- Email: [email protected]
Trace biogenic amines: a possible functional role in the CNS
TIPS - October 1983
426 exist with flexible odorant molecules (more odour aspects for one molecule). One odorant molecule interacts with one receptor site. If a receptor site could interact with a larger number of molecules, structure-activity relationships should not exist. Also, the receptor site is chirally active. Since humans can distinguish between optical isomers (R and s enantiomers) 5, some type of a diastereo-isomeric interaction between optical active stimulus and optical active receptor site has to occur. The interaction between stimulus and receptor site may be only electronic (strong polar molecules), or steric (bollsymmetric molecules), but is usually a combination of both factors. The first interaction (association) can often be electronic (dipole interaction, van der Waals forces, Shallenberger principle), but this is not always necessary (alkanes, bollsymmetric molecules). After more or less chemical interaction the dynamic receptor site' measures' the profile
of the odorant molecule (handgrip-model). Some parts of the molecule are important only as steric, or spacefilling, elements (possible replacement of polar by apolar groups). The electrical impulse (Na+-K + exchange across the cell membrane) is generated after blocking of the receptor site. The generation of the impulse may be either direct or indirect due to enzymatic processes9,lo. The generated impulse is a function of the electronic interaction (stimulus to site) and the space occupied at the receptor site.
Science Publishers, London 5 0 h l o f f , G. (1980) in OIfaction and Taste (van der Starre, H., ed.), Vol. VII, pp. 3--11, Information Retrieval Ltd, London 6 Benz, G. (1976) Structure-Activity Relationships m Chemorecepnon, Information Retrieval Ltd, London
7 Kax)eze,J. H. A. (1979)Preference Behaviourin Chemoreception, Informaaon Retrieval Ltd, London 8 Theimer, E. T. (1982) Fragrance Chemistry (The Science of the Sense of Smell), Academic Press, New York and London 9 Gutron, M. (1978)Am. Sci. 66, 202-208 10 Aritns, E. J. (1979) Trends PharmacoL Sci. 1, 11-15
Reading list 1 Mark, C. (1981-1982)Chemoreception Titles, Vols 9, 10, Cambridge Scientific Abstracts, Bethesda 2 Monerieff, R. W. (1967) The Chemical Senses, Leonard Hill, London 3 Amoore, J. E. (1979) Chem. Senses Flavour 4, 153-161 4 Beets, M. G. J. (1978)Structure-Actiwty Rela-
Trace biogenic amines: a possible functional role in the CNS Roland S. G. Jones Biology Research Department, C1BA-Geigy A G, Basel, 4002, Switzerland.
A considerable number o f biochemical studies ~'3have indicated that biogenic amines which occur in trace amounts in the CNS, such as tryptamine, octopamine and tyramine, could have important central functions. Electrophysiological studies have now demonstrated that these amines can exert marked effects on central neuronal activity and can also strongly modify the responsiveness o f central neurones to putative neurotransmitter agents. Work on brain amines has long been concentrated on the catecholamines noradrenaline (NA) and dopamine (DA) and the indoleamine, 5-hydroxytryptamine (5HT). The normal brain, however, contains several other neuronally-associatexl amines which, because of their low endogenous concentrations (less than 1 nmol g-l) have received scant attention. Included in this group are tyramine (m- and p- isomers), phenylethylamine, octopamine (m- and pisomers) and t/'yptamine. The structures of these amines together with the transmitter amines to which they are metabolically related are shown in Fig. 1. With regard to the endogenous existence of these trace biogenic amines, the general assumption seems to have been that they
tionships in Human Chemoreception, Apphed
arise as metabolic by-products in the synthesis of the more abundant amines and, as such, possess no active neuronal function. It is clear that the mere presence of a substance in the CNS need not necessarily indicate an active function, but it is equally certain that low endogenous levels need not mitigate against function. This is evidenced by the increasing importance of many neuropeptides in the CNS, some of which are present in very small amounts. In any case, the low endogenous concentrations of the trace amines may be offset to some extent by turnover rates which are much greater than those of the more abundant amines (e.g. see Ref. 1). Interest in the trace amines has generally been limited to pharmacological actions,
1983Elsevlex Science PublishersB V , Amsterdam 0165- 6147/83/$0100
H. Boelens studied chem~try at the Universities of Groningen and Amsterdam. He worked for Naarden Internattonal in The Netherlands for 25 years, latterly as head of the Departments for Synthetic Organic Chemistry and Olfactory Investigations. Since 1982 he has been Vice-Presidentofthe Chemical Division of Destiluciones Bordas Chinchureta in Sevdle, Spam.
