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Chapter 1 Amines of Biological Interest and their Analysis
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Chapter 1 AMINES OF BIOLOGICAL INTEREST AND THEIR ANALYSIS GLEN B. BAKER AND RONALD T. COUTTS Neurochemical Research Unit, Department of Psychiatry and Faculty o f Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2G3 (Canada) INTRODUCTION Biogenic or naturally-occurring amines have been the subject o f a great deal of research, particularly in the neurosciences. Much of this research has centered around the catecholamines dopamine and noradrenaline and the indolalkylamine 5hydroxytryptamine (5-HT; serotonin). There is now a reasonable body of evidence supporting the role of these amines as neurotransmitters, and the term "biogenic amine" has become synonymous with the catecholamines and 5-HT. However, in recent years, there has been increased interest in histamine and the 'trace' amines, and in this book these are also included in the term biogenic amines. 'Trace' amines are defined as a number of naturally-occurring amines which are present in the central nervous system in much lower absolute quantities than the catecholamines and 5-HT, and include 6-phenylethylamine, m- and p-tyramine, phenylethanolamine, m- and p-octopamine and tryptamine. The role o f these substances in neurotransmission is unclear, but it is known that their concentrations in brain are affected markedly by a number of psychotropic drugs. They have also been implicated in a variety of psychiatric and neurologic disorders, and this will be discussed in further detail below. There is now a voluminous literature on biogenic amines, and space does not allow for a comprehensive review of the research which has been done on these substances in biological systems. Rather, it is the purpose of this introductory chapter to highlight important aspects of the biogenic amines and to give a brief description of the format of the remainder o f the book. 1.1
1.2 CATECHOLAMINES AND THEIR 0-METHYLATED AMINE METABOLITES The catecholamines (Fig. 1.1) have been the most extensively studied of the biogenic amines because of interest in their role as neurohumors. A number of excellent books and reviews are available describing the synthesis, metabolism and localization of the catecholamines in nervous tissue (e.9. 1-14). It has been proposed that one or more o f the catecholamines are involved in the etiology and/ or symptomatology of a number of neurological and psychiatric disorders, including migraine, schizophrenia, anxiety, depression, aggression, pheochromocytoma and parkinsonism (1-3,7,9,14,15-22). In addition, a wide variety of psychotropic
2
HO
b
a
HO
OH
C
Yb.,,,, H3ch HO
d
OH
e
Fig. 1.1. Structures o f the catecholamines and their 0-methylated amine derivatives: a) dopamine, b ) noradrenaline, c ) adrenaline, d ) 3-methoxytyramine, e) normetanephrine and f ) metanephrine.
3
and cardiac drugs are thought to interact with the synthesis, storage, metabolism and/or receptor activity o f the catecholamines (1-4,7,11,13,15,19-30). The ability t o form fluorescent derivatives o f catecholamines with relative ease and specificity has meant that much is now known about the localization o f nerve tracts containing these substances (see Chapter 5 o f this volume). Electrolytic or chemical lesions o f these tracts as well as the administration o f catecholaminedepleting drugs have been used in animal models to study the involvement o f the catecholamines in a number o f behavioural and physiological functions such as locomotion, exploratory activity, hunger, thirst and sexual activity (1-3,7-9,15,18, 21,26,31). The distribution o f the catecholamines dopamine (DA), noradrenaline (NA) and adrenaline (A) and the ratios o f each one to the others vary widely between the peripheral and central nervous system, within the central nervous system itself and amongst various species (1,2,6,7). 3-Methoxytyramine (3-MTA), normetanephrine (NMN) and metanephrine (MN) (Fig. 1. are produced by the enzymatic action o f catechol 0-methyl transferase (COMT) on DA NA and A respectively. These 0-methylated amines have been identified in various tissues and body fluids (32-39). Concentrations o f these compounds in these locations can be altered dramatically in certain disease states and after administration o f a number of psychotropic drugs. 1.3
5-HYDROXYTRYPTAMINE 5-Hydroxytryptamine (Fig. 1.2), a substance which possesses strong vasoconstrictive properties on smooth muscle, is found in many parts o f the body, and is located in nonneuronal sites (platelets, mast cells, enterochromaffin cells) as well as in neurones (7,40,41). Although only 1-2% o f this indolealkylamine in the body is located in the brain (7), 5-HT has been o f interest to neuroscientists for some time because o f its putative role as a neurotransmitter and its apparent
CH2CH2NH2
H
Fig. 1.2. Structure o f 5-hydroxytryptamine.
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i n v o l v e m e n t i n a number o f p s y c h o l o g i c a l and p h y s i o l o g i c a l f u n c t i o n s , i n c l u d i n g As
e m o t i o n , s l e e p , h u n g e r , t h i r s t and s e x u a l a c t i v i t y (5,7,8,15,26,31,40-45).
w i t h t h e catecholamines, a wide v a r i e t y o f psychotropic drugs a f f e c t t h e synthesis, m e t a b o l i s m , s t o r a g e and r e c e p t o r a c t i v i t y o f 5-HT ( 7 , l l - 1 3 , 1 5 , 2 1 - 2 5 , 3 0 , 4 0 - 4 5 ) . The l o c a l i z a t i o n o f 5 - H T - c o n t a i n i n g n e r v e t r a c t s has a l s o been i n v e s t i g a t e d e x t e n s i v e l y (4,7,8,15,41-44).
The i n v o l v e m e n t o f 5-HT i n a number o f n e r v o u s d i s -
o r d e r s , i n c l u d i n g m i g r a i n e , d e p r e s s i o n and s c h i z o p h r e n i a has been s u g g e s t e d (15, 16,21,22,41-49). 1.4
TRACE A M I N E S The t r a c e amines ( F i g . 1 . 3 ) have n o t been i n v e s t i g a t e d as t h o r o u g h l y as t h e
c a t e c h o l a m i n e s o r 5-HT.
The p r i m a r y r e a s o n f o r t h i s i s t h e v e r y l o w c o n c e n t r a t i o n
o f t h e s e s u b s t a n c e s i n t h e n e r v o u s system, w h i c h has n e c e s s i t a t e d t h e d e v e l o p m e n t o f h i g h l y s e n s i t i v e and s p e c i f i c a n a l y t i c a l t e c h n i q u e s .
