5.7- Dihydroxytryptamine

Toxins that gain access to a neuron through its uptake process and then destroy it in some way. This approach has been used mainly to destroy monoamine neurons with 5,6 or 5,7-dihydroxytryptamine targeting 5-HT neurons, 6-hydroxydopamine for dopamine (and to a lesser extent noradrenergic) neurons and MPTP for dopamine neurons (see Chapter 7). Only the latter is fully specific and effective systemically. The others need to be administered directly into the appropriate brain areas and while they may only affect the intended NT neurons, the injection may not affect all of them. 

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). 

Baumgarten, H.G. Bjorklund, A. Lachenmayer, L. and Nobin, A. Evaluation of the effects of 5,7-dihydroxytryptamine on serotonin and catecholamine neurons in the rat CNS. Acta Physiol Scand [Suppl] 391 1-19, 1973. 

Leccese, A.R, Lyness, W.H. The effects of putative 5-hydroxytryptamine receptor active agents on D-amphetamine self-administration in controls and rats with 5,7-dihydroxytryptamine median forebrain bundle lesions. Brain Res. 303 153, 1984. 

Hall, F.S., Devries, A.C., Fong, G.W., Huang, S., and Pert, A., Effects of 5,7-dihydroxytryptamine depletion of tissue serotonin levels on extracellular serotonin in the striatum assessed with in vivo microdialysis relationship to behavior, Synapse 33(1), 16-25, 1999. 

Hole, K., Fuxe, K., and Jonsson, G. (1976) Behavioral effects of 5,7-dihydroxytryptamine lesions of ascending 5-hydroxytryptamine pathways. Brain Res., 107 385-399. 

Hole, K., Jonsson, G., and Berge, O. (1977) 5,7-Dihydroxytryptamine lesions of ascending 5-hydroxytryptamine pathways Habituation, motor activity and agonistic behavior. Pharmacol. Biochem. Behav., 7 205-210. 

Trulson, M. E., Eubanks, E. E., and Jacobs, B. L. (1976) Behavioral evidence for supersensitivity following destruction of central serotonergic nerve terminals by 5,7-dihydroxytryptamine. J. Pharmacol. Exp. Ther., 198 23. 

Pozio, F., and Jonsson, G. (1978) Effects of neonatal 5,7-dihydroxytryptamine treatment on the development of serotonin neurons and their transmitter metabolism. Dev. Neurosci., 1 80— 89. 

Gerard C, el Mestikawy S, Lebrand C, et al. Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mRNA in the central nervous system of control or 5, 7-dihydroxytryptamine-treatedrats. Synapse 1996 23 164-173. 

Verge D, Daval G, Marcinkiewicz M, et al. Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 1986 6 3474-3482. 

Fischette CT, Nock B, Renner K. Effects of 5,7-dihydroxytryptamine on sero-toninl and serotonin2 receptors throughout the rat central nervous system using quantitative autoradiography. Brain Res 1987 421 263-279. 

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). 

In rats deprived of a 5-HT input, via lesions with 5,7-dihydroxytryptamine (5,7-DHT) or by p-chlorophenylalanine (PCPA), chronic administration of DMI failed to down-regulate p-adrenoceptors, although the usual desensitization of NE sensitive adenylate cyclase was still observed.62,63 when NE receptors were desensitized and reduced in number by the DMI treatment, PCPA reversed the decrease of p-receptors without affecting the cyclase.1 These persistent P-receptors may be "uncoupled", since their affinity for isoproterenol is reduced.64 Possibly, the step from uncoupled receptors to actual disappearance of NE receptors is interrupted by the loss of 5-HT input. An interesting corollary is the observation that depressed patients benefiting from either imipramine or tranylcypromine showed... 

Lehmann O, Jeltsch H, Lehnardt O, Pain L, Lazarus C, Cassel JC. Combined lesions of cholinergic and serotonergic neurons in the rat brain using 192 IgG-saporin and 5,7-dihydroxytryptamine neurochemical and behavioural characterization. Eur J Neurosci 2000 12 67-79. 

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