such as the well-documented indirect sympathomimetic actions of tyramine, or to the possibility that they may accumulate abnormally in certain pathological conditions and subserve a false transmitter function. In recent years, however, there has been an intensification of interest in these substances as mediators or modulators of synaptic transmission in their own right2,s. Electrophysiological studies using extracellular recording and drug application by iontophoresis have now demonstrated that trace amines can have profound effects on neuronal activity in the CNS and can also alter the responsiveness of single neurones to the 'classical' amine transmitters. It is primarily the results of these studies that I wish to describe in this article. Effects of trace amines on neuronal firing
p-Tyramine Iontophoretic application ofp-tyramine to single neurones in the cerebral cortex or the caudate nucleus evoked both excitatory and depressant responses. These responses always mimicked the effects of catecholamines (NA or DA) applied to the same cells but were always weaker and less consistenP ,5. The tyramine responses were also slower in onset and offset than the response to the catecholamine, possibly suggesting that the effect of tyramine on neuronal firing resulted from the release of NA and/or DA from presynaptic terminals. These studies therefore provide little evidence for the existence of specific tyramine receptors in the cortex or caudate nucleus. However, it should be noted that the existence of such receptors cannot be ruled out
TIPS - October 1983
427
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Tryptamine has usually been considered to be an agonist at 5HT receptors. In the cerebral cortex, however, there again H appears to be little correlation between the p-TYRAMINE p- OCTOPAMINE TRYPTAMINE PHENYLETHYLAMINE effects of the 2 indoleamines applied ionFig. 1 The structures •f n•radrenalme• d•pamine• 5•hydr•xytryptamine and the metab••ica••y•related trace tophoreticallyxs. Tryptamine, in contrast to amines. the other trace amines rarely evokes excitatory responses. In fact, 95% of reand has, in fact, been postulated previously versa in all 3 brain regions. In addition, the sponsive cells are depressed by tryptamine, on the basis of behavioural studiese. iontophoretic application of propranoiol but about half of these are excited by 5HT. often blocked the NA responses without Depressant responses to tryptamine are Octopamine affecting the response to octopamine. invariably more pronounced than those The simple correlation of effects of evoked by 5HT and they can be antagonp-tyramine and NA and DA described P h e n y l e t h y l a m i n e ized effectively by iontophoretically above does not apply in the case of Only one study has investigated in detail applied metergoline at ejecting currents octopamine. Thus, iontophorefic studies neuronal responses to iontophorefically which cause no reduction in responses to have demonstrated divergent responses of applied pbenylethylamine'. Comparison 5HT TM. It is also of interest that neurones to NA and octopamine in the of the effects of NA and phenylethylamine intrahypothalamic injections of 5HT and cerebral cortex 7,8, spinal cord9, and on rabbit cortical neurones also revealed tryptamine result in opposite changes in thalamusag. Many cells excited by opposite responses on a large number of body temperature, hypo- and hyperoctopamine were depressed by NA and vice cells tested. The possible existence of thermia respectively. These changes can be
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the same neurone. 5 H T applied iontophoretically caused a decrease m cell firing and these depressions were unaffected by a weak background application of ptyramme (pTA). However, on the same neurone, we see that the depression of ~ring evoked by the application of dopamine (DA) is greatly enhanced by p-tyramine. The record in B taken from a different neurone shows potentiation of respon.~es to noradrenaline by ptyramine.
TIPS - October 1983
428 differentially antagonized by various '5HT antagonists' (Ref. 14). There seems a strong possibility that there may be a separate population of tryptamine receptors in the CNS, and this likelihood gained considerable strength from the recent demonstration of specific binding sites for tryptamine in the rat brain Is. Finally, extensive pharmacological analysis of cortical neurone responses evoked by stimulation of nerve cell bodies, in the midbraln rapbe nucleus has convincingly indicated that these responses may be mediated in part by release of tryptamine TM.