The amount o f l i t e r a t u r e
on t h e s e amines has i n c r e a s e d e n o r m o u s l y i n r e c e n t y e a r s as t h e s e methods have been a p p l i e d t o b r a i n and body f l u i d s . A l t h o u g h t h e y a r e p r e s e n t i n t h e CNS i n m i n u t e q u a n t i t i e s , t h e t u r n o v e r r a t e o f most o f t h e t r a c e amines i s v e r y r a p i d (50-53) and 8 - p h e n y l e t h y l a m i n e and t r y p t a m i n e c a n c r o s s t h e b l o o d - b r a i n - b a r r i e r w i t h ease ( 5 4 ) ; t h e s e t w o f a c t o r s may be v e r y i m p o r t a n t f r o m a p h y s i o l o g i c a l s t a n d p o i n t .
B o u l t o n ( 5 5 ) has p o i n t e d
o u t t h a t t h e t r a c e amines, l i k e t h e c a t e c h o l a m i n e s and 5-HT,
are d i s t r i b u t e d hetero-
g e n o u s l y amongst b r a i n a r e a s . M o s t o f t h e t r a c e amines e x e r t r a t h e r s t r o n g e f f e c t s o n u p t a k e and r e l e a s e o f t h e c a t e c h o l a m i n e s and 5-HT ( 5 6 - 5 9 ) and m e t a b o l i c c o n v e r s i o n s between some o f t h e t r a c e amines and t h e c a t e c h o l a m i n e s have been r e p o r t e d ( 6 0 - 6 3 ) .
Recent micro-
i o n t o p h o r e t i c s t u d i e s i n b r a i n have r e v e a l e d t h a t a p p l i c a t i o n o f t r a c e amines a t c u r r e n t s i n s u f f i c i e n t t o a f f e c t b a s e l i n e f i r i n g r a t e s o f n e u r o n e s c a n a l t e r dramat i c a l l y t h e r e s p o n s e o f c e l l s t o DA, NA o r 5-HT w h i c h a r e a p p l i e d s u b s e q u e n t l y (64,65).
A l t h o u g h much y e t r e m a i n s t o b e known a b o u t t h e r o l e o f t r a c e amines i n
t h e CNS, t h e above f i n d i n g s and s t r u c t u r a l s i m i l a r i t i e s t o t h e p u t a t i v e n e u r o t r a n s m i t t e r amines s u g g e s t t h a t t h e i r f u n c t i o n may be a s s o c i a t e d i n t i m a t e y w i t h OA, NA and 5-HT. 1 .4.1
6-Phenyl e t h y l ami ne
The n e u r o c h e m i s t r y , m e t a b o l i s m a n d . pharmacology o f B - p h e n y l e t h y l a m i n e and i t s e f f e c t s o n a n i m a l b e h a v i o u r have been r e v i e w e d e x t e n s i v e l y (66,67
PEA) .
A
number o f monoamine o x i d a s e i n h i b i t o r s a r e known t o cause d r a m a t i c i n c r e a s e s i n b r a i n c o n c e n t r a t i o n s o f PEA ( 6 8 - 7 2 ) .
One o f t h e b i o c h e m i c a l a b n o r m a l i t i e s r e s u l t -
i n g f r o m p h e n y l k e t o n u r i a i s an i n c r e a s e d p r o d u c t i o n o f PEA and hence a g r e a t l y e l e v a t e d u r i n e l e v e l o f PEA and i t s m a j o r m e t a b o l i t e , p h e n y l a c e t i c a c i d ( P A A ) (73,741.
5
a
b
C
d
e
f
F i g . 1.3. S t r u c t u r e s o f some ' t r a c e ' amines: a ) 8 - p h e n y l e t h y l a m i n e , b ) p h e n y l e t h a n o l a m i n e , c ) p t y r a m i n e , d ) p - t y r a m i n e , e ) m-octopamine, f ) p - o c t o p a m i n e and g) t r y p t a m i n e .
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U r i n a r y l e v e l s o f PEA a r e r e p o r t e d t o be d e c r e a s e d i n d e p r e s s i o n and i n c r e a s e d i n mania and c e r t a i n t y p e s o f s c h i z o p h r e n i a ( 7 5 - 7 7 ) .
The i n v o l v e m e n t o f PEA i n t h e
e t i o l o g y o f m i g r a i n e , d e p r e s s i o n and c e r t a i n t y p e s o f s c h i z o p h r e n i a has been suggested (78-82).
I t has a l s o been r e p o r t e d t h a t plasma l e v e l s o f f r e e and c o n j u g a t e d
PAA a r e e l e v a t e d i n a g g r e s s i v e p s y c h o p a t h s ( 8 3 ) . 1.4.2
Meta- and p a r a - t y r a m i n e
The a b i l i t y o f p a r a - t y r a m i n e (p-TA) t o be t a k e n up i n t o n o r a d r e n e r g i c t e r m i n a l s a p p e a r s t o e x p l a i n t h e h y p e r t e n s i v e c r i s e s e x p e r i e n c e d b y some p a t i e n t s who a r e r e c e i v i n g monoamine o x i d a s e i n h i b i t o r s and who have i n g e s t e d f o o d s w h i c h c o n t a i n p-TA ( 8 4 ) .
I n a b o u t 30% o f p a t i e n t s w i t h c l a s s i c a l m i g r a i n e , headaches c a n be
i n d u c e d b y p-TA and p - T A - c o n t a i n i n g f o o d s .
These T A - s e n s i t i v e p a t i e n t s a p p e a r t o
s u f f e r f r o m a d e f i c i e n c y i n t h e enzyme r e s p o n s i b l e f o r t h e f o r m a t i o n o f t h e s u l f a t e c o n j u g a t e o f p-TA (85,86).
A c o r r e l a t i o n between a b n o r m a l i t i e s i n t h e EEG
r e c o r d and h i g h e r t h a n normal u r i n a r y e x c r e t i o n o f p-TA has been r e p o r t e d i n s c h i z o p h r e n i a and P a r k i n s o n i s m ( 8 7 - 8 9 ) .
Abnormal u r i n a r y e x c r e t i o n o f p-TA a n d / o r
i t s p r i n c i p a l a c i d m e t a b o l i t e , p h y d r o x y p h e n y l a c e t i c a c i d (p-HPAA),
has been ob-
s e r v e d i n h y p e r t y r o s i n a e m i a ( g o ) , c o e l i a c d i s e a s e , c y s t i c f i b r o s i s ( 9 1 ) , pheochromocytoma ( 9 2 ) and p h e n y l k e t o n u r i a ( 9 3 ) .
