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Chapter category: Neurodegenerative Disease

Behavioral Recovery of Functional Responses

Chapter authors:
Lazaros C. Triarhou

Studies in rats have shown that unilateral destruction of the nigrostriatal pathway by 6-hydroxydopamine (6-OHDA) results in a spontaneous rotational bias to the side ipsilateral to the lesion.¹ With time, spontaneous rotational behavior subsides, but it can still be induced pharmacologically; amphetamine, an agent that releases dopamine (DA) from presynaptic terminals, causes a rotational bias to the side ipsilateral to the lesion;² apomorphine, a DA receptor agonist, causes rotation to the side contralateral to the lesion.³ The effect of apomorphine is presumably a result of activating a greater number of DA receptors on the side of the lesion, due to the increase in receptors as a function of denervation supersensitivity.^1,4

Reinnervation of the chemically denervated striatum by grafted DA neurons in those rodents has been shown to rectify the rotational bias displayed by animals with unilateral lesions.^5-11 Unilateral transplantation of DA cells into the striatum of rats with unilateral 6OHDA lesions of the nigrostriatal pathway reverses the amphetamineinduced turning bias according to the rotational asymmetry model of Ungerstedt and Arbuthnott.² Unilateral grafts can also improve spontaneous (i.e., not druginduced) behaviors resulting from striatal DA denervation, such as simple sensorimotor orientation, forelimb stepping functions, and response latency in disengage behavior.^12,13 Bilateral grafts into the striatum of rats with bilateral lesions of the ascending DA pathway are efficient in reversing sensorimotor and akinetic impairments induced by 6OHDA.¹⁴

Since both sides of the substantia nigra degenerate in the weaver, nongrafted mutants do not display any rotational bias to either side. On the other hand, in weaver mutants with unilateral DA-containing mesencephalic grafts into the dorsal striatum, in the form of either solid tissue or cell suspensions, methamphetamine elicits a significant circling bias toward the contralateral, nongrafted side^15-21 (Fig. 1a,b). Such an effect seems to be specific for DAcontaining cells, as vehicle-sham grafts, nonsurviving grafts, cortical cavities only, cerebellar grafts or grafts of noradrenalinecontaining neurons from the locus ceruleus do not affect rotational behavior.^15,16,20

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