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Interactions of trace amines with 'transmitter' amines p-Tyramine
I have conducted an extensive investigation of the interactions ofp-tyramine with several putative transmitters on neurones in both the cortex and caudate nucleus of the raP. In these studies, as in all the interaction studies described below, the trace amine was applied with very weak iontophoretic ejecting currents such that it caused no change in the ongoing firing rate of the cell and the responses of the cell to a transmitter substance determined before, during and after, the trace amine application. The most striking observation made was the ability of p-tyramine to strongly potentiate the responses of cells, either excitatory or depressant, to NA and DA without altering responses to 5HT, GABA or glutamate. Examples of the potentiation of catecholamine responses are shown in Fig. 2. Whether the facilitatory actions of tyramine at the neuronal level are linked to its ability to release and inhibit the reuptake of catecholamines is unknown at present. However, it is extremely interesting that p-tyramine levels in the caudate nucleus appear to be inversely related to the level of activity in DA terminals ~ and this could be indicative of a role ofp-tyramine in maintaining normal transmission at DAmediated synapses. Octopamine
On single neurones in the rat cortex 7 and cerebellumTM octopamine has been shown to facilitate responses to iontophoretically applied NA in a similar fashion to the tyramine effects described above. Octopamine, like tyramine, failed to alter responses to 5HT but, unlike tyramine, also failed to alter responses to DA. It has been suggested that octopamine may act as a 'co-transmitter' with NA, being released alongside the adrenergic transmitter and somehow enhancing its postsynaptic effect. These electrophysiological results could support this postulate.
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actions and interactions of trace amines demonstrable electro-physiologically, that these substances can be dismissed as being unimportant by-products of the synthesis or metabolism of other central transmitter substances. In the case of several of these substances, particularly tryptamine, evidence is rapidly accumulating to suggest that they may possess important synaptic effects which are independent of actions on the 'classical' amine transmitter systems. In addition, it is clear that all the trace amines studied can profoundly alter the neuronal responsiveness to related substances which are likely to act as central transmitters. While the studies described in this article are all essentially pharmacological, in that the techniques involved exogenous applications of the amines studied, the normal physiological occurrence of the trace amines in the CNS suggests that interactions such as those described are feasible in the intrinsic functioning of aminergic neurones. A final note concerns actions of trace amines other than those on, or involved Conclusions It seems unlikely, in view of the strong with, aminergic systems. In my own
Tryptamine
Interaction studies between tryptamine and 5HT gave similar results in part to the other interactions described above. Thus, weak applications of tryptamine to single cortical neurones greatly enhanced depressant responses to 5HT without affecting the baseline firing rate TM. However, when 5HT was excitatory, an entirely different phenomenon was observed. In this case, weak applications of tryptamine usually abolished the excitation and replaced it with a depressant response to 5HT. Both types of tryptamine-5HT interaction are shown in Fig. 3. Evidence has also been presented to suggest that responses of cortical neurones to synapticaily released 5HT may be modified by tryptamine in a similar fashion to those evoked by iontophoretically applied 5HT. Thus, stimulation of 5HTcontaining pathways evokes both excitatory and inhibitory effects on cortical cells and tryptamine can antagonize the former and enhance certain of the latte# 9.
429
TIPS - October 1983 studies I have shown that both tryptamine and p-tyramine can sometimes antagonize neuronal responses to acetylcholine. There are also indications in the literature that tryptamine may modify glutamate. mediated transmission in some species and that phenylethylamine can interact with opioid peptides. Thus the possibilities exist for a group of much neglected substances to become very important in our conception of the normal functioning of central synaptic information transfer.
Acknowledgements Many thanks are due to Dr Alan Boulton for his enthusiastic support and encouragement, his comments on this manuscript and the provision of the facilities which enabled many of the studies described to he done in the Psychiatric Research Division, Saskatoon, Canada.
Reading 1 Wu, P. and Bodton, A. A (1974) Can. J. Biochem. 52, 374--381 2 Bouhon, A. A. (1976) m Trace Amines in the Brain (Usdin, E. and Sandier, M., eds), pp. 22-39, Marcel Dckker, New York 3 Boulton, A. A (1979)Int. Rev. Biochem. 26, 179-206 4 Jones, R. S. G. (1981)J Neurosci. Res 6, 49--61 5 Bevan, P., Bradshaw, C. M , Pun, R. Y. K., Slater, N.T. and Szabadi, E. (1978) Br. J. Pharmacol. 63,651--657 6 Smof, J. C., Dem, A L. and Mulder, A. H. (1976) Arch. Int. pharmacodyn. Ther 220, 62-71 7 Jones, R. S. G. (1982) Eur. J. Pharmacol. 77, 159-162 8 Hicks, T. P. and McLennan, H (1978) Br. J. Pharmacol. 64, 485-.-491 9 Hacks, T. P. and McLemmn, H. ( 1978) Brain Res. 157,402--406 10 Dao, W. P. C. and Walker, R J. (1980) Br. J. Pharmacol. 68, 132P 11 Gmrdma, W. J , Pedemonte, W. A and Sabelh, H. C. (1973)Llfe Sci. 12, 153-161 12 Hauger, R. L., Skolnick, P and Paul, S. M.