The mean 24 h u r i n a r y e x c r e t i o n o f
p-HPAA b y a d u l t m a l e and f e m a l e p a t i e n t s w i t h p r i m a r y d e p r e s s i o n has been r e p o r t e d t o be s i g n i f i c a n t l y l o w e r t h a n i n c o n t r o l s ( 9 4 ) ; t h e a u t h o r s s u g g e s t e d t h a t t h i s i n d i c a t e d a d e f i c i e n t p r o d u c t i o n o f p-TA i n d e p r e s s i o n . J u o r i o (95,96) has r e p o r t e d t h a t a c u t e a d m i n i s t r a t i o n o f c l i n i c a l l y a c t i v e n e u r o l e p t i c s t o m i c e r e d u c e s c o n c e n t r a t i o n s o f p-TA i n s t r i a t u m w h i l e h a v i n g no e f f e c t on &-tyramine
( y - T A ) and DA l e v e l s .
I n cases where s t r u c t u r a l i s o m e r s
e x i s t ( e . g . a- and B - f l u p e n t h i x o l ) , t h e i s o m e r w i t h n e u r o l e p t i c a c t i v i t y was f o u n d t o r e d u c e s t r i a t a l p-TA l e v e l s w h i l e t h e i n a c t i v e i s o m e r had no e f f e c t . 1.4.3
P h e n y l e t h a n o l a m i n e , meta- and p a r a - o c t o p a m i n e
The p r i m a r y r o u t e o f f o r m a t i o n o f p h e n y l e t h a n o l a m i n e (PEOH) (K-OA)
,e-octopamine
and p a r a - o c t o p a m i n e (p-OA) a p p e a r s t o be by B - h y d r o x y l a t i o n o f PEA, m-TA
and p-TA r e s p e c t i v e l y .
As w i t h most o f t h e o t h e r amines, t h e s e compounds a r e d i s -
t r i b u t e d h e t e r o g e n o u s l y amongst b r a i n a r e a s ( 9 7 - 1 0 0 ) .
Saavedra
c c.( 1 0 1 )
r e p o r t e d h i g h e r PEOH/NA and p-DA/NA r a t i o s i n f e t a l r a t s t h a n i n a d u l t r a t s .
have There
i s now a r e a s o n a b l e body o f e v i d e n c e i n s u p p o r t o f a r o l e f o r p O A i n i n v e r t e b r a t e n e r v o u s systems ( 1 0 2 - 1 0 5 ) , b u t l i t t l e i s known a b o u t t h e f u n c t i o n o f t h e OAs and
PEOH i n mammalian n e r v o u s s y s t e m s .
L e s i o n i n g e x p e r i m e n t s have i n d i c a t e d t h a t a t
l e a s t p a r t o f t h e OAs and PEOH p r e s e n t i n c e r t a i n t i s s u e s i s a s s o c i a t e d w i t h n e r v e endings (106-109). Plasma l e v e l s o f PEOH a r e r e p o r t e d t o b e s i g n i f i c a n t l y i n c r e a s e d i n p a t i e n t s w i t h h e p a t i c e n c e p h a l o p a t h y and i n t h e plasma and CSF o f dogs i n
hepatic coma
7 D a v i d ( 1 1 1 ) f o u n d t h a t p-OA l e v e l s i n t h e hypothalamus and i n b r a i n stem
(110).
were 2 - 3 t i m e s g r e a t e r , a n d m-OA l e v e l s were 5 - 6 t i m e s g r e a t e r , i n h y p e r t e n s i v e r a t s t h a n i n normal c o n t r o l s .
E l e v a t e d l e v e l s o f p - O A o r i t s m e t a b o l i t e s have been
f o u n d i n body f l u i d s f r o m p a t i e n t s w i t h h e p a t i c coma (112-116) and d e c r e a s e d l e vels i n s u f f e r e r s o f primary depression (94).
H i g h e r t h a n n o r m a l u r i n a r y concen-
t r a t i o n s o f p-OA i n h y p e r t h y r o i d c h i l d r e n have been r e p o r t e d ( 1 1 7 ) , and e l e v a t e d l e v e l s o f p - O A have been f o u n d i n t h e CSF o f e p i l e p t i c s ( 1 1 8 ) . 1 .4.4
T r y p t a m i ne
A b n o r m a l l y l o w amounts o f t r y p t a m i n e ( T ) have been r e p o r t e d t o b e e x c r e t e d b y d e p r e s s e d p a t i e n t s (119,120)
and Coppen
9 fl.
( 1 2 0 ) have f o u n d t h a t u r i n a r y T
i n c r e a s e s i n p a t i e n t s upon r e c o v e r y f r o m d e p r e s s i o n .
Dewhurst ( 7 8 ) r e p o r t e d a
marked i n c r e a s e i n u r i n a r y T i n d e p r e s s e d p a t i e n t s f o l l o w i n g a d m i n i s t r a t i o n o f p h e n e l z i n e , t h e i n c r e a s e s b e i n g much g r e a t e r t h a n t h o s e o b s e r v e d f o r 5 - h y d r o x y t r y p t a m i n e (5-HT) o r f o r 0 - m e t h y l a t e d c a t e c h o l a m i n e s .
S e v e r a l w o r k e r s have demon-
s t r a t e d t h a t a d m i n i s t r a t i o n o f monoamine o x i d a s e (MAO) i n h i b i t o r s r e s u l t s i n d r a m a t i c i n c r e a s e s i n b r a i n c o n c e n t r a t i o n s o f T i n r o d e n t s (70,71,121-124).
In a
s t u d y o f i n d i v i d u a l s c h i z o p h r e n i c s , Brune and Himwich ( 1 2 5 ) f o u n d t h a t T t e n d e d t o i n c r e a s e when b e h a v i o u r worsened and t o d e c r e a s e when b e h a v i o u r i m p r o v e d . H e r k e r t and Keup ( 1 2 6 ) s u g g e s t e d t h a t h i g h T l e v e l s accompanied b y l o w 5-HT l e v e l s may b e a f a c t o r i n t h e d e v e l o p m e n t o f p s y c h o s i s .
E l e v a t e d u r i n a r y T has been
r e p o r t e d i n p h e n y l k e t o n u r i a ( 1 2 7 ) and i n cases o f c a r c i n o i d tumor ( 1 2 8 ) and t h y r o t o x i c o s i s (129). 1.5
HISTAMINE H i s t a m i n e ( H A ) ( F i g . 1 . 4 ) i s a u b i q u i t o u s compound w h i c h i s i n v o l v e d i n a number
o f bodily functions.
