(6-OHDA) A neurotoxin that selectively damages neurons that contain CATECHOLAMINES as NEUROTRANSMITTERS, including DOPAMINERGIC and NORADRENERGIC neurons. The route of administration determines the population of neurons to be lesioned (see LESION; NEUROTOXINS). Intraperitoneal injections result in chemical ‘sympathectomy’ which is permanent in neonates but temporary in adults. Systemic injections largely spare central catecholamine neurons because 6-OHDA does not readily cross the BLOOD-BRAIN BARRIER. Selective lesions of central catecholamine neurons can be achieved by injections of the neurotoxin into their target area, or alternatively, in the vicinity of their cell bodies. Such lesions appear to be permanent and there is little evidence for fibre regeneration. The selectivity of 6-OHDA to catecholamine neurons is based on their ability to take up 6-OHDA via selective dopamine or noradrenaline transporters that are present only on catecholamine neurons. The selectivity for dopamine neurons can be achieved by pretreatment with the noradrenaline uptake blocker DESIPRAMINE, which prevents uptake of the neurotoxin into noradrenergic neurons. The mechanism underlying the toxicity of 6-OHDA is not well understood, but is thought to involve the formation of toxic products or by-products during the auto-oxidation process of internalized 6-OHDA. Recent studies have suggested that the formation of neurotoxic free radicals is stimulated by 6-OHDA and that increasing the concentration of certain nerve growth factors in the lesioned area (either by direct injection or by prior gene transfer) can reduce neuronal loss significantly.
Injections of the neurotoxin are made into the STRIATUM, SUBSTANTIA NIGRA or MEDIAL FOREBRAIN BUNDLE. The latter con-tains nigrostriatal dopamine fibres. Animals with bilateral injections of 6-OHDA show a behavioural syndrome resembling Parkinson’s disease, including BRADYKINESIA, ADIPSIA, APHAGIA, decreased exploration and difficulty in initiating motor activity. However, as in Parkinson’s disease, the behavioural syndrome and significant reduction in striatal dopamine release occur only when more than 80% of dopamine neurons are damaged due to compensatory mechanisms. Unlike bilaterally lesioned animals, animals with unilateral lesions typically do not show Parkinsonian-like behaviours. They are therefore easier to maintain and more commonly used. One feature of the unilateral lesion model is that it leads to supersensitivity or up-regulation of striatal dopamine receptors on the side of the lesion. Upon pharmacological stimulation of these receptors, animals shows predictable rotational responses. For example, AMPHETAMINE, which enhances dopamine release, elicits rotation towards the side of the lesion. In contrast, dopamine receptor agonists such as APOMORPHINE elicit contralateral rotation. The mechanism of this rotation is not well understood, but animals with unilateral lesions have been used for screening various compounds to develop effective therapeutic agents for treating Parkinson’s disease.
