5.7- Dihydroxytryptamine neurotoxicity

In contrast, a similar injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) produced a zone of total 5-HT denervation at least 2 to 3 mm in diameter. These chronic intracerebral micro injection experiments lend further support to the view that the parent compound is not itself neurotoxic (Berger 1989 Berger et al., in preparation Molliver et al. 1986). 

Bjorklund, A. Nobin, A. and Stenevi, U. The use of neurotoxic dihydroxytryptamines as tools for morphological studies and localized lesioning of central indolamine neurons. Z Zellforsch 145 479-501, 1973. 

Commins, D.L. Axt, K.J. Vosmer, G. and Seiden, L.S. Endogenously produced 5,6-dihydroxytryptamine may mediate the neurotoxic effects of para-chloroamphetamine. Brain Res 419 253-261, 1987. 

There appear to be important exceptions to the rule that a decrease in the availability of 5-HT in the mesolimbic pathway leads to increases in locomotor and investigatory activity. In contrast to the dramatic and pervasive hyperactivity produced by electrolytic lesions of the median raphe, similar depletions of 5-HT following the neurotoxic dihydroxytryptamines produce relatively subtle effects that appear to be related to the environmental context in which the behavior is monitored. For instance, microinjections of 5,7-DHT into the median raphe had no effect on the level of activity in a novel environment, whereas the same animals were hyperactive in a familiar environment (54). 

It is well established that 5,7-dihydroxytryptamine (DHT) is toxic to serotonergic neurons. Lim and Foltz (19916) reported that THA and THM cyclize, thus forming an indole molecule that is similar in structure to DHT. The effect of DHT on hippocampal TPH activity was therefore examined (figure 7). This serotonergic neurotoxin decreased enzyme activity to 18 percent of control. When TPH was incubated under the reducing conditions described above, there was no reversal of the enzyme activity. This observation would argue against the possibility that DHT is the neurotoxin responsible for MDMA-induced neurotoxicity. 

Injection of 5,7-dihydroxytryptamine in the rat induced a reduction of tryptophan hydroxylase in all regions of the brain. It also caused depletion of norepinephrine, but did not deplete dopamine. The pretreatment of laboratory animals with desmethylimipramine (desipramine) blocked the neurotoxic reaction to the norepinephrine reuptake system, but did not protect the serotonergic reuptake system. (Lovenburg 1978). 

Other studies in the field concern the oxidation of 5,6-dihydroxytryptamine in relation to the mechanism of neurotoxicity in the central nervous system. In aqueous solution at pH 7.2, the neurotoxin is converted to 2,7 -i is(5,6-dihydroxytryptamine) (90JMC3035). A minor route involves the formation of two trihydroxytryptamines and other products. 

The reaction schemes shown in Figures 8, 9, 12 and 13 indicate that the oxidation chemistry of 5-HT and 5-HTPP is quite complex. Furthermore, radical intermediates and 4,5-dihydroxytryptamine derivatives are formed under very mild oxidizing conditions and such compounds are either expected to be or indeed are neurotoxic. Of all the other products of oxidation of 5-HT and 5-HTPP which have been thus far isolated only one, 5-hydroxytryptamine-4,7-dione (9), has been tested for its neurotoxic properties and it is clearly the most powerful indolic or catecholamine neurotoxin yet discovered. It does not, however, appear to exhibit any selective toxicity for particular neurons. Nevertheless, it seems probable that many other hydroxylated oxidation products of 5-HT, 5-HTPP and the other 5-hydroxyindoles found in the CNS might be neurotoxic. 

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