I n r e c e n t y e a r s , t h e p o s s i b l e r o l e o f HA as a n e u r o t r a n s -
m i t t e r i n t.he CNS has been a n a c t i v e a r e a o f r e s e a r c h ( 1 3 0 - 1 3 5 ) .
It f u l f i l s a
number o f t h e c r i t e r i a f o r a n e u r o t r a n s m i t t e r s u b s t a n c e , and a n a s c e n d i n g h i s t a m i n e r g i c pathway i n r a t b r a i n has been d e s c r i b e d w h i c h passes t h r o u g h t h e f o r e b r a i n b u n d l e and d i f f u s e s o v e r t h e e n t i r e t e l e n c e p h a l o n ( 1 3 1 ) .
F i g . 1.4.
Structure o f histamine.
8
Several workers (136-138) have now demonstrated t h a t a number of antidepressants and neuroleptics of diverse s t r u c t u r e have in common the a b i l i t y t o block central HA receptors. Snyder (137) has suggested t h a t the CNS HA receptor blocking action
of antidepressant drugs may r e s u l t , by a n unknown mechanism, in an increase o f synaptic l e v e l s of NA a n d 5-HT. Histamine may a l s o be involved in other mental diseases.
I t has been reported
t h a t schizophrenics have a r e l a t i v e l y low incidence of a l l e r g i e s a n d the onset of schizophrenia (and manic depressive psychosis) i s sometimes accompanied by a remission of asthma (139). I t has a l s o been observed t h a t schizophrenics display a marked tolerance t o intradermally administered HA, and schizophreniform psychoses have been reported (140) following antihistamine overdose. The s t u d i e s mentioned above have d e a l t primarily w i t h the presence of biogenic amines i n nervous t i s s u e a n d body f l u i d s and t h i s i s c e r t a i n l y a most a c t i v e area of research.
However, many of these amines may a l s o be present in a number of
a g r i c u l t u r a l products a n d analysis of such compounds in foodstuffs i s an expanding area of i n t e r e s t .
As mentioned above, i t has been known f o r some time t h a t foods
rich in p-TA can cause hypertensive c r i s e s in individuals taking MA0 i n h i b i t o r s . I t i s conceivable t h a t other s t r u c t u r a l l y s i m i l a r amines present in foods can a l s o contribute t o such e f f e c t s . Histamine a n d r e l a t e d compounds a r e thought t o be responsible f o r the unpleasant symptoms a r i s i n g in scombroid f i s h poisoning (140, 1 4 1 ) . Amines in foods may a l s o be responsible for misleading r e s u l t s in urinary s t u d i e s on the excretion o f biogenic amines or t h e i r metabolites.
In such s t u d i e s
d i e t should be c a r e f u l l y controlled. 1.6
PURPOSE OF THE BOOK
Our understanding of the l o c a l i z a t i o n a n d functioning of biogenic amines has increased rapidly in recent years with the development of new assay techniques a n d the refinement of old ones.
Many analytical techniques a r e presently a v a i l -
a b l e , a n d the needs of a researcher studying the biogenic amines will depend on the amine(s) of i n t e r e s t , the finances, manpower and instrumentation f a c i l i t i e s a v a i l a b l e , a n d the p a r t i c u l a r problem t o be solved.
The purpose of t h i s book i s t o gather in one place a number of review a r t i c l e s by recognized experts. As well as discussing the h i s t o r i c a l development of the techniques in question, c o n t r i butors have a l s o d e a l t t o some degree with possible f u t u r e applications o f these methods a n d have discussed the merits a n d l i m i t a t i o n s of the techniques r e l a t i v e t o other procedures a v a i l a b l e . I t i s hoped t h a t such discussions will be useful t o b o t h workers experienced in the analysis of biogenic amines who a r e contemplat i n g changing or expanding techniques, a n d t o researchers planning t o enter the f i e l d of biogenic amine research a n d requiring an overview o f the methodologies a v a i l a b l e . I t should be emphasized t h a t although t h i s book deals primarily with
9 a n a l y s i s o f b i o g e n i c amines, many o f t h e t e c h n i q u e s d e s c r i b e d c a n be m o d i f i e d f o r measurement o f m e t a b o l i t e s o f t h e s e amines, o t h e r p h y s i o l o g i c a l l y i m p o r t a n t subs t a n c e s , and a number o f d r u g s .
Some o f t h e t e c h n i q u e s , such as b i o a s s a y s , r a d i o -
immunoassays and r a d i o r e c e p t o r assays have been used much more e x t e n s i v e l y i n q u a n t i t a t i n g s u b s t a n c e s o t h e r t h a n b i o g e n i c amines and some o f t h e s e s u b s t a n c e s have been i n c l u d e d i n t h e d e s c r i p t i o n s o f t h e t e c h n i q u e s because o f t h e i r i m p o r tance i n t h e development o f these procedures.
I t i s hoped t h a t t h e d i s c u s s i o n s
o f t h e " s t a t e o f t h e a r t " o f t h e t e c h n i q u e s i n c l u d e d i n t h i s volume w i l l g i v e t h e r e a d e r an o v e r v i e w o f t h e p r i n c i p a l p r o c e d u r e s now i n u s e f o r a n a l y s i s o f b i o g e n i c amines and a n i d e a o f l i k e l y f u t u r e d e v e l o p m e n t s . REFERENCES
10 11 12 13 14 15 16 17 18 19
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13
131 J.C. Schwartz, L i f e Sci., 25 (1979) 895-912. 132 J.P. Green, C.L. Johnson and H. Weinstein, i n M.A. L i p t o n , A. D i Mascio and K.F. K i l l a m , Psychopharmacology: A Generation o f Progress. Raven Press, New York, 1978, pp. 319-332. 133 M. Garbarg, G. Barbin, S. B i s c h o f f , H. P o l l a r d and J.C. Schwartz, B r a i n Res., 106 (1976) 333-348. 134 J.C. Schwartz, G. Barbin, M. Baudry, M. Garbarg, M.P. Martres, H. P o l l a r d and M. Verdiere, i n W.B. Essman and L. V a l z e l l i , Current Developments i n Psychopharmacology, Vol. 5 , SP Medical & S c i e n t i f i c Books, New York, 1979, pp. 173261. 135 J.C. Schwartz, H. P o l l a r d and T.T. (luach, 3. Neurochem., 35 (1980) 26-33. 136 J.P. Green and S. Maayani, Nature, 269 (1977) 163-165. 137 P.D. Kanof and P. Greengard, Nature, 272 (1978) 329-333. 138 S.H. Snyder, J . Contin. Educ. Psychiat., 39 (1978) 21-30. 139 F.P. Rauscher, H.A. N a s r a l l a h and R.J. Wyatt, i n E. Usdin, D.A. Hamburg and J.D. Barchas (Eds.), Neuroregulators and P s y c h i a t r i c Disorders, Oxford U n i v e r s i t y Press, New York, 1977, pp. 416-424. 140 D. Roman, B r . J. P s y c h i a t r . , 121 (1972) 619-620. 141 Canada Diseases Weekly Report, Vol. 7-16, H e a l t h and Welfare Canada, Ottawa, 1981, pp. 77-78. 142 Canada Diseases Weekly Report, Vol. 7-24, Health and Welfare Canada, Ottawa, 1981, pp. 117-118.
