Decarboxylation, instead of hydroxylation, of the amino-acid precursors of DA and 5-HT results in the formation of amines that are only found in trace amounts in the CNS but have distinct effects when administered into the brain (Fig. 13.7). Since such decarboxylation can be achieved by the non-specific L-aromatic amino acid decarboxylase there is considerable potential for its occurrence, especially if there is a rise in the concentration of the appropriate precursor or some malfunction in their normal hydroxylation through rate-limiting processes. This could shunt tyrosine, tryptophan and phenylalanine through to tyramine, tryptamine and phenylethylamine rather than to the more normally formed dopa, 5-HT and tyroxine (Fig. 13.7). It is this potential for synthesis together with the known central effects of these amines when injected, that preserves an interest in them despite their very low concentrations in whole brain, i.e. phenylethylamine 1.8, ^-tyramine 2.0, m-tyramine 0.3 and tryptamine 0.5ng/g. Generally concentrations are highest in the striatum (4, 11, 0.3 and 1.5ng/g respectively) but still very much lower than DA (10 ^/g). Unlike the catecholamines their concentration rises dramatically (50 times) after inhibition of MAO. Turnover can also be increased easily by the provision of extra substrate since decarboxylation is not rate limiting. Distinct anatomical pathways have not been identified since there is no specific enzyme involved in their synthesis that can be used for immunohistochemistry, and they are not sufficiently concentrated for ordinary histofluorescence.
Although tryptamine can be detected in brain there has been much debate over whether it exists separately from 5-HT or merely co-exists with it. Specific high-affinity binding sites have been demonstrated for tryptamine in rat cortex. These appear to be different from 5-HT sites but until appropriate antagonists are found it remains possible that they form a subset of the ever-increasing number of 5-HT receptors (see Chapter 9). The behavioural response in rats to tryptophan plus a MAO inhibitor (Grahame-Smith 1971) is accompanied by an elevation of brain tryptamine as well as 5-HT and is less marked if the synthesis of tryptamine is reduced by a decarboxylase inhibitor that does not have a significant effect on 5-HT levels. In fact after a MAOI, tryptamine produces a behavioural response in rats similar to that of tryptophan apart from the absence of certain features like tremor and wet-dog shake. The complexity of the situation is illustrated by studies of the effect of intra-hypothalamic injections of 5-HT and tryptamine on rat body temperature (Cox, Lee and Martin 1981). In these it was shown that 5-HT decreased temperature while tryptamine actually increased it but it was not possible to block one effect preferentially with a whole range of antagonists, despite
NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION ©
ho chj— ch2— nhj Dopamine ch—ch2—nh oh Octopamine
Tryptophan Tryptamine cooh cooh
Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, p-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase; (2) phenylaline hydroxylase; (3) tyrosine hydroxylase; (4) tryptophan hydroxylase
Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, p-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase; (2) phenylaline hydroxylase; (3) tyrosine hydroxylase; (4) tryptophan hydroxylase some differences in effectiveness. Also although it was the tryptamine and not the 5-HT response, which was abolished after destruction of 5-HT neurons with 5,7-dihydroxytryptamine and implies that tryptamine was releasing 5-HT, it was found that raphe (5-HT) neuron stimulation produces hyperthermia, like tryptamine, rather than hypothermia, like 5-HT.
These opposing effects of tryptamine and 5-HT are also seen when they are applied directly to cortical neurons by iontopheresis. Tryptamine is predominantly depressant while 5-HT is mainly excitatory. Surprisingly, the 5-HT antagonist metergoline is more effective against tryptamine and the depressant effects. When the medial Raphe nucleus is stimulated this produces inhibition of cortical neurons followed by excitation but it is the inhibition (tryptamine-like) that is blocked by metergoline. In keeping with this finding is the observation that depletion of 5-HT with pCPA reduced only the excitatory (5-HT) response while 5,7-dihydroxytryptamine, which destroys the neurons, abolished both effects (see Jones 1983). The inference from these studies and those on temperature is that some neurons in the raphe nucleus release something other than 5-HT. This might be tryptamine but if it is not, then its effects are presumably modified by tryptamine.
Possibly there is a subclass of 5-HT receptors that would be preferentially activated by tryptamine if its endogenous concentrations were ever adequate. Indeed the term 'tryptamine receptor' as first used by Gaddum to describe the effects of all indole amines may be one to which we should return.
The relationship of phenylethylamine to dopamine is not unlike that of tryptamine to 5-HT. Present in low concentrations in the brain there is some evidence for distinct binding sites but not for specific neurons. When injected icv it causes stereotyped behaviour similar to, but more marked than, that seen with amphetamine. These effects are blocked by neuroleptics (DA antagonists) and since phenylethylamine does not bind directly to DA receptors it is assumed to release DA, like amphetamine. This is substantiated by the fact that in rats with unilateral 6-OHDA lesions of the SN its systemic administration causes ipsilateral rotation like amphetamine (see Chapter 6). Phenylethylamine certainly increases the overflow of [3H]-DA from striatal synapto-somes and slices and of endogenous DA in vivo, but part of this may be due to block of DA uptake. In any case such effects only occur with concentrations of 5 x 10~5 M, which are not likely to be encountered in vivo and it is not Ca2+-dependent. Peripherally phenylethylamine causes contractions of the rat fundus just like amphetamine, tryptamine and 5-HT. These are reduced by some 5-HT antagonists, like methysergide, but not by DA antagonists. Thus some of its central effects may be mediated through a tryptamine receptor. Needless to say, the DA and amphetamine-like activity and structure of phenylethylamine, together with the facility for its synthesis in the CNS, has led to unproven suggestions of its involvement in schizophrenia. In fact there is some evidence for increased excretion of its metabolite (phenyl acetic acid) in the subgroup of paranoid schizophrenics.
^-Tyramine is produced by decarboxylation of tyrosine and is present in the CNS in higher (threefold) concentrations than m-tyramine, the hydroxylated derivative of phenylethylamine. In the periphery ^-tyramine is easily hydroxylated to octopamine, which has some direct effects on a1 adrenoceptors, unlike tyramine which functions by releasing NA. When tested on central neurons tyramine always produces the same effects as NA but they are slower and less marked, implying an indirect action. By contrast octopamine often produces the opposite effect to NA and it is probable that octopamine may have a functional role in the invertebrate CNS where it is found in higher concentrations (5 ^/g) than in the mammalian brain (0.5ng/g). Neither tyramine nor octopamine have distinct behavioural effects, unlike phenylethylamine, and little is known of their central effects, although depressed patients have been shown to excrete less conjugated tyramine than normal subjects after challenge with tyrosine.
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