CNS stimulants:
(1982)Eur. J. Pharmacol. 83,147-148 13 Jones, R. S. G. (1982)Neuropharmacology 21, 209-214 14 Cox, B., Lee, T. F andMartin, D. (1981)Br. J. PharmacoL 72,477--482 15 Kellar, K. J. and Cascio, C. S. (1982) Eur..L Pharmacol. 78, 475--478 16 Jones, R. S. G. and Brtmdl~nt, J. (1982) Eur. J. Pharmacol. 81,681--685 and refetence~ therein 17 Jt~no, A. V (1979) Br. J. Pharmacol. 66, 377-384 18 Kostolxmlos, G. K. and Yarbrough, G. G. (1975) J. Pharm. Pharmacol. 27, 408--412 19 Jones, R. S. G. and Boulton, A. A. (1980) Life Scl. 27, 1849-1856 20 Jones, R. S. G (1982) Brain Res. Bull. 8, 435-437
Roland S G. Jones obtained his Ph.D. in the Depanmem o f Physiology, University College, Cardiff, UK in 1978. He was a post-doctoral Fellow in the Psychiatric Research Division, 8askatoon, Canada during 1978--1981. At present he is a Research Fellow with Ciba-Geigy Ltd, Basel, Switzerland.
CNS behavioral stimulants can be subdivided into 2 classes o f drugs. The amphetamine class o f drugs are direct releasers, as well as re.uptake inhibitors, o f dopamine and norepinephrine and these effects are demonstrable both in vivo and in vitro using brain slices or synaptosomes. Drugs in the non-amphetamine class block dopamine and~or norepinephrine reuptake, but enhance dopamine release in vivo only, with no evidence o f enhanced release in vitro. This differentiation between monoamines by the non-amphetamine drugs is due to differences in storage and releasable pools o f dopamine and norepinephrine. These differences should be taken into account when comparing the pharmacology o f these 2 monaminergic neuronal systems.
both classes of drugs in the rat brain, as the cause of stimulated behavior. Thus, there must be 2 different mechanisms for enhancing the release of dopamine. Biochemical data obtained in situ is in close harmony with the behavioral data. Chieull and Moore ~'s demonstrated that (+)-amphetamine and methylphenidate release [aH]dopamine formed from [aH]tyrosine in steady-state perfusions of the cat lateral ventricle. Release of dopamine by (+)-amphetamine was enhanced slightly by reserpine and inhibited by c~-methyl-p-tyrosine ~. As in behavioral studies, methylphenidate, induced release of [SH]dopamine was inhibited by reserpine pretreatment and not by a-methyl-p-tyrosinea. Obviously, (+)amphetamine was releasing dopamine from a pool that was insensitive to reserpine, but dependent upon the newly formed amine. On the other hand methylpbenldate was releasing dopamine from a synthesisindependent pool that could be depleted by reserpine.
A large number of drugs are known to stimulate behavioral activity and are generally classified as amphetamine,type CNS stimulants. However, these drugs can be subdivided on the basis of whether the stereotypies and increased locomotor activi t y a r e inhibited by reserpine. The amphetamine class of stimulants (amphetamine, methamphetamine, pherv metrazine or pemoline) are not inhibited by reserpine,induced depletion of catecholamines1. The non-amphetamine
Amphetamine-induced release: exchange-diffusion We now probably have a better understanding of amphetamine's mechanism of action. It has long been known that amphetamine not only blocks reuptake of exogenous monoamines, but will release previously accumulated [aH]dopamine or [*H]norepinephrine from brain synaptosomes. Drugs, such as methylphenidate, cocaine, mazindol, amfonelic acid (AFA) or nomifensine4-s, inhibit the reuptake
two distinct mechanisms of action for amphetamine-like drugs Brian A. McMillen Department o f Pharmacology, School o f Medicine, East Carolina University, Greenville, N C 2 7834, USA.