Chapter 1 AMINES OF BIOLOGICAL INTEREST AND THEIR ANALYSIS GLEN B. BAKER AND RONALD T. COUTTS Neurochemical Research Unit, Department of Psychiatry and Faculty o f Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2G3 (Canada) INTRODUCTION Biogenic or naturally-occurring amines have been the subject o f a great deal of research, particularly in the neurosciences. Much of this research has centered around the catecholamines dopamine and noradrenaline and the indolalkylamine 5hydroxytryptamine (5-HT; serotonin). There is now a reasonable body of evidence supporting the role of these amines as neurotransmitters, and the term "biogenic amine" has become synonymous with the catecholamines and 5-HT. However, in recent years, there has been increased interest in histamine and the 'trace' amines, and in this book these are also included in the term biogenic amines. 'Trace' amines are defined as a number of naturally-occurring amines which are present in the central nervous system in much lower absolute quantities than the catecholamines and 5-HT, and include 6-phenylethylamine, m- and p-tyramine, phenylethanolamine, m- and p-octopamine and tryptamine. The role o f these substances in neurotransmission is unclear, but it is known that their concentrations in brain are affected markedly by a number of psychotropic drugs. They have also been implicated in a variety of psychiatric and neurologic disorders, and this will be discussed in further detail below. There is now a voluminous literature on biogenic amines, and space does not allow for a comprehensive review of the research which has been done on these substances in biological systems. Rather, it is the purpose of this introductory chapter to highlight important aspects of the biogenic amines and to give a brief description of the format of the remainder o f the book. 1.1
1.2 CATECHOLAMINES AND THEIR 0-METHYLATED AMINE METABOLITES The catecholamines (Fig. 1.1) have been the most extensively studied of the biogenic amines because of interest in their role as neurohumors. A number of excellent books and reviews are available describing the synthesis, metabolism and localization of the catecholamines in nervous tissue (e.9. 1-14). It has been proposed that one or more o f the catecholamines are involved in the etiology and/ or symptomatology of a number of neurological and psychiatric disorders, including migraine, schizophrenia, anxiety, depression, aggression, pheochromocytoma and parkinsonism (1-3,7,9,14,15-22). In addition, a wide variety of psychotropic
2
HO
b
a
HO
OH
C
Yb.,,,, H3ch HO
d
OH
e
Fig. 1.1. Structures o f the catecholamines and their 0-methylated amine derivatives: a) dopamine, b ) noradrenaline, c ) adrenaline, d ) 3-methoxytyramine, e) normetanephrine and f ) metanephrine.
3
and cardiac drugs are thought to interact with the synthesis, storage, metabolism and/or receptor activity o f the catecholamines (1-4,7,11,13,15,19-30). The ability t o form fluorescent derivatives o f catecholamines with relative ease and specificity has meant that much is now known about the localization o f nerve tracts containing these substances (see Chapter 5 o f this volume). Electrolytic or chemical lesions o f these tracts as well as the administration o f catecholaminedepleting drugs have been used in animal models to study the involvement o f the catecholamines in a number o f behavioural and physiological functions such as locomotion, exploratory activity, hunger, thirst and sexual activity (1-3,7-9,15,18, 21,26,31). The distribution o f the catecholamines dopamine (DA), noradrenaline (NA) and adrenaline (A) and the ratios o f each one to the others vary widely between the peripheral and central nervous system, within the central nervous system itself and amongst various species (1,2,6,7). 3-Methoxytyramine (3-MTA), normetanephrine (NMN) and metanephrine (MN) (Fig. 1. are produced by the enzymatic action o f catechol 0-methyl transferase (COMT) on DA NA and A respectively. These 0-methylated amines have been identified in various tissues and body fluids (32-39). Concentrations o f these compounds in these locations can be altered dramatically in certain disease states and after administration o f a number of psychotropic drugs. 1.3
5-HYDROXYTRYPTAMINE 5-Hydroxytryptamine (Fig. 1.2), a substance which possesses strong vasoconstrictive properties on smooth muscle, is found in many parts o f the body, and is located in nonneuronal sites (platelets, mast cells, enterochromaffin cells) as well as in neurones (7,40,41). Although only 1-2% o f this indolealkylamine in the body is located in the brain (7), 5-HT has been o f interest to neuroscientists for some time because o f its putative role as a neurotransmitter and its apparent
CH2CH2NH2
H
Fig. 1.2. Structure o f 5-hydroxytryptamine.
4
i n v o l v e m e n t i n a number o f p s y c h o l o g i c a l and p h y s i o l o g i c a l f u n c t i o n s , i n c l u d i n g As
e m o t i o n , s l e e p , h u n g e r , t h i r s t and s e x u a l a c t i v i t y (5,7,8,15,26,31,40-45).
w i t h t h e catecholamines, a wide v a r i e t y o f psychotropic drugs a f f e c t t h e synthesis, m e t a b o l i s m , s t o r a g e and r e c e p t o r a c t i v i t y o f 5-HT ( 7 , l l - 1 3 , 1 5 , 2 1 - 2 5 , 3 0 , 4 0 - 4 5 ) . The l o c a l i z a t i o n o f 5 - H T - c o n t a i n i n g n e r v e t r a c t s has a l s o been i n v e s t i g a t e d e x t e n s i v e l y (4,7,8,15,41-44).
