Chronic l-DOPA treatment attenuates behavioral and biochemical deficits induced by unilateral lactacystin administration into the rat substantia nigra

Decreased behavioral response to intranigrally administered GABAA agonist muscimol in the lactacystin model of Parkinson's disease may result from partial lesion of nigral non-dopamine neurons: Comparison to the classical neurotoxin 6-OHDA

“…The disturbances lasted even longer than in the 6-OHDA group, in which motor deficits only affected spontaneous locomotion (first 15 min of measurement). These results are in line with our recent study showing a pronounced catalepsy and a significant reduction in the use of contralateral (compromised) forelimb in the cylinder test after intranigral administration of the same dose of lactacystin [21]. However, they are not consistent with the recent study [16] which did not find any significant deficits in the contralateral hindlimb movements in the tapered ledged beam task 2 and 8 weeks after intranigral administration of the similar dose of lactacystin (2 g), despite a 70% decrease in the number of DA neurons in the lesioned SNc.…”

“…Thus, both denervation of the nigrostriatal pathway and preservation of the GABA neurons in the SNr are required for the behavioral expression of apomorphine effects. In accordance with this assumption, we previously demonstrated that systemically administered apomorphine produced weak ipsilateral rotations 6 weeks after lactacystin (2.5 g/2 l)-induced lesion of the SN [21]. Similarly, ipsilateral rotations, but with a greater intensity, were observed after unilateral intranigral administration of MPP + [59,72] or rotenone [61,72].…”

“…3-5 weeks after lesion rats were tested for rotational behavior induced by intranigral administration of muscimol, in automated rotameters (Panlab, Barcelona, Spain) [21]. Immediately following muscimol injection the rats were individually placed in hemispheric bowls.…”

“…DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) were assayed in striatal and nigral homogenates, separately for the ipsi-and contralateral side, by HPLC with a coulometric detection, as described previously [21]. Tissue samples were weighted and homogenized in 0.5 ml (striatum) or 0.1 ml (substantia nigra) icecold 0.1 M perchloric acid containing 0.05 mM ascorbic acid.…”

“…A number of studies have shown that lactacystin induces death of DA cells in vitro [10][11][12][13] as well as degeneration of nigral DA neurons in vivo [14][15][16][17][18][19][20]. Neuronal degeneration was accompanied by a sharp decrease in the striatal DA content and impairment of the motor dysfunction, reversed by l-DOPA treatment [21]. Furthermore, lactacystin treatment led to the formation of cytoplasmic ␣-synuclein-and ubiquitinimmunopositive inclusion in the SN [18,19,[22][23][24][25].…”