class (methylphenidate, pipradol, nomifensine, cocaine and amfonelic acid) are potently inhibited by reserpine pretreatment. In contrast, if a-methyLp-tyrosine is used to inhibit catecholamine synthesis, only the amphetamine class of drugs are inhibitedt. These results, obtained in several laboratories (see Ref. 1), clearly indicate 2 mechanisms of action for producing CNS stimulation. Results from several laboratories implicated increased release of dopamine, rather than norepinephrine, by
(~ 1983El~vl~ $ c ~ Publlsl~caB V , ~
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426 exist with flexible odorant molecules (more odour aspects for one molecule). One odorant molecule interacts with one receptor site. If a receptor site could interact with a larger number of molecules, structure-activity relationships should not exist. Also, the receptor site is chirally active. Since humans can distinguish between optical isomers (R and s enantiomers) 5, some type of a diastereo-isomeric interaction between optical active stimulus and optical active receptor site has to occur. The interaction between stimulus and receptor site may be only electronic (strong polar molecules), or steric (bollsymmetric molecules), but is usually a combination of both factors. The first interaction (association) can often be electronic (dipole interaction, van der Waals forces, Shallenberger principle), but this is not always necessary (alkanes, bollsymmetric molecules). After more or less chemical interaction the dynamic receptor site' measures' the profile
of the odorant molecule (handgrip-model). Some parts of the molecule are important only as steric, or spacefilling, elements (possible replacement of polar by apolar groups). The electrical impulse (Na+-K + exchange across the cell membrane) is generated after blocking of the receptor site. The generation of the impulse may be either direct or indirect due to enzymatic processes9,lo. The generated impulse is a function of the electronic interaction (stimulus to site) and the space occupied at the receptor site.
Science Publishers, London 5 0 h l o f f , G. (1980) in OIfaction and Taste (van der Starre, H., ed.), Vol. VII, pp. 3--11, Information Retrieval Ltd, London 6 Benz, G. (1976) Structure-Activity Relationships m Chemorecepnon, Information Retrieval Ltd, London
7 Kax)eze,J. H. A. (1979)Preference Behaviourin Chemoreception, Informaaon Retrieval Ltd, London 8 Theimer, E. T. (1982) Fragrance Chemistry (The Science of the Sense of Smell), Academic Press, New York and London 9 Gutron, M. (1978)Am. Sci. 66, 202-208 10 Aritns, E. J. (1979) Trends PharmacoL Sci. 1, 11-15
Reading list 1 Mark, C. (1981-1982)Chemoreception Titles, Vols 9, 10, Cambridge Scientific Abstracts, Bethesda 2 Monerieff, R. W. (1967) The Chemical Senses, Leonard Hill, London 3 Amoore, J. E. (1979) Chem. Senses Flavour 4, 153-161 4 Beets, M. G. J. (1978)Structure-Actiwty Rela-
Trace biogenic amines: a possible functional role in the CNS Roland S. G. Jones Biology Research Department, C1BA-Geigy A G, Basel, 4002, Switzerland.
A considerable number o f biochemical studies ~'3have indicated that biogenic amines which occur in trace amounts in the CNS, such as tryptamine, octopamine and tyramine, could have important central functions. Electrophysiological studies have now demonstrated that these amines can exert marked effects on central neuronal activity and can also strongly modify the responsiveness o f central neurones to putative neurotransmitter agents. Work on brain amines has long been concentrated on the catecholamines noradrenaline (NA) and dopamine (DA) and the indoleamine, 5-hydroxytryptamine (5HT). The normal brain, however, contains several other neuronally-associatexl amines which, because of their low endogenous concentrations (less than 1 nmol g-l) have received scant attention. Included in this group are tyramine (m- and p- isomers), phenylethylamine, octopamine (m- and pisomers) and t/'yptamine. The structures of these amines together with the transmitter amines to which they are metabolically related are shown in Fig. 1. With regard to the endogenous existence of these trace biogenic amines, the general assumption seems to have been that they
tionships in Human Chemoreception, Apphed
arise as metabolic by-products in the synthesis of the more abundant amines and, as such, possess no active neuronal function. It is clear that the mere presence of a substance in the CNS need not necessarily indicate an active function, but it is equally certain that low endogenous levels need not mitigate against function. This is evidenced by the increasing importance of many neuropeptides in the CNS, some of which are present in very small amounts. In any case, the low endogenous concentrations of the trace amines may be offset to some extent by turnover rates which are much greater than those of the more abundant amines (e.g. see Ref. 1). Interest in the trace amines has generally been limited to pharmacological actions,
1983Elsevlex Science PublishersB V , Amsterdam 0165- 6147/83/$0100
H. Boelens studied chem~try at the Universities of Groningen and Amsterdam. He worked for Naarden Internattonal in The Netherlands for 25 years, latterly as head of the Departments for Synthetic Organic Chemistry and Olfactory Investigations. Since 1982 he has been Vice-Presidentofthe Chemical Division of Destiluciones Bordas Chinchureta in Sevdle, Spam.