The i n v o l v e m e n t o f 5-HT i n a number o f n e r v o u s d i s -
o r d e r s , i n c l u d i n g m i g r a i n e , d e p r e s s i o n and s c h i z o p h r e n i a has been s u g g e s t e d (15, 16,21,22,41-49). 1.4
TRACE A M I N E S The t r a c e amines ( F i g . 1 . 3 ) have n o t been i n v e s t i g a t e d as t h o r o u g h l y as t h e
c a t e c h o l a m i n e s o r 5-HT.
The p r i m a r y r e a s o n f o r t h i s i s t h e v e r y l o w c o n c e n t r a t i o n
o f t h e s e s u b s t a n c e s i n t h e n e r v o u s system, w h i c h has n e c e s s i t a t e d t h e d e v e l o p m e n t o f h i g h l y s e n s i t i v e and s p e c i f i c a n a l y t i c a l t e c h n i q u e s .
The amount o f l i t e r a t u r e
on t h e s e amines has i n c r e a s e d e n o r m o u s l y i n r e c e n t y e a r s as t h e s e methods have been a p p l i e d t o b r a i n and body f l u i d s . A l t h o u g h t h e y a r e p r e s e n t i n t h e CNS i n m i n u t e q u a n t i t i e s , t h e t u r n o v e r r a t e o f most o f t h e t r a c e amines i s v e r y r a p i d (50-53) and 8 - p h e n y l e t h y l a m i n e and t r y p t a m i n e c a n c r o s s t h e b l o o d - b r a i n - b a r r i e r w i t h ease ( 5 4 ) ; t h e s e t w o f a c t o r s may be v e r y i m p o r t a n t f r o m a p h y s i o l o g i c a l s t a n d p o i n t .
B o u l t o n ( 5 5 ) has p o i n t e d
o u t t h a t t h e t r a c e amines, l i k e t h e c a t e c h o l a m i n e s and 5-HT,
are d i s t r i b u t e d hetero-
g e n o u s l y amongst b r a i n a r e a s . M o s t o f t h e t r a c e amines e x e r t r a t h e r s t r o n g e f f e c t s o n u p t a k e and r e l e a s e o f t h e c a t e c h o l a m i n e s and 5-HT ( 5 6 - 5 9 ) and m e t a b o l i c c o n v e r s i o n s between some o f t h e t r a c e amines and t h e c a t e c h o l a m i n e s have been r e p o r t e d ( 6 0 - 6 3 ) .
Recent micro-
i o n t o p h o r e t i c s t u d i e s i n b r a i n have r e v e a l e d t h a t a p p l i c a t i o n o f t r a c e amines a t c u r r e n t s i n s u f f i c i e n t t o a f f e c t b a s e l i n e f i r i n g r a t e s o f n e u r o n e s c a n a l t e r dramat i c a l l y t h e r e s p o n s e o f c e l l s t o DA, NA o r 5-HT w h i c h a r e a p p l i e d s u b s e q u e n t l y (64,65).
A l t h o u g h much y e t r e m a i n s t o b e known a b o u t t h e r o l e o f t r a c e amines i n
t h e CNS, t h e above f i n d i n g s and s t r u c t u r a l s i m i l a r i t i e s t o t h e p u t a t i v e n e u r o t r a n s m i t t e r amines s u g g e s t t h a t t h e i r f u n c t i o n may be a s s o c i a t e d i n t i m a t e y w i t h OA, NA and 5-HT. 1 .4.1
6-Phenyl e t h y l ami ne
The n e u r o c h e m i s t r y , m e t a b o l i s m a n d . pharmacology o f B - p h e n y l e t h y l a m i n e and i t s e f f e c t s o n a n i m a l b e h a v i o u r have been r e v i e w e d e x t e n s i v e l y (66,67
PEA) .
A
number o f monoamine o x i d a s e i n h i b i t o r s a r e known t o cause d r a m a t i c i n c r e a s e s i n b r a i n c o n c e n t r a t i o n s o f PEA ( 6 8 - 7 2 ) .
One o f t h e b i o c h e m i c a l a b n o r m a l i t i e s r e s u l t -
i n g f r o m p h e n y l k e t o n u r i a i s an i n c r e a s e d p r o d u c t i o n o f PEA and hence a g r e a t l y e l e v a t e d u r i n e l e v e l o f PEA and i t s m a j o r m e t a b o l i t e , p h e n y l a c e t i c a c i d ( P A A ) (73,741.
5
a
b
C
d
e
f
F i g . 1.3. S t r u c t u r e s o f some ' t r a c e ' amines: a ) 8 - p h e n y l e t h y l a m i n e , b ) p h e n y l e t h a n o l a m i n e , c ) p t y r a m i n e , d ) p - t y r a m i n e , e ) m-octopamine, f ) p - o c t o p a m i n e and g) t r y p t a m i n e .
6
U r i n a r y l e v e l s o f PEA a r e r e p o r t e d t o be d e c r e a s e d i n d e p r e s s i o n and i n c r e a s e d i n mania and c e r t a i n t y p e s o f s c h i z o p h r e n i a ( 7 5 - 7 7 ) .
The i n v o l v e m e n t o f PEA i n t h e
e t i o l o g y o f m i g r a i n e , d e p r e s s i o n and c e r t a i n t y p e s o f s c h i z o p h r e n i a has been suggested (78-82).
I t has a l s o been r e p o r t e d t h a t plasma l e v e l s o f f r e e and c o n j u g a t e d
PAA a r e e l e v a t e d i n a g g r e s s i v e p s y c h o p a t h s ( 8 3 ) . 1.4.2
Meta- and p a r a - t y r a m i n e
The a b i l i t y o f p a r a - t y r a m i n e (p-TA) t o be t a k e n up i n t o n o r a d r e n e r g i c t e r m i n a l s a p p e a r s t o e x p l a i n t h e h y p e r t e n s i v e c r i s e s e x p e r i e n c e d b y some p a t i e n t s who a r e r e c e i v i n g monoamine o x i d a s e i n h i b i t o r s and who have i n g e s t e d f o o d s w h i c h c o n t a i n p-TA ( 8 4 ) .
I n a b o u t 30% o f p a t i e n t s w i t h c l a s s i c a l m i g r a i n e , headaches c a n be
i n d u c e d b y p-TA and p - T A - c o n t a i n i n g f o o d s .
These T A - s e n s i t i v e p a t i e n t s a p p e a r t o
s u f f e r f r o m a d e f i c i e n c y i n t h e enzyme r e s p o n s i b l e f o r t h e f o r m a t i o n o f t h e s u l f a t e c o n j u g a t e o f p-TA (85,86).
