. 5-HTP decarboxylase 

			   (= aromatic aa decarboxylase = DOPA decarboxylase)

		3. Serotonin (5-HT = 5-hydroxytryptamine)
                

			a. usual output for indoleaminergic neuronal cells, but


			b. converted by N-acetyltransferase +
	   		   hydroxyindole-O-methyltransferase (HIOMT)


		4. Melatonin is synthesized from 5-HT 


			a. a hormone made in the pineal

			
	B. Reuptake and Degradation


		1. (like other transmitters) most is taken back up
		   by 5-HT transporter


			a. transport direction depends on [5-HT]


			b. from transporter gene family; including transporters for
			   NE, DA, GABA and glycine


				i. transporter genes are regulated by hormones


		2. primary metabolite is 5-HIAA (5-hydroxyindoleacetic acid)



			a. MAO & aldehyde dehydrogenase

	C. Receptors


		1. 5-HT1A,5-HT1B,5-HT1D, 5-HT1E, 5-HT1F: Gi


			a. most often 5-HT is thought of as an inhibitory transmitter


			b. 5-HT1A in high density in raphe & hippocampus


				i. inhibits by hyperpolarization: opens K+ channels
				
				
				ii. 5-HT1A in raphe are somatodendritic
				    autoreceptors and inhibit 5-HT cell firing
				    and release
					
					
			c. 5-HT1B,5-HT1D in substantia nigra


		2. 5-HT2A, 5-HT2B, 5-HT2C, 5-HT2D: Gp


			a. 5-HT2A & 5-HT2D are dense in hippocampus


		3. 5-HT3:  5-HT-gated non-selective cation (Na+, K+, Ca++)
		    channels ® depolarization

		
		
			a. 4 transmembrane segments
			
			
			b. gene/protein family with GABA, Glu, Gly & Nicotinic-Rs

						
		4. 5-HT4, 5-HT6, 5-HT7 : Gs


			a. LSD is an 5-HT6 & 5-HT7 agonist


			b. 5-HT4 in dense in hippocampus,
			   5-HT7 dense in thalamus, hypothalamus & amygdala


		5. 5-HT5A:Gs ® ¯ AC?
		    5-HT5B: G?



	D. histamine  (H)  also a monoamine
	
	
		1. precursor: histidine

			a. histidine decarboxylase (similar to aaad)
			
			
		2. catabolized by histamine-N-methyltransferase, MAO and
		   aldehyde dehydrogenase


			a. 1,4-methylhistamine is a major catabolite


		3. 3 receptor subtypes H1-3
		
		
			a. H1: Gp ® PLC ® DG/IP3 ® Ca++/PKC
				or Gs ® AC ®cAMP & ­ arachadonic acid


				i. sedative, antidepressant, smooth muscle contraction
				
				
			b. H2:Gs ® AC ®cAMP & ¯ arachadonic acid


			c. H3: G?
			
			
				i. autoreceptor - inhibit/regulate H synthesis and release


		4. projects in the median forebrain bundle from the brain stem to
		   hypothalamus and telencephalon (also in mast cells)


			a. increased blood pressure, HR, dipsogenesis, hypothermia

XX. Central Anatomy of Transmitters

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