such as the well-documented indirect sympathomimetic actions of tyramine, or to the possibility that they may accumulate abnormally in certain pathological conditions and subserve a false transmitter function. In recent years, however, there has been an intensification of interest in these substances as mediators or modulators of synaptic transmission in their own right2,s. Electrophysiological studies using extracellular recording and drug application by iontophoresis have now demonstrated that trace amines can have profound effects on neuronal activity in the CNS and can also alter the responsiveness of single neurones to the 'classical' amine transmitters. It is primarily the results of these studies that I wish to describe in this article. Effects of trace amines on neuronal firing
p-Tyramine Iontophoretic application ofp-tyramine to single neurones in the cerebral cortex or the caudate nucleus evoked both excitatory and depressant responses. These responses always mimicked the effects of catecholamines (NA or DA) applied to the same cells but were always weaker and less consistenP ,5. The tyramine responses were also slower in onset and offset than the response to the catecholamine, possibly suggesting that the effect of tyramine on neuronal firing resulted from the release of NA and/or DA from presynaptic terminals. These studies therefore provide little evidence for the existence of specific tyramine receptors in the cortex or caudate nucleus. However, it should be noted that the existence of such receptors cannot be ruled out
TIPS - October 1983
427
OH
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H2
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H2
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Tryptamine has usually been considered to be an agonist at 5HT receptors. In the cerebral cortex, however, there again H appears to be little correlation between the p-TYRAMINE p- OCTOPAMINE TRYPTAMINE PHENYLETHYLAMINE effects of the 2 indoleamines applied ionFig. 1 The structures •f n•radrenalme• d•pamine• 5•hydr•xytryptamine and the metab••ica••y•related trace tophoreticallyxs. Tryptamine, in contrast to amines. the other trace amines rarely evokes excitatory responses. In fact, 95% of reand has, in fact, been postulated previously versa in all 3 brain regions. In addition, the sponsive cells are depressed by tryptamine, on the basis of behavioural studiese. iontophoretic application of propranoiol but about half of these are excited by 5HT. often blocked the NA responses without Depressant responses to tryptamine are Octopamine affecting the response to octopamine. invariably more pronounced than those The simple correlation of effects of evoked by 5HT and they can be antagonp-tyramine and NA and DA described P h e n y l e t h y l a m i n e ized effectively by iontophoretically above does not apply in the case of Only one study has investigated in detail applied metergoline at ejecting currents octopamine. Thus, iontophorefic studies neuronal responses to iontophorefically which cause no reduction in responses to have demonstrated divergent responses of applied pbenylethylamine'. Comparison 5HT TM. It is also of interest that neurones to NA and octopamine in the of the effects of NA and phenylethylamine intrahypothalamic injections of 5HT and cerebral cortex 7,8, spinal cord9, and on rabbit cortical neurones also revealed tryptamine result in opposite changes in thalamusag. Many cells excited by opposite responses on a large number of body temperature, hypo- and hyperoctopamine were depressed by NA and vice cells tested. The possible existence of thermia respectively. These changes can be
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the same neurone. 5 H T applied iontophoretically caused a decrease m cell firing and these depressions were unaffected by a weak background application of ptyramme (pTA). However, on the same neurone, we see that the depression of ~ring evoked by the application of dopamine (DA) is greatly enhanced by p-tyramine. The record in B taken from a different neurone shows potentiation of respon.~es to noradrenaline by ptyramine.
TIPS - October 1983
428 differentially antagonized by various '5HT antagonists' (Ref. 14). There seems a strong possibility that there may be a separate population of tryptamine receptors in the CNS, and this likelihood gained considerable strength from the recent demonstration of specific binding sites for tryptamine in the rat brain Is. Finally, extensive pharmacological analysis of cortical neurone responses evoked by stimulation of nerve cell bodies, in the midbraln rapbe nucleus has convincingly indicated that these responses may be mediated in part by release of tryptamine TM.
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Interactions of trace amines with 'transmitter' amines p-Tyramine
I have conducted an extensive investigation of the interactions ofp-tyramine with several putative transmitters on neurones in both the cortex and caudate nucleus of the raP. In these studies, as in all the interaction studies described below, the trace amine was applied with very weak iontophoretic ejecting currents such that it caused no change in the ongoing firing rate of the cell and the responses of the cell to a transmitter substance determined before, during and after, the trace amine application. The most striking observation made was the ability of p-tyramine to strongly potentiate the responses of cells, either excitatory or depressant, to NA and DA without altering responses to 5HT, GABA or glutamate. Examples of the potentiation of catecholamine responses are shown in Fig. 2. Whether the facilitatory actions of tyramine at the neuronal level are linked to its ability to release and inhibit the reuptake of catecholamines is unknown at present. However, it is extremely interesting that p-tyramine levels in the caudate nucleus appear to be inversely related to the level of activity in DA terminals ~ and this could be indicative of a role ofp-tyramine in maintaining normal transmission at DAmediated synapses. Octopamine
On single neurones in the rat cortex 7 and cerebellumTM octopamine has been shown to facilitate responses to iontophoretically applied NA in a similar fashion to the tyramine effects described above. Octopamine, like tyramine, failed to alter responses to 5HT but, unlike tyramine, also failed to alter responses to DA. It has been suggested that octopamine may act as a 'co-transmitter' with NA, being released alongside the adrenergic transmitter and somehow enhancing its postsynaptic effect. These electrophysiological results could support this postulate.