A c o r r e l a t i o n between a b n o r m a l i t i e s i n t h e EEG
r e c o r d and h i g h e r t h a n normal u r i n a r y e x c r e t i o n o f p-TA has been r e p o r t e d i n s c h i z o p h r e n i a and P a r k i n s o n i s m ( 8 7 - 8 9 ) .
Abnormal u r i n a r y e x c r e t i o n o f p-TA a n d / o r
i t s p r i n c i p a l a c i d m e t a b o l i t e , p h y d r o x y p h e n y l a c e t i c a c i d (p-HPAA),
has been ob-
s e r v e d i n h y p e r t y r o s i n a e m i a ( g o ) , c o e l i a c d i s e a s e , c y s t i c f i b r o s i s ( 9 1 ) , pheochromocytoma ( 9 2 ) and p h e n y l k e t o n u r i a ( 9 3 ) .
The mean 24 h u r i n a r y e x c r e t i o n o f
p-HPAA b y a d u l t m a l e and f e m a l e p a t i e n t s w i t h p r i m a r y d e p r e s s i o n has been r e p o r t e d t o be s i g n i f i c a n t l y l o w e r t h a n i n c o n t r o l s ( 9 4 ) ; t h e a u t h o r s s u g g e s t e d t h a t t h i s i n d i c a t e d a d e f i c i e n t p r o d u c t i o n o f p-TA i n d e p r e s s i o n . J u o r i o (95,96) has r e p o r t e d t h a t a c u t e a d m i n i s t r a t i o n o f c l i n i c a l l y a c t i v e n e u r o l e p t i c s t o m i c e r e d u c e s c o n c e n t r a t i o n s o f p-TA i n s t r i a t u m w h i l e h a v i n g no e f f e c t on &-tyramine
( y - T A ) and DA l e v e l s .
I n cases where s t r u c t u r a l i s o m e r s
e x i s t ( e . g . a- and B - f l u p e n t h i x o l ) , t h e i s o m e r w i t h n e u r o l e p t i c a c t i v i t y was f o u n d t o r e d u c e s t r i a t a l p-TA l e v e l s w h i l e t h e i n a c t i v e i s o m e r had no e f f e c t . 1.4.3
P h e n y l e t h a n o l a m i n e , meta- and p a r a - o c t o p a m i n e
The p r i m a r y r o u t e o f f o r m a t i o n o f p h e n y l e t h a n o l a m i n e (PEOH) (K-OA)
,e-octopamine
and p a r a - o c t o p a m i n e (p-OA) a p p e a r s t o be by B - h y d r o x y l a t i o n o f PEA, m-TA
and p-TA r e s p e c t i v e l y .
As w i t h most o f t h e o t h e r amines, t h e s e compounds a r e d i s -
t r i b u t e d h e t e r o g e n o u s l y amongst b r a i n a r e a s ( 9 7 - 1 0 0 ) .
Saavedra
c c.( 1 0 1 )
r e p o r t e d h i g h e r PEOH/NA and p-DA/NA r a t i o s i n f e t a l r a t s t h a n i n a d u l t r a t s .
have There
i s now a r e a s o n a b l e body o f e v i d e n c e i n s u p p o r t o f a r o l e f o r p O A i n i n v e r t e b r a t e n e r v o u s systems ( 1 0 2 - 1 0 5 ) , b u t l i t t l e i s known a b o u t t h e f u n c t i o n o f t h e OAs and
PEOH i n mammalian n e r v o u s s y s t e m s .
L e s i o n i n g e x p e r i m e n t s have i n d i c a t e d t h a t a t
l e a s t p a r t o f t h e OAs and PEOH p r e s e n t i n c e r t a i n t i s s u e s i s a s s o c i a t e d w i t h n e r v e endings (106-109). Plasma l e v e l s o f PEOH a r e r e p o r t e d t o b e s i g n i f i c a n t l y i n c r e a s e d i n p a t i e n t s w i t h h e p a t i c e n c e p h a l o p a t h y and i n t h e plasma and CSF o f dogs i n
hepatic coma
7 D a v i d ( 1 1 1 ) f o u n d t h a t p-OA l e v e l s i n t h e hypothalamus and i n b r a i n stem
(110).
were 2 - 3 t i m e s g r e a t e r , a n d m-OA l e v e l s were 5 - 6 t i m e s g r e a t e r , i n h y p e r t e n s i v e r a t s t h a n i n normal c o n t r o l s .
E l e v a t e d l e v e l s o f p - O A o r i t s m e t a b o l i t e s have been
f o u n d i n body f l u i d s f r o m p a t i e n t s w i t h h e p a t i c coma (112-116) and d e c r e a s e d l e vels i n s u f f e r e r s o f primary depression (94).
H i g h e r t h a n n o r m a l u r i n a r y concen-
t r a t i o n s o f p-OA i n h y p e r t h y r o i d c h i l d r e n have been r e p o r t e d ( 1 1 7 ) , and e l e v a t e d l e v e l s o f p - O A have been f o u n d i n t h e CSF o f e p i l e p t i c s ( 1 1 8 ) . 1 .4.4
T r y p t a m i ne
A b n o r m a l l y l o w amounts o f t r y p t a m i n e ( T ) have been r e p o r t e d t o b e e x c r e t e d b y d e p r e s s e d p a t i e n t s (119,120)
and Coppen
9 fl.
( 1 2 0 ) have f o u n d t h a t u r i n a r y T
i n c r e a s e s i n p a t i e n t s upon r e c o v e r y f r o m d e p r e s s i o n .
Dewhurst ( 7 8 ) r e p o r t e d a
marked i n c r e a s e i n u r i n a r y T i n d e p r e s s e d p a t i e n t s f o l l o w i n g a d m i n i s t r a t i o n o f p h e n e l z i n e , t h e i n c r e a s e s b e i n g much g r e a t e r t h a n t h o s e o b s e r v e d f o r 5 - h y d r o x y t r y p t a m i n e (5-HT) o r f o r 0 - m e t h y l a t e d c a t e c h o l a m i n e s .
S e v e r a l w o r k e r s have demon-
s t r a t e d t h a t a d m i n i s t r a t i o n o f monoamine o x i d a s e (MAO) i n h i b i t o r s r e s u l t s i n d r a m a t i c i n c r e a s e s i n b r a i n c o n c e n t r a t i o n s o f T i n r o d e n t s (70,71,121-124).
