6- Hydroxydopamine

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. 

While the nigrostriatal pathways are ipsilateral some crossing occurs in fibres from the ventral tegmental AlO nucleus. These pathways are shown diagramatically in Fig. 7.1. Further details can be obtained from Moore and Bloom (1978) and Lindvall and Bjorkland (1978). The nuclei provide distinct loci for activating the dopamine systems for electrophysiological, release and behavioural studies and for their destruction by electrolytic lesion or injection of the toxin 6-hydroxydopamine (6-OHDA). 

The 6-hydroxylated form of DA, 6-hydroxydopamine (6-OEIDA) is taken up into both DA and NA nerve terminals where it is readily oxidised to compounds that cause... 

Figure 7.7 Dopamine-induced rotation in the rat in which one (left) nigrostriatal dopamine pathway from the substantia nigra (SN) to the caudate putamen (CP) has been lesioned by a prior injection (14 days) of 6-hydroxydopamine. Amphetamine, an indirectly acting amine, releases DA and so can only act on the right side. Since the animal moves away from the dominating active side it induces ipsilateral rotation (i.e. towards the lesioned side). By contrast, the development of postS5maptic supersensitivity to DA on the lesioned side ensures that apomorphine, a directly acting agonist, is actually more active on that side and so the animal turns away from it (contralateral rotation)...

Hydroxydopamine (6-OHDA) is a neurotoxin that destroys catecholaminergic neurons in the brain. This toxicity is believed to be related to the production of ROS by the neurotoxin. Rats were fed chronically with vitamin E and then challenged with 6-OHDA. The usual depletion of SOD and reduced glutathione (GSH) in most brain regions was attenuated by the vitamin E pretreatment. The authors attributed this success to scavenging by the augmented brain levels of vitamin E (Perumal et al., 1992). 

Seiden, L.S., and Vosmer. G. Formation of 6-hydroxydopamine in caudate nucleus of the rat brain after a single large dose of methylamphetamine. Pharmacol Biochem Behav 21 29-31, 1984. 

Deminiere, J.M. Taghzouti, K. Tassin, J.P. Le Moal, M. and Simon, H. Increased sensitivity to amphetamine and facilitation of amphetamine selfadministration after 6-hydroxydopamine lesions of the amygdala. Psychopharmacology 94 232-236, 1988. 

Joyce, E.M., and Koob, G.F. Amphetamine-, seopolamine-, and eaffeine-induced locomotor activity following 6-hydroxydopamine lesions of the mesolimbic dopamine system. Psychopharmacology 73 311-313, 1981. 

Martin-Iversen, M.T. Szostak, C. and Fibiger, H.C. 6-Hydroxydopamine lesions of the medial prefrontal eortex fail to influence intravenous selfadministration of cocaine. Psychopharmacology 88 310-314, 1986. 

Roberts, D.C. Koob, G.F. Klonoff, P. and Fibiger, H.C. Extinetion and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 12 781-787, 1980. 

Roberts, D.C.S., and Vickers, G. Increased motivation to self-administer apomorphine following 6-hydroxydopamine lesion of the nueleus aeeum-bens. In Kalivas, P.W., and Nemeroff, C.B., eds. The Mesocortico-limbic Dopamine System. Vol. 537. New York Annals of the New York Academy of Science, 1988. pp. 523-524. 

Heffner, T.G., and Seiden, L.S. The effeet of depletion of brain dopamine by 6-hydroxydopamine on toleranee to the anorexic effect of fi -amphetamine and fenfluramine in rats. J Pharmacol Exp Ther 208 134-143, 1979. 

Levine, T.E. McGuire, P.S. Heffner, T.G. and Seiden, L.S. DRL performance in 6-hydroxydopamine-treated rats. Pharmacol Biochem Behav 12 287-291, 1980. 

I think the results are compatible with the idea that Dr. Seiden has, that it is 6-hydroxydopamine. I think that it could be a 6-hydroxydopamine or some other reactive metabolite of dopamine that is causing the effect. 

COMMENT Right, and it wouldn t explain a 6-hydroxydopamine mechanism. It is fascinating that there is that D], D2 relationship. 

QUESTION Did you mention that 6-hydroxydopamine blocks or elevates neurotensin levels ... 

ANSWER Yes, 6-hydroxydopamine by itself elevates neurotensin levels. When you combine it with methamphetamine, you do not get any additivity. It is just a 6-hydroxydopamine action. It is a bit complicated to interpret, but it appears that it is still the nigral striatal dopamine pathway that is mediating the methamphetamine effect. 

Graham, D.G. Tiffany, S.M. Bell, W.R., Jr. and Gutknecht, W.F. Autooxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 14 644-653, 1978. 

Turning behavior in rats was measured after unilateral administration of 8 pg of 6-hydroxydopamine into the substantia nigra. 

French, E.D., and Vantini, G. Phencyclidine-induced locomotor activity in the rat is blocked by 6-hydroxydopamine lesion of the nucleus accumbens Comparisons to other psycomotor stimulants. Psvchopharmacoloqy 82 83-88, 1984. 

Laguzzi, R. F., Adrien, J., Bourgoin, S. Hamon, M. (1979). Effects of intraventricular injection of 6-hydroxydopamine in the developing kitten. 1. On the sleepwaking cycles. Brain Res. 160, 445-59. 

Figure 7.5 Histograms illustrating typical behavioral state changes observed following bilateral lesions of dopaminergic ventral tegmental pathways in rats receiving 6-hydroxydopamine into the nucleus accumbens (217). Notable amounts of REM sleep are evident during both the major wake (1900-0700) and major sleep (0700-1900) periods. Maintenance of the rest and activity periods to the 12 12 h light dark schedule, respectively, demonstrates the relative preservation of circadian processes.

Tenn, C. C. Niles, L. P. (1995). Central-type benzodiazepine receptors mediate the antidopaminergic effect of clonazepam and melatonin in 6-hydroxydopamine lesioned rats involvement of a GABAergic mechanism. J. Pharmacol. Exp. Ther. 274, 84-9. 

Huang R, Han L, Li J, Ren F, Ke W, Jiang C, Pei Y (2009) Neuroprotection in a 6-hydroxydopamine-lesioned Parkinson model using lactoferrin-modilied nanoparticles. J Gene Med 11 754-763... 

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