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Fig. 3. Interactions of tryptamine with 5HT on single coracal neurones. The record in A shows the pronounced potentiation of the depressant effects of 5 H T by an application of tryptamine which itself does not alter cell firing. B and C which are a continuous record from the same cell demonstrate that when 5HT is excitatory on cell firing the background application of tryptamine results in rmtigation of the excitation and replacement with a depression.
actions and interactions of trace amines demonstrable electro-physiologically, that these substances can be dismissed as being unimportant by-products of the synthesis or metabolism of other central transmitter substances. In the case of several of these substances, particularly tryptamine, evidence is rapidly accumulating to suggest that they may possess important synaptic effects which are independent of actions on the 'classical' amine transmitter systems. In addition, it is clear that all the trace amines studied can profoundly alter the neuronal responsiveness to related substances which are likely to act as central transmitters. While the studies described in this article are all essentially pharmacological, in that the techniques involved exogenous applications of the amines studied, the normal physiological occurrence of the trace amines in the CNS suggests that interactions such as those described are feasible in the intrinsic functioning of aminergic neurones. A final note concerns actions of trace amines other than those on, or involved Conclusions It seems unlikely, in view of the strong with, aminergic systems. In my own
Tryptamine
Interaction studies between tryptamine and 5HT gave similar results in part to the other interactions described above. Thus, weak applications of tryptamine to single cortical neurones greatly enhanced depressant responses to 5HT without affecting the baseline firing rate TM. However, when 5HT was excitatory, an entirely different phenomenon was observed. In this case, weak applications of tryptamine usually abolished the excitation and replaced it with a depressant response to 5HT. Both types of tryptamine-5HT interaction are shown in Fig. 3. Evidence has also been presented to suggest that responses of cortical neurones to synapticaily released 5HT may be modified by tryptamine in a similar fashion to those evoked by iontophoretically applied 5HT. Thus, stimulation of 5HTcontaining pathways evokes both excitatory and inhibitory effects on cortical cells and tryptamine can antagonize the former and enhance certain of the latte# 9.
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TIPS - October 1983 studies I have shown that both tryptamine and p-tyramine can sometimes antagonize neuronal responses to acetylcholine. There are also indications in the literature that tryptamine may modify glutamate. mediated transmission in some species and that phenylethylamine can interact with opioid peptides. Thus the possibilities exist for a group of much neglected substances to become very important in our conception of the normal functioning of central synaptic information transfer.
Acknowledgements Many thanks are due to Dr Alan Boulton for his enthusiastic support and encouragement, his comments on this manuscript and the provision of the facilities which enabled many of the studies described to he done in the Psychiatric Research Division, Saskatoon, Canada.
Reading 1 Wu, P. and Bodton, A. A (1974) Can. J. Biochem. 52, 374--381 2 Bouhon, A. A. (1976) m Trace Amines in the Brain (Usdin, E. and Sandier, M., eds), pp. 22-39, Marcel Dckker, New York 3 Boulton, A. A (1979)Int. Rev. Biochem. 26, 179-206 4 Jones, R. S. G. (1981)J Neurosci. Res 6, 49--61 5 Bevan, P., Bradshaw, C. M , Pun, R. Y. K., Slater, N.T. and Szabadi, E. (1978) Br. J. Pharmacol. 63,651--657 6 Smof, J. C., Dem, A L. and Mulder, A. H. (1976) Arch. Int. pharmacodyn. Ther 220, 62-71 7 Jones, R. S. G. (1982) Eur. J. Pharmacol. 77, 159-162 8 Hicks, T. P. and McLennan, H (1978) Br. J. Pharmacol. 64, 485-.-491 9 Hacks, T. P. and McLemmn, H. ( 1978) Brain Res. 157,402--406 10 Dao, W. P. C. and Walker, R J. (1980) Br. J. Pharmacol. 68, 132P 11 Gmrdma, W. J , Pedemonte, W. A and Sabelh, H. C. (1973)Llfe Sci. 12, 153-161 12 Hauger, R. L., Skolnick, P and Paul, S. M.