In a
s t u d y o f i n d i v i d u a l s c h i z o p h r e n i c s , Brune and Himwich ( 1 2 5 ) f o u n d t h a t T t e n d e d t o i n c r e a s e when b e h a v i o u r worsened and t o d e c r e a s e when b e h a v i o u r i m p r o v e d . H e r k e r t and Keup ( 1 2 6 ) s u g g e s t e d t h a t h i g h T l e v e l s accompanied b y l o w 5-HT l e v e l s may b e a f a c t o r i n t h e d e v e l o p m e n t o f p s y c h o s i s .
E l e v a t e d u r i n a r y T has been
r e p o r t e d i n p h e n y l k e t o n u r i a ( 1 2 7 ) and i n cases o f c a r c i n o i d tumor ( 1 2 8 ) and t h y r o t o x i c o s i s (129). 1.5
HISTAMINE H i s t a m i n e ( H A ) ( F i g . 1 . 4 ) i s a u b i q u i t o u s compound w h i c h i s i n v o l v e d i n a number
o f bodily functions.
I n r e c e n t y e a r s , t h e p o s s i b l e r o l e o f HA as a n e u r o t r a n s -
m i t t e r i n t.he CNS has been a n a c t i v e a r e a o f r e s e a r c h ( 1 3 0 - 1 3 5 ) .
It f u l f i l s a
number o f t h e c r i t e r i a f o r a n e u r o t r a n s m i t t e r s u b s t a n c e , and a n a s c e n d i n g h i s t a m i n e r g i c pathway i n r a t b r a i n has been d e s c r i b e d w h i c h passes t h r o u g h t h e f o r e b r a i n b u n d l e and d i f f u s e s o v e r t h e e n t i r e t e l e n c e p h a l o n ( 1 3 1 ) .
F i g . 1.4.
Structure o f histamine.
8
Several workers (136-138) have now demonstrated t h a t a number of antidepressants and neuroleptics of diverse s t r u c t u r e have in common the a b i l i t y t o block central HA receptors. Snyder (137) has suggested t h a t the CNS HA receptor blocking action
of antidepressant drugs may r e s u l t , by a n unknown mechanism, in an increase o f synaptic l e v e l s of NA a n d 5-HT. Histamine may a l s o be involved in other mental diseases.
I t has been reported
t h a t schizophrenics have a r e l a t i v e l y low incidence of a l l e r g i e s a n d the onset of schizophrenia (and manic depressive psychosis) i s sometimes accompanied by a remission of asthma (139). I t has a l s o been observed t h a t schizophrenics display a marked tolerance t o intradermally administered HA, and schizophreniform psychoses have been reported (140) following antihistamine overdose. The s t u d i e s mentioned above have d e a l t primarily w i t h the presence of biogenic amines i n nervous t i s s u e a n d body f l u i d s and t h i s i s c e r t a i n l y a most a c t i v e area of research.
However, many of these amines may a l s o be present in a number of
a g r i c u l t u r a l products a n d analysis of such compounds in foodstuffs i s an expanding area of i n t e r e s t .
As mentioned above, i t has been known f o r some time t h a t foods
rich in p-TA can cause hypertensive c r i s e s in individuals taking MA0 i n h i b i t o r s . I t i s conceivable t h a t other s t r u c t u r a l l y s i m i l a r amines present in foods can a l s o contribute t o such e f f e c t s . Histamine a n d r e l a t e d compounds a r e thought t o be responsible f o r the unpleasant symptoms a r i s i n g in scombroid f i s h poisoning (140, 1 4 1 ) . Amines in foods may a l s o be responsible for misleading r e s u l t s in urinary s t u d i e s on the excretion o f biogenic amines or t h e i r metabolites.
In such s t u d i e s
d i e t should be c a r e f u l l y controlled. 1.6
PURPOSE OF THE BOOK
Our understanding of the l o c a l i z a t i o n a n d functioning of biogenic amines has increased rapidly in recent years with the development of new assay techniques a n d the refinement of old ones.
Many analytical techniques a r e presently a v a i l -
a b l e , a n d the needs of a researcher studying the biogenic amines will depend on the amine(s) of i n t e r e s t , the finances, manpower and instrumentation f a c i l i t i e s a v a i l a b l e , a n d the p a r t i c u l a r problem t o be solved.
The purpose of t h i s book i s t o gather in one place a number of review a r t i c l e s by recognized experts. As well as discussing the h i s t o r i c a l development of the techniques in question, c o n t r i butors have a l s o d e a l t t o some degree with possible f u t u r e applications o f these methods a n d have discussed the merits a n d l i m i t a t i o n s of the techniques r e l a t i v e t o other procedures a v a i l a b l e . I t i s hoped t h a t such discussions will be useful t o b o t h workers experienced in the analysis of biogenic amines who a r e contemplat i n g changing or expanding techniques, a n d t o researchers planning t o enter the f i e l d of biogenic amine research a n d requiring an overview o f the methodologies a v a i l a b l e . I t should be emphasized t h a t although t h i s book deals primarily with
9 a n a l y s i s o f b i o g e n i c amines, many o f t h e t e c h n i q u e s d e s c r i b e d c a n be m o d i f i e d f o r measurement o f m e t a b o l i t e s o f t h e s e amines, o t h e r p h y s i o l o g i c a l l y i m p o r t a n t subs t a n c e s , and a number o f d r u g s .
Some o f t h e t e c h n i q u e s , such as b i o a s s a y s , r a d i o -
immunoassays and r a d i o r e c e p t o r assays have been used much more e x t e n s i v e l y i n q u a n t i t a t i n g s u b s t a n c e s o t h e r t h a n b i o g e n i c amines and some o f t h e s e s u b s t a n c e s have been i n c l u d e d i n t h e d e s c r i p t i o n s o f t h e t e c h n i q u e s because o f t h e i r i m p o r tance i n t h e development o f these procedures.
I t i s hoped t h a t t h e d i s c u s s i o n s
o f t h e " s t a t e o f t h e a r t " o f t h e t e c h n i q u e s i n c l u d e d i n t h i s volume w i l l g i v e t h e r e a d e r an o v e r v i e w o f t h e p r i n c i p a l p r o c e d u r e s now i n u s e f o r a n a l y s i s o f b i o g e n i c amines and a n i d e a o f l i k e l y f u t u r e d e v e l o p m e n t s . REFERENCES
10 11 12 13 14 15 16 17 18 19
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