CNS stimulants:
(1982)Eur. J. Pharmacol. 83,147-148 13 Jones, R. S. G. (1982)Neuropharmacology 21, 209-214 14 Cox, B., Lee, T. F andMartin, D. (1981)Br. J. PharmacoL 72,477--482 15 Kellar, K. J. and Cascio, C. S. (1982) Eur..L Pharmacol. 78, 475--478 16 Jones, R. S. G. and Brtmdl~nt, J. (1982) Eur. J. Pharmacol. 81,681--685 and refetence~ therein 17 Jt~no, A. V (1979) Br. J. Pharmacol. 66, 377-384 18 Kostolxmlos, G. K. and Yarbrough, G. G. (1975) J. Pharm. Pharmacol. 27, 408--412 19 Jones, R. S. G. and Boulton, A. A. (1980) Life Scl. 27, 1849-1856 20 Jones, R. S. G (1982) Brain Res. Bull. 8, 435-437
Roland S G. Jones obtained his Ph.D. in the Depanmem o f Physiology, University College, Cardiff, UK in 1978. He was a post-doctoral Fellow in the Psychiatric Research Division, 8askatoon, Canada during 1978--1981. At present he is a Research Fellow with Ciba-Geigy Ltd, Basel, Switzerland.
CNS behavioral stimulants can be subdivided into 2 classes o f drugs. The amphetamine class o f drugs are direct releasers, as well as re.uptake inhibitors, o f dopamine and norepinephrine and these effects are demonstrable both in vivo and in vitro using brain slices or synaptosomes. Drugs in the non-amphetamine class block dopamine and~or norepinephrine reuptake, but enhance dopamine release in vivo only, with no evidence o f enhanced release in vitro. This differentiation between monoamines by the non-amphetamine drugs is due to differences in storage and releasable pools o f dopamine and norepinephrine. These differences should be taken into account when comparing the pharmacology o f these 2 monaminergic neuronal systems.
both classes of drugs in the rat brain, as the cause of stimulated behavior. Thus, there must be 2 different mechanisms for enhancing the release of dopamine. Biochemical data obtained in situ is in close harmony with the behavioral data. Chieull and Moore ~'s demonstrated that (+)-amphetamine and methylphenidate release [aH]dopamine formed from [aH]tyrosine in steady-state perfusions of the cat lateral ventricle. Release of dopamine by (+)-amphetamine was enhanced slightly by reserpine and inhibited by c~-methyl-p-tyrosine ~. As in behavioral studies, methylphenidate, induced release of [SH]dopamine was inhibited by reserpine pretreatment and not by a-methyl-p-tyrosinea. Obviously, (+)amphetamine was releasing dopamine from a pool that was insensitive to reserpine, but dependent upon the newly formed amine. On the other hand methylpbenldate was releasing dopamine from a synthesisindependent pool that could be depleted by reserpine.
A large number of drugs are known to stimulate behavioral activity and are generally classified as amphetamine,type CNS stimulants. However, these drugs can be subdivided on the basis of whether the stereotypies and increased locomotor activi t y a r e inhibited by reserpine. The amphetamine class of stimulants (amphetamine, methamphetamine, pherv metrazine or pemoline) are not inhibited by reserpine,induced depletion of catecholamines1. The non-amphetamine
Amphetamine-induced release: exchange-diffusion We now probably have a better understanding of amphetamine's mechanism of action. It has long been known that amphetamine not only blocks reuptake of exogenous monoamines, but will release previously accumulated [aH]dopamine or [*H]norepinephrine from brain synaptosomes. Drugs, such as methylphenidate, cocaine, mazindol, amfonelic acid (AFA) or nomifensine4-s, inhibit the reuptake
two distinct mechanisms of action for amphetamine-like drugs Brian A. McMillen Department o f Pharmacology, School o f Medicine, East Carolina University, Greenville, N C 2 7834, USA.
class (methylphenidate, pipradol, nomifensine, cocaine and amfonelic acid) are potently inhibited by reserpine pretreatment. In contrast, if a-methyLp-tyrosine is used to inhibit catecholamine synthesis, only the amphetamine class of drugs are inhibitedt. These results, obtained in several laboratories (see Ref. 1), clearly indicate 2 mechanisms of action for producing CNS stimulation. Results from several laboratories implicated increased release of dopamine, rather than norepinephrine, by
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